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1
Shain, Sydney A. "Exogenous Fibroblast Growth Factors Maintain Viability, Promote Proliferation, and Suppress GADD45α and GAS6 Transcript Content of Prostate Cancer Cells Genetically Modified to Lack Endogenous FGF-2." Molecular Cancer Research 2, no. 11 (November 1, 2004): 653–61. http://dx.doi.org/10.1158/1541-7786.653.2.11.
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Abstract Understanding processes regulating prostate cancer cell survival is critical to management of advanced disease. We used prostate cancer cell transfectants genetically modified to be deficient in either endogenous fibroblast growth factor (FGF-1) or endogenous FGF-2 to examine FGF maintenance of transfectant survival and proliferation and FGF-2-regulated expression of transfectant growth arrest DNA damage (GADD) and growth arrest sequences (GAS) family genes (known modulators of cell cycle progression and survival) and the AS3 gene (an androgen-modulated effector of prostate cell proliferation). When propagated in the absence of exogenous FGFs, FGF-2-deficient transfectants undergo exponential death, whereas FGF-1-deficient transfectants proliferate. Exogenous FGF-1, FGF-2, FGF-7, or FGF-8 promote survival and proliferation of FGF-2-deficient transfectants and enhance FGF-1-deficient transfectant proliferation. Transfectants express FGF receptor FGFR1, FGFR2(IIIb), FGFR2(IIIc), and FGFR3 transcripts, findings consistent with the effects of exogenous FGFs. FGF-2-deficient transfectants express high levels of AS3, GADD45α, GADD45γ, GAS8, and GAS11 transcripts and moderate levels of GADD153, GAS2, GAS3, and GAS6 transcripts and lack demonstrable GAS1 or GAS5 transcripts. FGF withdrawal-mediated death of FGF-2-deficient transfectants did not significantly affect cell AS3, GADD153, GADD45γ, GAS2, GAS3, GAS7, GAS8, or GAS11 transcript content, whereas GADD45α and GAS6 transcript content was elevated. These studies establish that endogenous FGF-2 dominantly regulates prostate cancer cell survival and proliferation and that exogenous FGFs may assume this function in the absence of endogenous FGF-2. Additionally, we provide the first evidence that FGFs regulate prostate GADD45α and GAS6 transcript content. The latter observations suggest that GADD45α and GAS6 proteins may be effectors of processes that regulate prostate cancer cell survival. Additional studies are required to examine this possibility in detail.
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Ragni, Enrico, Alison Coluccio, Eleonora Rolli, José Manuel Rodriguez-Peña, Gaia Colasante, Javier Arroyo, Aaron M. Neiman, and Laura Popolo. "GAS2 and GAS4, a Pair of Developmentally Regulated Genes Required for Spore Wall Assembly in Saccharomyces cerevisiae." Eukaryotic Cell 6, no. 2 (February 2007): 302–16. http://dx.doi.org/10.1128/ec.00321-06.
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ABSTRACT The GAS multigene family of Saccharomyces cerevisiae is composed of five paralogs (GAS1 to GAS5). GAS1 is the only one of these genes that has been characterized to date. It encodes a glycosylphosphatidylinositol-anchored protein functioning as aβ (1,3)-glucan elongase and required for proper cell wall assembly during vegetative growth. In this study, we characterize the roles of the GAS2 and GAS4 genes. These genes are expressed exclusively during sporulation. Their mRNA levels showed a peak at 7 h from induction of sporulation and then decreased. Gas2 and Gas4 proteins were detected and reached maximum levels between 8 and 10 h from induction of sporulation, a time roughly coincident with spore wall assembly. The double null gas2 gas4 diploid mutant showed a severe reduction in the efficiency of sporulation, an increased permeability of the spores to exogenous substances, and production of inviable spores, whereas the single gas2 and gas4 null diploids were similar to the parental strain. An analysis of spore ultrastructure indicated that the loss of Gas2 and Gas4 proteins affected the proper attachment of the glucan to the chitosan layer, probably as a consequence of the lack of coherence of the glucan layer. The ectopic expression of GAS2 and GAS4 genes in a gas1 null mutant revealed that these proteins are redundant versions of Gas1p specialized to function in a compartment at a pH value close to neutral.
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FLEMING, V. John, M. Susan HAY, D. Nicholas HARRIES, and D. William REES. "Effects of nutrient deprivation and differentiation on the expression of growth-arrest genes (gas and gadd) in F9 embryonal carcinoma cells." Biochemical Journal 330, no. 1 (February 15, 1998): 573–79. http://dx.doi.org/10.1042/bj3300573.
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The growth-arrest genes (gas and gadd) are widely expressed during mammalian embryogenesis and may be useful as markers of nutritional stress in the embryo. F9 embryonal carcinoma cells have been used to characterize the effect of serum or amino acid deficiency on growth-arrest gene expression in a differentiating embryonic cell. The differentiation markers, homeobox B2 (HoxB2), collagen type IV and laminin B2, were not induced by growth arrest. Treatment with all-trans retinoic acid (RA) produced a dose-dependent increase in alkaline phosphatase activity, which was unchanged in lysine-deficient medium and reduced in low-serum medium. Low-serum medium also reduced HoxB2 expression. There was a transient 2-6-fold increase in mRNAs for C/EBP-β, gadd153/CHOP-10 and gas5 genes 24 h after transfer to amino-acid-deficient media. The mRNAs for the gas2 and gas6 genes began to rise slowly by 5-10-fold after a delay of approx. 24 h. The transient increases did not occur in low-serum medium where there was a much smaller and slower increase. Differentiation caused 1-2-fold increases in gas2, gas3 and gas6 mRNA levels. The transient overexpression of gas5, gadd153/CHOP-10 and CCAAT-enhancer-binding protein-β, and the later expression of gas6 mRNAs in response to amino acid deficiency, were not affected by differentiation. RA treatment increased the expression of gas3 and caused gas2 to be transiently overexpressed in amino-acid-deficient medium. Differentiation in serum-deficient medium did not significantly alter the levels of the growth-arrest gene mRNAs. These results show that in F9 cells the growth-arrest genes are expressed sequentially as a result of nutrient stress.
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Rolli, Eleonora, Enrico Ragni, María de Medina-Redondo, Javier Arroyo, Carlos R. Vázquez de Aldana, and Laura Popolo. "Expression, stability, and replacement of glucan-remodeling enzymes during developmental transitions inSaccharomyces cerevisiae." Molecular Biology of the Cell 22, no. 9 (May 2011): 1585–98. http://dx.doi.org/10.1091/mbc.e10-03-0268.
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Sporulation is a developmental variation of the yeast life cycle whereby four spores are produced within a diploid cell, with proliferation resuming after germination. The GAS family of glycosylphosphatidylinositol-anchored glucan-remodeling enzymes exemplifies functional interplay between paralogous genes during the yeast life cycle. GAS1 and GAS5 are expressed in vegetative cells and repressed during sporulation while GAS2 and GAS4 exhibit a reciprocal pattern. GAS3 is weakly expressed in all the conditions and encodes an inactive protein. Although Gas1p functions in cell wall formation, we show that it persists during sporulation but is relocalized from the plasma membrane to the epiplasm in a process requiring End3p-mediated endocytosis and the Sps1 protein kinase of the p21-activated kinase family. Some Gas1p is also newly synthesized and localized to the spore membrane, but this fraction is dispensable for spore formation. By way of contrast, the Gas2–Gas4 proteins, which are essential for spore wall assembly, are rapidly degraded after spore formation. On germination, Gas1p is actively synthesized and concentrated in the growing part of the spore, which is essential for its elongation. Thus Gas1p is the primary glucan-remodeling enzyme required in vegetative growth and during reentry into the proliferative state. The dynamic interplay among Gas proteins is crucial to couple glucan remodeling with morphogenesis in developmental transitions.
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Wu, Wenming, and Dongming Liang. "Effect of Long-Chain Non-Coding RNA GAS5 on Osteogenic/Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells Under Oxidative Stress Through Targeting MiR-365." Journal of Biomaterials and Tissue Engineering 9, no. 12 (December 1, 2019): 1751–57. http://dx.doi.org/10.1166/jbt.2019.2206.
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Oxidative stress affects BMSCs. LncRNA GAS5 regulates cell proliferation and apoptosis. However, the effect of LncRNA GAS5 on osteogenesis/adipogenic differentiation of BMSCs under oxidative stress has not been reported. Rat BMSCs were cultured and randomly divided into 4 groups, normal control group; oxidative stress group; GAS5 siRNA group; GAS5 siRNA+ miR-365 inhibitor group followed by analysis of LncRNA GAS5 expression by Real time PCR, cell proliferation by MTT assay, Caspase3 activity, GAS5 and miR-365 targeting relationship by luciferase reporter assay, ALP activity, expression of Runx2, OP and PPAR 2 by Real time PCR, as well as ROS content and SOD activity. In oxidative stress group, GAS5 expression was significantly increased along with inhibited cell proliferation, increased Caspase3 activity, decreased ALP activity and the expression of Runx2 and OP, increased PPAR 2 expression and ROS content, and decreased SOD activity compared to control group (P < 0 05). miR-365 was the target miRNA of GAS5. GAS5 siRNA down-regulated GAS5 expression, significantly promoted cell proliferation, inhibited Caspase3 activity, increased ALP activity and Runx2 and OP expression, decreased PPAR 2 expression and ROS content, and increased SOD activity. (P < 0 05). However, GAS5 siRNA+ miR-365 inhibitor group reversed the effect of GAS5 siRNA. Oxidative stress promotes LncRNA GAS5 expression in BMSCs. LncRNA GAS5 regulates oxidative stress by targeting miR-365. Knockdown of GAS5 can promote BMSCs proliferation and osteogenic differentiation and inhibit adipogenic differentiation under oxidative stress.
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Wen, Qirong, Yan Liu, Huabing Lyu, Xiaying Xu, Qingxia Wu, Ni Liu, Qi Yin, Juan Li, and Xiujie Sheng. "Long Noncoding RNA GAS5, Which Acts as a Tumor Suppressor via microRNA 21, Regulates Cisplatin Resistance Expression in Cervical Cancer." International Journal of Gynecologic Cancer 27, no. 6 (July 2017): 1096–108. http://dx.doi.org/10.1097/igc.0000000000001028.
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ObjectivesThe aims of this study were to investigate the functions of GAS5 as a tumor suppressor in cervical cancer and explore the mechanism.MethodsThe expression of GAS5 and microRNA 21 (miR-21) was detected in primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. We identified the interaction of GAS5 and miR-21 by quantitative polymerase chain reaction, Western blot, and dual-luciferase reporter assay. We also studied the functions of GAS5 in proliferation, apoptosis, migration, and invasion in cervical cancer cells in vitro and vivo. Finally, the impact of GAS5 on cisplatin resistance and its mechanism in cervical cancer cells was also identified.ResultsThe expression of GAS5 and miR-21 was detected in primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. GAS5, which is a tumor suppressor playing roles in inhibiting the malignancy of cervical cancer cells, including proliferation in vivo and vitro, migration, and invasion, has a low expression in cervical cancer tissue and cervical cancer cell lines, whereas miR-21 expression is high. GAS5 significantly decreased the expression of miR-21, and there is a reciprocal repression of gene expression between GAS5 and miR-21. Besides, most importantly, we found that high expression of GAS5 and low expression of miR-21 can enhance the sensitivity of SiHa/cDDP cancer cells to cisplatin. A further experiment for identifying the mechanism of cisplatin resistance by GAS5 showed that GAS5 can not only regulate phosphatase and tensin homolog through miR-21 but also influence the phosphorylation of Akt.ConclusionsOur results indicate that GAS5 is a direct target of miR-21 and can predict the clinical staging of cervical cancer. Most importantly, GAS5 can also influence cisplatin resistance in cervical cancer via regulating the phosphorylation of Akt. All of these suggest that GAS5 may be a novel therapeutic target for treating cervical cancer.
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Liu, Jianmin, Ming Chen, Longyang Ma, Xingbo Dang, and Gongliang Du. "LncRNA GAS5 Suppresses the Proliferation and Invasion of Osteosarcoma Cells via the miR-23a-3p/PTEN/PI3K/AKT Pathway." Cell Transplantation 29 (January 1, 2020): 096368972095309. http://dx.doi.org/10.1177/0963689720953093.
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Accumulating evidence has shown that long noncoding RNA GAS5 is a well-known tumor suppressor in the pathogenesis of a variety of human cancers. However, the detailed role of GAS5 in osteosarcoma is still largely unclear. In this study, we found that GAS5 was downregulated in human osteosarcoma tissues and cell lines compared with matched adjacent tissues and normal osteoblast cells. Overexpression of GAS5 could significantly suppress the growth and invasion of osteosarcoma cells, while downregulation of GAS5 promoted cell proliferation and invasion. We confirmed that GAS5 could directly bind with miR-23a-3p by using luciferase reporter gene and RNA immunoprecipitation and pull-down assay. Downregulation of miR-23a-3p repressed cell proliferation and invasion. Overexpression of miR-23a-3p counterbalanced the inhibition effect of GAS5 on cell proliferation and invasion. Further studies indicated that overexpression of GAS5 inhibited cell proliferation and metastasis by regulating phosphatase and tensin homolog (PTEN). PTEN was authenticated as a target of miR-23a-3p. Upregulation of GAS5 or silence of miR-23a-3p increased the level of PTEN, while downregulation of GAS5 or overexpression of miR-23a-3p suppressed the expression of PTEN. In addition, overexpression of GAS5 could neutralize the effect of downregulating PTEN on osteosarcoma cell functions. We proved that GAS5 regulated the viability and invasion of osteosarcoma cells through the PI3K/AKT pathway. Moreover, overexpression of GAS5 could inhibit tumor growth in a xenograft nude mouse model in vivo. In summary, GAS5 functions as a competing endogenous RNA, sponging miR-23a-3p, to promote PTEN expression and suppress cell growth and invasion in osteosarcoma by regulating the PI3K/AKT pathway.
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Qin, Xiaohua, Yanling Jiang, Xiaojun Zhang, and Dan Li. "lncRNA GAS5 Induces Cell Apoptosis in Acute Myeloid Leukemia by Targeting Nrf2." Disease Markers 2022 (August 24, 2022): 1–8. http://dx.doi.org/10.1155/2022/5178122.
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Objective. This study is aimed at investigating the molecular mechanism of lncRNA GAS5-induced cell apoptosis in acute myeloid leukemia (AML) by targeting Nrf2. Methods. The RNA interfering technique was utilized to silence THP-1 in AML cell line, and lncRNA GAS5 expression in cell line was determined by real-time PCR. EdU experiment and flow cytometry were used to detect the apoptosis and proliferation ability of cells in different groups. PD-L1, STAT3, AKT, and MMP9 expressions were determined by Western blot. Results. The si-RNA significantly inhibited the expression of lncRNA GAS5 in THP-1 cells. Compared with the si-NC group, the difference in cell apoptosis between lncRNA GAS5 and Nrf2 groups was significant ( P < 0.05 ). Compared with the lncRNA GAS5 group, the number of apoptotic cells in the lncRNA GAS5+Nrf2 group significantly reduced ( P < 0.05 ). Compared with the si-NC group, the differences in the levels of four proteins between lncRNA GAS5 and Nrf2 groups were significant ( P < 0.05 ). In lncRNA GAS5+Nrf2 and lncRNA GAS5 groups, PD-L1 expression increased, while the expression of STAT3, AKT, and MMP9 decreased. Conclusion. In AML cells, lncRNA GAS5 with Nrf2 could regulate the proliferation and apoptosis of AML cells. lncRNA GAS5 inhibited Nrf2 expression, regulated cell apoptosis and proliferation, and further inhibited the progression of AML disease.
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Shen, Zheng, and Qiang She. "Association Between the Deletion Allele of Ins/Del Polymorphism (Rs145204276) in the Promoter Region of GAS5 with the Risk of Atherosclerosis." Cellular Physiology and Biochemistry 49, no. 4 (2018): 1431–43. http://dx.doi.org/10.1159/000493447.
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Background/Aims: LncRNA is a growth arrest-specific transcript 5 (GAS5) with tumor suppressor activities in some cancers, but its role in atherosclerosis is unclear. Methods: Bioinformatics algorithm analysis was utilized to search the target of GAS5 and miR-21, followed by luciferase assay to confirm these targets. Real-time PCR and western-blot were utilized to verify the connection among GAS5, miR-21 and Programmed cell death 4 (PDCD4). MTT assay and flow cytometry analysis were performed to explore the mechanism of GAS5 in the regulation of atherosclerosis. Results: GAS5 directly targets miR-21 and functions as a competing endogenous RNA to suppress miR-21 expression. We also observed that rs145204276 polymorphism, including INS/INS and DEL/DEL, on GAS5 promoter increased transcription activity of GAS5, but the presence of rs145204276 DEL/DEL allele significantly promoted the transcription of GAS5 promoter compared with rs145204276 INS/INS allele. PDCD4 was predicted as a direct target gene of miR-21 with a binding site on PDCD4 3’UTR. It was further confirmed by luciferase assay that miR-21 significantly reduced the luciferase activity of wild-type PDCD4 3’UTR but not that of mutant PDCD4 3’UTR. In addition, high glucose significantly inhibited the growth rate of EC genotyped as DEL/DEL or INS/ INS, and apparently promoted the apoptotic rate of either DEL/DEL or INS/INS genotype ECs. Furthermore, the effect of high glucose was stronger in the INS/INS group, while the expression of GAS5 was dramatically upregulated with the presence of GAS5 DEL/DEL, while GAS5 positively regulated PDCD4 expression via inhibiting miR-21 expression. GAS5 siRNA and miR-21 mimics significantly decreased GAS5 and PDCD4 expressions, and the inhibitory effects of GAS5 siRNA or miR-21 mimics on GAS5 and PDCD4 expressions in the INS/INS group was stronger. Moreover, GAS5 siRNA and miR-21 mimics remarkably triggered cells proliferation and suppressed cell apoptosis, and the inhibition effects of GAS5 siRNA or miR-21 mimics on either cell viability and apoptosis in the INS/INS group was stronger. In this study, we enrolled 1,306 subjects with or without atherosclerosis and found that the INS/DEL or DEL/DEL genotypes significantly decreased the risk of atherosclerosis compared with the ins/ins genotype (adjusted odds ratio: 0.74 and 0.40, respectively). Conclusion: In summary, rs145204276 was associated with the risk of atherosclerosis by affecting the proliferation and apoptosis of endothelial cells via regulating the GAS5/miR-21/PDCD4 signaling pathway.
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Filippova, Elena A., Marina V. Fridman, Alexey M. Burdennyy, Vitaly I. Loginov, Irina V. Pronina, Svetlana S. Lukina, Alexey A. Dmitriev, and Eleonora A. Braga. "Long Noncoding RNA GAS5 in Breast Cancer: Epigenetic Mechanisms and Biological Functions." International Journal of Molecular Sciences 22, no. 13 (June 24, 2021): 6810. http://dx.doi.org/10.3390/ijms22136810.
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Long noncoding RNAs (lncRNAs) have been identified as contributors to the development and progression of cancer through various functions and mechanisms. LncRNA GAS5 is downregulated in multiple cancers and acts as a tumor suppressor in breast cancer. GAS5 interacts with various proteins (e.g., E2F1, EZH2, and YAP), DNA (e.g., the insulin receptor promoter), and various microRNAs (miRNAs). In breast cancer, GAS5 binds with miR-21, miR-222, miR-221-3p, miR-196a-5p, and miR-378a-5p that indicates the presence of several elements for miRNA binding (MREs) in GAS5. Mediated by the listed miRNAs, GAS5 is involved in the upregulation of a number of mRNAs of suppressor proteins such as PTEN, PDCD4, DKK2, FOXO1, and SUFU. Furthermore, the aberrant promoter methylation is involved in the regulation of GAS5 gene expression in triple-negative breast cancer and some other carcinomas. GAS5 can stimulate apoptosis in breast cancer via diverse pathways, including cell death receptors and mitochondrial signaling pathways. GAS5 is also a key player in the regulation of some crucial signal pathways in breast cancer, such as PI3K/AKT/mTOR, Wnt/β-catenin, and NF-κB signaling. Through epigenetic and other mechanisms, GAS5 can increase sensitivity to multiple drugs and improve prognosis. GAS5 is thus a promising target in the treatment of breast cancer patients.
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Yang, Liang, and Jianshuai Jiang. "GAS5 Regulates RECK Expression and Inhibits Invasion Potential of HCC Cells by Sponging miR-135b." BioMed Research International 2019 (January 13, 2019): 1–11. http://dx.doi.org/10.1155/2019/2973289.
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Objectives. Long noncoding RNA (LncRNA) growth arrest-specific 5 (GAS5) has been characterized as a tumor suppressor in numerous kinds of human cancers. Its anticancer function in hepatocellular carcinoma (HCC) includes repression of cell proliferation and metastasis, leaving the internal mechanisms unclear. In this study, we intended to examine the anti-invasion effects of GAS5 on HCC and explore the downstream regulatory mechanisms.Methods. Expression of GAS5 and microRNA-135b (miR-135b) was analyzed by qRT-PCR in paired HCC tissue samples. Their correlation with HCC patients’ survival was determined. Transwell assays were done to evaluatein vitroinvasion ability. Targeting of GAS5 and RECK by miR-135b was confirmed by qRT-PCR, western blot, and luciferase reporter assays.Results. Decreased GAS5 and increased miR-135b in HCC inversely correlate with each other and both correlate with poor prognosis of HCC patients. Functionally, GAS5 suppresses while miR-135b promotes HCC cell invasion capacitiesin vitro. Mechanistically, GAS5 is a target of miR-135b. Furthermore, GAS5 positively regulates expression of RECK, also a target of miR-135b, which further inhibits MMP-2 expression and contributes to invasion repression.Conclusion. GAS5 acted as a tumor suppressor in HCC invasion in a competing endogenous RNA manner. Our findings indicate that GAS5 is a promising therapeutic target for HCC treatment.
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Wang, Yanfang, Shan Xin, Kai Zhang, Run Shi, and Xuanwen Bao. "Low GAS5 Levels as a Predictor of Poor Survival in Patients with Lower-Grade Gliomas." Journal of Oncology 2019 (February 3, 2019): 1–15. http://dx.doi.org/10.1155/2019/1785042.
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Introduction. Gliomas are infiltrative neoplasms of a highly invasive nature. Different stages of gliomas feature distinct genomic, genetic, and epigenetic changes. The long noncoding RNA Growth Arrest Specific Transcript 5 (GAS5) is an identified tumour suppressor involved in several cancers. However, the underlying roles of the GAS5 gene in lower-grade glioma (LGG) patients are not clear. Methods. Via bioinformatic analysis based on TCGA-LGG and TCGA-GBM data, we explored the mechanisms of GAS5 expression in LGG (grades II and III) and high-grade glioma (glioblastoma multiforme, grade IV). The log-rank test and multivariate Cox analysis were performed to find the association between GAS5 and overall survival (OS) in LGG patients. Weighted gene coexpression network analysis (WGCNA) and RNA-Seq analysis were applied to find the key gene network associated with GAS5. Results. We found that GAS5 expression was downregulated in both LGG and glioblastoma multiforme (GBM) compared with normal brain tissue. Low methylation in the GAS5 promoter region was detected in both LGG and GBM tissues. The amplification type was the predominant type of GAS5 gene alteration in both LGG and GBM. High GAS5 expression was more associated with long overall survival (OS) in LGG patients than in GBM patients. The multivariate survival analysis of GAS5 and clinical and molecular characteristics in LGG patients further confirmed the association between GAS5 and OS in LGG patients. We then developed a nomogram for clinical use. WGCNA and RNA-Seq analysis indicated that ribosomal biogenesis and translation initiation were the predominant events regulated by GAS5 in LGG patients. Conclusion. Taken together, these results demonstrate that GAS5 expression is associated with OS in LGG patients and that its underlying roles involve the regulation of ribosomal biogenesis and translation initiation, which may aid in identifying a new target for the treatment of LGG.
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Hsieh, Ming-Hong, Hsueh-Ju Lu, Chiao-Wen Lin, Chia-Yi Lee, Shang-Jung Yang, Pei-Hsuan Wu, Mu-Kuan Chen, and Shun-Fa Yang. "Genetic Variants of lncRNA GAS5 Are Associated with the Clinicopathologic Development of Oral Cancer." Journal of Personalized Medicine 11, no. 5 (April 26, 2021): 348. http://dx.doi.org/10.3390/jpm11050348.
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The long noncoding RNA, Growth arrest-specific 5 (GAS5) plays a crucial role in the development of oral cancer. However, potential genetic variants in GAS5 that affect the susceptibility and progression of oral cancer have rarely been explored. In this study, two loci of GAS5 single nucleotide polymorphisms (SNPs) (rs145204276 and rs55829688) were genotyped by using the TaqMan allelic discrimination in 1125 oral cancer patients and 1195 non-oral-cancer individuals. After statistical analyses, the distribution of both the GAS5 SNP rs145204276 and GAS5 SNP rs55829688 frequencies were similar between the study and control groups. However, the patients with GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) showed a higher tendency of moderate to poor cell differentiation of oral cancer (OR: 1.454, 95% CI: 1.041–2.031, p = 0.028). Moreover, the GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) in the non-alcohol-drinking population were associated with significantly advanced tumor stage (OR: 1.500, 95% CI: 1.081–2.081, p = 0.015) and larger tumor size (OR: 1.494, 95% CI: 1.076–2.074, p = 0.016). Furthermore, individuals with the GAS5 SNP rs145204276 variant were associated with a higher expression of GAS5 in the GTEx database (p = 0.002), and the higher GAS5 level was associated with poor cell differentiation, advanced tumor stage and larger tumor size in head and neck squamous cell carcinoma from the TCGA database (all p < 0.05). In conclusion, the GAS5 SNP rs145204276 variant is related to poor-differentiation cell status in oral cancer. Besides, the presence of the GAS5 SNP rs145204276 variant is associated with a worse tumor stage and tumor size in oral cancer patients without alcohol drinking.
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Fang, Peipei, Luxia Xiang, Weilai Chen, Shaoxun Li, Shanshan Huang, Jie Li, Lu Zhuge, et al. "LncRNA GAS5 enhanced the killing effect of NK cell on liver cancer through regulating miR-544/RUNX3." Innate Immunity 25, no. 2 (February 2019): 99–109. http://dx.doi.org/10.1177/1753425919827632.
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This study aimed to explore the role of lncRNA GAS5 in the regulation of the killing effect of NK cells on liver cancer. Compared with a control group, lncRNA GAS5, RUNX3, and NCR1 were down-regulated in NK cells of patients with liver cancer, whereas miR-544 expression was up-regulated in NK cells of patients with liver cancer. Activated NK cells had higher IFN-γ level. Knockdown of GAS5 in activated NK cells decreased IFN-γ secretion, NK cell cytotoxicity, the percentage of CD107a+ NK cells, and the apoptosis rate of HepG2 and Huh7 cells. We also proved the interaction of GAS5 and miR-544, and the negative regulation role of GAS5 on miR-544. GAS5 overexpression in activated NK cells increased RUNX3 expression, IFN-γ secretion, the NK cell cytotoxicity, the percentage of CD107a+ NK cells, and the apoptosis rate of HepG2 cells, while miR-544 mimic abolished the promotion effect of GAS5 overexpression. Finally, in vivo experiments indicated an inhibition effect of GAS5 in tumor growth. LncRNA GAS5 overexpression enhances the killing effect of NK cell on liver cancer through regulating miR-544/RUNX3.
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Yuan, Xuguang, Yanan Jing, Mengkai Guang, Junfei Zhu, Ji Wang, Yang Wang, and Ye Zhang. "GAS5 alleviates cisplatin drug resistance in oral squamous cell carcinoma by sponging miR-196a." Journal of International Medical Research 50, no. 10 (October 2022): 030006052211324. http://dx.doi.org/10.1177/03000605221132456.
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Objective The long non-coding RNA Growth-arrest-specific transcript 5 (GAS5) has been extensively linked with the ability of cancer cells to resist chemotherapeutic interventions. This prospective study aimed to investigate the role of GAS5 in oral squamous cell carcinoma (OSCC), which has been poorly characterized to date. Methods GAS5 and miR-196a expression levels were detected by quantitative real-time PCR analysis. Cisplatin (DDP) sensitivity and apoptosis levels were determined using Cell Counting Kit 8 and flow cytometry, respectively. Luciferase reporter and RNA immunoprecipitation assays were performed to confirm target miRNAs of GAS5. Results We found that GAS5 was expressed at low levels in DDP-resistant OSCC cell lines and tissues, and that GAS5 levels were intricately linked to the survival rates of OSCC patients. GAS5 overexpression led to the recovery of DDP sensitivity in CAL27/DDP cells. Additionally, in both DDP-resistant and -sensitive lines, GAS5 showed a cytoplasmic distribution and downregulated miR-196a in OSCC tissues. Exogenous transfection of miR-196a alleviated the effects of GAS5 on DDP sensitivity, confirming this as the mechanism of chemoresistance. Conclusions These findings may provide new targets for the treatment of chemotherapy-resistant OSCC.
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Li, Shanfeng, Feng Zhao, Yunliang He, Yajun E, and Cui Wang. "The Clinical Significance of Lncrna GAS5 And Mir-222-3p in Carotid Artery Stenosis." Heart Surgery Forum 25, no. 4 (July 13, 2022): E530—E535. http://dx.doi.org/10.1532/hsf.4739.
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Background: Carotid artery stenosis (CAS) is the major pathogen of cerebral infarction and brain death. Early detection and risk prediction could help the diagnosis and improve the outcome of patients. The clinical significance of lncRNA GAS5 (GAS5) and miR-222-3p in the diagnosis and prognosis of CAS was evaluated in this study to explore novel effective biomarkers of CAS. Methods: A total of 72 CAS patients and 63 healthy individuals (control) were enrolled in this study. The expression levels of GAS5 and miR-222-3p in study subjects were detected using PCR. The ROC, Kaplan-Meier, and Cox regression analyses were carried out to estimate the diagnostic and prognostic value of GAS5 and miR-222-3p in CAS. The interaction between GAS5 and miR-222-3p was disclosed by the dual-luciferase reporter. Results: The reduced expression of GAS5 and elevated expression of miR-222-3p were observed in CAS patients compared with the healthy controls, and a significant correlation between their expression levels in CAS was revealed. GAS5 and miR-222-3p could discriminate CAS patients from the healthy controls with high sensitivity and specificity. The GAS5 downregulation and miR-222-3p upregulation could predict the poor prognosis of CAS patients and may be associated with the severe development of patients. In human vascular smooth muscle cells, miR-222-3p could negatively regulate the luciferase activity of GAS5. Conclusion: Both GAS5 and miR-222-3p served as the diagnostic and prognostic biomarkers of CAS. The function of GAS5 might result from the regulation of miR-222-3p, which needs further validation.
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Xie, Juan, Jing-Jing Wang, Ya-Jun Li, Jia Wu, Xiao-Jing Gu, and Xiao-Rong Yang. "LncRNA GAS5 Suppresses Colorectal Cancer Progress by Target miR-21/LIFR Axis." Evidence-Based Complementary and Alternative Medicine 2022 (August 24, 2022): 1–16. http://dx.doi.org/10.1155/2022/3298939.
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GAS5 is abnormally high in colorectal cancer tissues, which is a specific expression of lncRNA in colorectal cancer (CRC). Nevertheless, its biological function in CRC has not been elucidated. The abnormal high expression of GAS5 in CRC is the specific expression of lncRNA in CRC. The purpose of our study is to explore the effect of GAS5 on CRC and its mechanism. The expression of GAS5 in 53 paired normal and colorectal cancer tissues and colorectal cancer cell lines was detected by real-time PCR. The biological effects of GAS5, miR-21, and LIFR were measured by functional assays, including wound healing, transwell assays, and in vivo assays. We ensured the carcinogenesis role of GAS5 in CRC in the xenograft nude model. The dual-luciferase reporter assay system and chromatin immunoprecipitation method were used for target evaluation and Western blot for verification. GAS5 was significantly decreased in tumor tissues and CRC cells, and the low expression of CAS5 in CRC promoted tumor metastasis and decreased the survival of patients. GAS5 knockdown increases the cell viability, inhibits apoptosis, and promotes migration. Xenografted tumors in nude mice studies showed that GAS5 knockdown promoted tumor growth and caused worse lesions in colorectal. Furthermore, GAS5 increases the expression level of target gene LIFR to promote the apoptosis of CRC cells by binding to miR-21. Our study revealed that a novel pathway about lncRNA GAS5 inhibited the proliferation and metastasis of CRC cells by targeting miR-21/LIFR which provides a new strategy to treat CRC.
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Li, Feng, Jianguang Sun, Shilei Huang, Gao Su, and Guofu Pi. "LncRNA GAS5 Overexpression Reverses LPS-Induced Inflammatory Injury and Apoptosis Through Up-Regulating KLF2 Expression in ATDC5 Chondrocytes." Cellular Physiology and Biochemistry 45, no. 3 (2018): 1241–51. http://dx.doi.org/10.1159/000487455.
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Background/Aims: Osteoarthritis (OA) is the most frequently occurring joint disease and characterized by degeneration of cartilage. As the unique cell type in cartilage, chondrocytes play a crucial role during OA. Our study explored the influence of long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) on lipopolysaccharides (LPS)-induced injury in ATDC5 cells. Methods: Cell viability, apoptosis and expression of inflammatory cytokines were all assessed to evaluate LPS-induce inflammatory injury. Expression of GAS5 in LPS-induced cells was evaluated by qRT-PCR. After cell transfection, effect of abnormally expressed GAS5 on LPS-induced inflammatory injury was determined. Then, the possible target of GAS5 was screened by bioinformatics and verified by qRT-PCR and luciferase activity assay. Together, whether aberrant expression of target gene affected the modulation of GAS5 in LPS-induced inflammatory injury was also assessed. Finally, the influences of aberrant expressed Kruppel-like factor 2 (KLF2) on nuclear factor κB (NF-κB) and Notch pathways were detected by Western blot analysis. Results: LPS reduced cell viability and promoted cell apoptosis and secretion of inflammatory cytokines, along with down-regulation of GAS5. LPS-induced injury was alleviated by GAS5 overexpression while was exacerbated by GAS5 silence. KLF2 was predicted and verified as a target of GAS5, and GAS5 functioned through regulating expression of KLF2. Besides, aberrant expression of KLF2 regulated expressions of key kinases involved in the NF-κB and Notch pathways. Conclusion: GAS5 might ameliorate LPS-induced inflammatory injury in ATDC5 chondrocytes by inhibiting the NF-κB and Notch signaling pathways.
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Li, Yan, Xing Ma, Jun Li, Saifei He, Juhua Zhuang, Guoyu Wang, Ying Ye, and Wei Xia. "LncRNA gas5 regulates granulosa cell apoptosis and viability following radiation by X-ray through sponging miR-205-5p and Wnt/β-catenin signaling pathway ingranulosa cell tumor of ovary." Tropical Journal of Pharmaceutical Research 19, no. 12 (March 12, 2021): 2491–98. http://dx.doi.org/10.4314/tjpr.v19i12.2.
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Purpose: The study explored the role of lncRNA gas5 in ovarian granulosa cells exposed to X-ray in granulosa cell tumor of ovary(GCTO).
Methods:Exposed the KGN cell line (KALANG, Beijing, China) to X-ray to mimic the radiotherapy for GCSO patients in vitro, cell viability was checked by CCK8 assays. RT-qPCR detected the RNA expression of apoptosis-related genes while Western Blot for biomarkers in wnt/β-catenin signaling. Differential expressions of lncRNA gas5 were examined after cells exposed to X ray for 0,24,48hs. We over expressed gas5 and assessed resultant cell viabilities, apoptosis and signaling. The sponging between gas5 and miR-205-5p was verified through Luciferase Assay. CCK8, RT-qPCR and Western Blot were applied for investigations into the correlation between miR-205-5p and cell viability and apoptosis after miR-205-5p augmentation. Similarly, the interactions between the gas5 and miR-205-5p were assessed after co-transfection of miR-205-5p mimics and oe-gas5. Last, wnt inhibitor was used to study the role of signaling pathway in KGN cells.
Results: Exposure of KGN toX-ray reduced cell viabilities and increased apoptosis. Gas5 had reduced expression in cells while miR-205-5p increased. Gas5 upregulation could protect the cells from apoptosis and add to the cell viability and activation of wnt//β-catenin signaling. lncRNA gas5 targeted miR-205-5p and miR-205-5p mimics could counteract functions of up-regulated lncRNA gas5, regulating Wnt/β-catenin signaling pathway. Inactivation in Wnt/β-catenin could suppress cell viability.
Conclusions: lncRNA gas5 regulated the cell apoptosis and viability after cellular radiation, which might be a potential therapeutic target to combine into radiotherapy for GCTO patients in clinical stage.
Keywords: Ovary, proliferation, apoptosis, lncRNA gas5, x-ray
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Huang, Zicheng, Yun’an Lin, Meiling Zhao, Simei Li, Yajia Wen, Zhixiang Liu, and Xiaofei Cao. "Bone Marrow Mesenchymal Stem Cells with Long Non-Coding RNA-Growth Arrest Specific 5 (LncRNA-GAS5) Modification Impede the Migration and Invasion Activities of Papillary Thyroid Carcinoma Cells." Journal of Biomaterials and Tissue Engineering 13, no. 1 (January 1, 2023): 73–79. http://dx.doi.org/10.1166/jbt.2023.3229.
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The impact of bone marrow mesenchymal stem cells (BMSCs) on the behaviors of papillary thyroid carcinoma (PTC) cells and LncRNAs remains poorly understood. This study mainly explores the mechanism of LncRNA-GAS5-modified BMSCs on the behaviors of PTC cells, aiming to further elucidate PTC carcinogenesis and provide evidence for drug development. PTC cell lines were assigned into blank group, BMSCs group (co-culture with BMSCs), GAS5 group (co-culture with LncRNA-GAS5-modified BMSCs) and positive control group (cultured in the presence of 60 μg/mL β-elemene) followed by analysis of LncRNA-GAS5 expression, the number of migrating and invading PTC cells, the quantity of EMT-related markers, MMP-9 and MMP-2. LncRNA-GAS5 level was lowest in the blank group, while highest in the GAS5 group (P <0.05), followed by positive control group and BMSCs group. Moreover, the number of migrated and invaded cells was highest in the blank group, while lowest in GAS5 group (P < 0.05), followed by positive control group and BMSCs group. PTC cells exhibited the highest expression of EMT-related markers (N-cadherin and Vimentin) and MMPs but lowest E-cadherin level in blank group and positive control group. These proteins showed an opposite trend in GAS5 group and BMSCs group. Additionally, a more remarkable difference was recorded in the GAS5 group (P <0.05). LncRNA-GAS5-modified BMSCs can down-regulate Vimentin and N-cadherin while up-regulate E-cadherin, thereby restraining the expression of MMP-9 and MMP-2. In this way, the EMT process can be manipulated, leading to inhibition of PTC cells behaviors by LncRNA-GAS5-modified BMSCs, indicating that LncRNA-GAS5 might be applied as a therapeutic target for PTC.
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Ma, Yan, Lei Yu, Wenxing Yan, Ling Qiu, Jianqiu Zhang, and Xiaojing Jia. "lncRNA GAS5 Sensitizes Breast Cancer Cells to Ionizing Radiation by Inhibiting DNA Repair." BioMed Research International 2022 (January 11, 2022): 1–7. http://dx.doi.org/10.1155/2022/1987519.
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Radioresistance of breast cancer is a major reason for therapeutic failure and limits further increases in the dose of radiation due to severe adverse effects. Recently, long noncoding RNAs (lncRNAs) have been shown to regulate cancer proliferation, chemoresistance, and radioresistance. Among these lncRNAs, lncRNA GAS5 expression was shown to be downregulated in breast cancer and related to trastuzumab resistance. However, its role in the radiation response is unclear. In this study, we demonstrated that lncRNA GAS5 expression was reduced in irradiated cells and that overexpression of GAS5 reduced cell viability and promoted cell apoptosis after irradiation. Moreover, overexpression of GAS5 resulted in increased G2/M arrest and unrepaired DNA damage, indicating a radiosensitizing role of GAS5 in breast cancer cells. Finally, we found that a GAS5-interacting miRNA, miR-21, reversed the radiosensitizing effects of GAS5 by inhibiting the apoptotic pathway. In conclusion, we found that lncRNA GAS5 sensitized breast cancer cells to ionizing radiation by inhibiting DNA repair and suppressing miR-21, identifying novel targets for breast cancer radiosensitization.
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Tian, Yingjie, Li Sun, and Tao Qi. "Long noncoding RNA GAS5 ameliorates chronic constriction injury induced neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis." Canadian Journal of Physiology and Pharmacology 98, no. 12 (December 2020): 870–77. http://dx.doi.org/10.1139/cjpp-2020-0036.
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Neuropathic pain is a type of spontaneous pain that causes damage to the central nervous system. Long noncoding RNAs (lncRNAs) participate in the progression of various nervous system diseases, including neuropathic pain. However, the biological function of GAS5 in neuropathic pain remains unclear. Our findings revealed that GAS5 was downregulated in chronic constriction injury (CCI) rats. Besides, ELISA showed that the concentration of IL‐6, TNF-α, and IL‐1β were reduced by overexpressed GAS5 in spinal cord homogenates of CCI rats. Moreover, mechanical allodynia and thermal hyperalgesia in CCI rats were inhibited by GAS5 overexpression, suggesting that GAS5 overexpression attenuated neuropathic pain. Subsequently, we found that GAS5 served as a sponge for miR-452-5p in CCI rats and CELF2 was the downstream target of miR-452-5p. Finally, through a rescue assay, we found that GAS5 ameliorated neuropathic pain in CCI rats by sponging miR-452-5p to regulate CELF2 expression. Our study confirmed that GAS5 ameliorated neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis, which may provide some clues for neuropathic pain treatment.
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Xu, Yingying, and Yiqun Ouyang. "Long non-coding RNA growth arrest specific 5 regulates the T helper 17/regulatory T balance by targeting miR-23a in myasthenia gravis." Journal of International Medical Research 50, no. 6 (June 2022): 030006052110537. http://dx.doi.org/10.1177/03000605211053703.
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Objective Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder. Recent studies report that long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of various diseases. This study explored the molecular mechanism of lncRNA growth arrest specific 5 (GAS5) in regulating the T helper 17 (Th17)/regulatory T (Treg) cell balance in MG. Methods GAS5 and miR-23a expression levels were detected by quantitative reverse transcription polymerase chain reaction. Flow cytometry was performed to examine the proportion of Th17 and Treg cells in CD4+ T cells from MG patients. The interaction between GAS5 and miR-23a was verified by luciferase reporter and RNA immunoprecipitation assays. Levels of Th17 and Treg-related proteins were examined using western blots and enzyme-linked immunosorbent assays. Results GAS5 expression levels were significantly decreased in the CD4+ T cells of MG patients, and GAS5 overexpression restrained Th17 differentiation in CD4+ T cells. Moreover, miR-23a was confirmed as a downstream target of GAS5 and negatively regulated by GAS5 through a direct interaction. Further exploration showed that GAS5 can inhibit Th17 differentiation by downregulating miR-23a. Conclusion Collectively, our results indicate that GAS5 can regulate the Th17/Treg balance by targeting miR-23a expression, providing a scientific basis for clinical therapeutic development for MG.
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Lee, Heejin, Hoin Kang, Chongtae Kim, Ja-Lok Ku, Sukwoo Nam, and Eun Kyung Lee. "Long Non-Coding RNA GAS5 Promotes BAX Expression by Competing with microRNA-128-3p in Response to 5-Fluorouracil." Biomedicines 11, no. 1 (December 26, 2022): 58. http://dx.doi.org/10.3390/biomedicines11010058.
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The acquisition of drug resistance is a major hurdle for effective cancer treatment. Although several efforts have been made to overcome drug resistance, the underlying mechanisms have not been fully elucidated. This study investigated the role of long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) in drug resistance. GAS5 was found to be downregulated in colon cancer cell lines that are resistant to 5-fluorouracil (5-FU). Downregulation of GAS5 decreased the viability of HCT116 cells and the level of the pro-apoptotic BAX protein, while GAS5 overexpression promoted cell death in response to 5-FU. The interaction between GAS5 and BAX mRNA was investigated using MS2-tagged RNA affinity purification (MS2-trap) followed by RT-qPCR, and the results showed that GAS5 bound to the 3′-untranslated region of BAX mRNA and enhanced its expression by interfering with the inhibitory effect of microRNA-128-3p, a negative regulator of BAX. In addition, ectopic expression of GAS5 increased the sensitivity of resistant cells in response to anti-cancer drugs. These results suggest that GAS5 promoted cell death by interfering with miR-128-3p-mediated BAX downregulation. Therefore, GAS5 overexpression in chemo-resistant cancer cells may be a potential strategy to improve the anti-cancer efficacy of drugs.
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Yang, Rui-qi, Zhe-zhu Jin, San-ya Jiang, and Yong-jun Jin. "LncRNA GAS5 Interacts with MicroRNA-10b to Inhibit Cell Proliferation and Migration and Induces Apoptosis in Colorectal Cancer." Computational and Mathematical Methods in Medicine 2022 (January 22, 2022): 1–16. http://dx.doi.org/10.1155/2022/4996870.
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Objective. The purpose of this study was to study the effects of the GAS5/microRNA-10b (miR-10b) axis on proliferation, migration, and apoptosis of colorectal cancer (CRC). Methods. The expression levels of GAS5 and miR-10b in CRC tissues and cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Wound healing experiment was used to detect the effects of GAS5 and miR-10b on the migration of CRC cells. The luciferase reporter gene experiment was used to verify miRNA targets. Immunohistochemical assay was used to detect the expression of proteins related to metastasis and apoptosis in tumor tissues. Results. The expression of GAS5 was downregulated in CRC tissues and cell lines. The overexpression of GAS5 can inhibit cell proliferation and progression, induce apoptosis in vitro, and inhibit the growth of CRC tumor in vivo. In contrast, the expression of miR-10b, a downstream target of GAS5, was increased in CRC tissues and cells. Suppression of the miR-10b gene can inhibit proliferation and metastasis and cause apoptosis of CRC cells. In addition, luciferase reports show that GAS5 inhibits the progression of CRC cells by binding to miR-10b. Rescue experiments showed that overexpressed miR-10b could reverse GAS5-mediated antitumor effect on CRC cells in vivo and in vitro. Conclusions. LncRNA GAS5 interacts with miR-10b to inhibit cell proliferation and migration and induces apoptosis in colorectal cancer. GAS5 and miR-10b could become potential therapeutic targets for CRC.
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Wang, Yang, and Daliang Kong. "LncRNA GAS5 Represses Osteosarcoma Cells Growth and Metastasis via Sponging MiR-203a." Cellular Physiology and Biochemistry 45, no. 2 (2018): 844–55. http://dx.doi.org/10.1159/000487178.
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Background/Aims: LncRNA GAS5, a growth suppressor, has been reported to exert anti-tumor actions in various cancers, whereas the exact mechanism underling the anti-tumor action is still unclear. This study was aimed to investigate the effect of lncRNA GAS5 on osteosarcoma and tried to decode the underling mechanisms. Methods: Expressions of lncRNA GAS5 in MG-63 cells were silenced by shRNA transfection, while were overexpressed by vector transfection. Cell viability, migration, invasion and apoptosis were respectively assessed by MTT, Transwell assay and flow cytometry. Regulations between lncRNA GAS5 and miR-203a, as well as between miR-203a and TIMP2 were detected by qPCR, western blot and dual luciferase activity assay. Results: LncRNA GAS5 was down-regulated in MG-63 and OS-732 cells compared to hFOB1.19 cells. Silence of lncRNA GAS5 significantly promoted MG-63 cells viability, migration and invasion, and up-regulated Cyclin D1, Cyclin B1, CDK1 and CDK4 expressions. miR-203a was negatively regulated by lncRNA GAS5. The promoting activities of lncRNA GAS5 silence on MG-63 cells growth and metastasis were reversed by miR-203a suppression. TIMP2 was a target of miR-203a and the anti-growth and anti-metastasis actions of miR-203a suppression were reversed by TIMP2 silence. Further, lncRNA GAS5 silence, miR-203a overexpression, and TIMP2 silence could activate PI3K/AKT/GSK3β signaling while block NF-κB signaling. Conclusion: LncRNA GAS5 might be a tumor suppressor in osteosarcoma via sponging miR-203a, sequestering miR-203a away from TIMP2.
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Jin, Feiyan, Ning Wang, Yanan Zhu, Lianghui You, Lintao Wang, Wei De, and Wei Tang. "Downregulation of Long Noncoding RNA Gas5 Affects Cell Cycle and Insulin Secretion in Mouse Pancreatic β Cells." Cellular Physiology and Biochemistry 43, no. 5 (2017): 2062–73. http://dx.doi.org/10.1159/000484191.
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Background: Evidence shows that long non-coding RNAs (lncRNAs) are involved in individual development, cell differentiation, cell cycle processes and other important life processes and are closely related to major human diseases, including diabetes. Recent studies have reported that lncRNAs are involved in β cell functions and that lncRNA Gas5 levels decreased in T2DM patients’ serum. The purpose of this study was to clarify the role of lncRNA Gas5 in mouse β cell functions in vitro and in vivo. Methods: lncRNA Gas5 expression in T2DM and normal mouse tissues was analyzed using qRT-PCR. RNAi, qRT-PCR, Annexin V-FITC assays, western blot, GSIS and RIA were performed to detect the effects of lncRNA Gas5 on insulin synthesis and secretion in vitro and in vivo. Results: The lncRNA Gas5 level was significantly decreased in db/db mice. However, lncRNA Gas5 expression was relatively high in the pancreas of normal mice. Knockdown of lncRNA Gas5 expression led to cell cycle G1 arrest and impaired insulin synthesis and secretion in Min6 cells. Further, knockdown of lncRNA Gas5 expression in primary isolated islets resulted in decreased expression of insulin gene and transcription factors, Pdx1 and MafA. These results indicate that lncRNA Gas5 might perform as a new regulator, maintaining β cell identity and function by affecting insulin synthesis and secretion.
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Lucafò, Marianna, Letizia Pugnetti, Matteo Bramuzzo, Debora Curci, Alessia Di Silvestre, Annalisa Marcuzzi, Alberta Bergamo, et al. "Long Non-Coding RNA GAS5 and Intestinal MMP2 and MMP9 Expression: A Translational Study in Pediatric Patients with IBD." International Journal of Molecular Sciences 20, no. 21 (October 24, 2019): 5280. http://dx.doi.org/10.3390/ijms20215280.
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Background: The long non-coding RNA (lncRNA) growth arrest–specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. Methods: In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. Results: Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. Conclusion: These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.
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Li, Yan, Xing Ma, Jun Li, Saifei He, Juhua Zhuang, Guoyu Wang, Ying Ye, and Wei Xia. "LncRNA gas5 regulates granulosa cell apoptosis and viability following radiation by x-ray via sponging miR-205- 5p and Wnt/β-catenin signaling pathway in granulosa cell tumor of ovary." Tropical Journal of Pharmaceutical Research 19, no. 6 (November 13, 2020): 1153–59. http://dx.doi.org/10.4314/tjpr.v19i6.5.
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Purpose: To investigate the role of lncRNA gas5 in ovarian granulosa cells exposed to x-ray in granulosa cell tumor of ovary (GCTO).
Methods: KGN cell line was exposed to X-ray to mimic the radiotherapy for GCSO patients in vitro, cell viability was checked by CCK8 assays. RNA expression of apoptosis-related genes was determined by quantitative reverse transcriptase-polymerase reaction (qRT-PCR) while Western Blot for biomarkers in wnt/β-catenin signaling. Differential expressions of lncRNA gas5 were examined after cells were exposed to a ray for 0,24,48hs. We over expressed gas5 and assessed resultant cell viability, apoptosis and signaling. The sponging between gas5 and miR-205-5p was verified by luciferase assay. CCK8, qRT-PCR and Western blot were applied to investigate the correlation between miR-205-5p, cell viability, and apoptosis after miR-205-5p augmentation. Similarly, interaction between gas5 and miR-205-5p was assessed after co-transfection of miR-205-5p mimics and oe-gas5. Finally, wnt inhibitor was used to study the role of signaling pathway in KGN cells.
Results: Exposure of KGN to x-ray reduced cell viability and increased apoptosis. Gas5showed reduced expression in the cells, while miR-205-5p expression increased. Gas5 upregulation protected the cells against apoptosis and contributed to cell viability and activation of wnt//β-catenin signaling. lncRNA gas5 targeted miR-205-5p and miR-205-5p mimics counteracted the functions of up-regulated lncRNA gas5, regulating Wnt/β-catenin signaling pathway. Inactivation of Wnt/β-catenin suppressed cell viability.
Conclusions: lncRNA gas5 regulates cell apoptosis and viability following cellular radiation, thus presenting a potential therapeutic target for the application radiotherapy in GCTO patients.
Keywords: Ovary, Proliferation, Apoptosis, lncRNA gas5, Radiotherapy, β-catenin signaling
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Liu, Wenlin, Jiandong Zhan, Rong Zhong, Rui Li, Xiaoli Sheng, Mimi Xu, Zhongming Lu, and Siyi Zhang. "Upregulation of Long Noncoding RNA_GAS5 Suppresses Cell Proliferation and Metastasis in Laryngeal Cancer via Regulating PI3K/AKT/mTOR Signaling Pathway." Technology in Cancer Research & Treatment 20 (January 1, 2021): 153303382199007. http://dx.doi.org/10.1177/1533033821990074.
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Background: Laryngeal cancer is one of the most common malignant tumors among head and neck cancers. Accumulating studies have indicated that long noncoding RNAs (lncRNAs) play an important role in laryngeal cancer occurrence and progression, however, the functional roles and relative regulatory mechanisms of lncRNA growth arrest-specific transcript 5 (GAS5) in laryngeal cancer progression remain unclear. Methods: The expression of lncRNA GAS5 in both laryngeal cancer tissues and cell lines was evaluated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay. The relationships between lncRNA GAS5 expression and clinical parameters were also analyzed. To determine the biological function of lncRNA GAS5, a lncRNA GAS5-specific plasmid was first transfected into laryngeal cancer cells using lentiviral technology. Cell counting kit-8 assay, flow cytometry, and Transwell assays were used to detect in vitro cell proliferation, apoptosis, cycle distribution, and metastasis abilities, respectively. Furthermore, in vivo cell growth experiments were also performed using nude mice. Additionally, western blotting was performed to identify the underlying regulatory mechanism. Results: In the current study, lncRNA GAS5 was downregulated in laryngeal cancer tissues and its low expression was closely associated with poor tumor differentiation, advanced TNM stage, lymph node metastasis, and shorter overall survival time. In addition, lncRNA GAS5 upregulation significantly inhibited laryngeal cancer cell proliferation both in vitro and in vivo. Moreover, in response to lncRNA GAS5 overexpression, more laryngeal cancer cells were arrested at the G2/M stage, accompanied by increased cell apoptosis rates and suppressed migration and invasion capacities. Mechanistically, our data showed that the overexpression of lncRNA GAS5 significantly regulated the PI3K/AKT/mTOR signaling pathway. Conclusion: LncRNA GAS5 might act as a suppressor gene during laryngeal cancer development, as it suppressed cell proliferation and metastasis by regulating the PI3K/AKT/mTOR signaling pathway; thus, lncRNA GAS5 is a promising therapeutic biomarker for the treatment of laryngeal cancer.
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Tang, Gui-Yan, Ping Yu, Chen Zhang, Hong-Yu Deng, Mei-Xiu Lu, and Jiang-Hua Le. "The Neuropeptide-Related HERC5/TAC1 Interactions May Be Associated with the Dysregulation of lncRNA GAS5 Expression in Gestational Diabetes Mellitus Exosomes." Disease Markers 2022 (February 8, 2022): 1–12. http://dx.doi.org/10.1155/2022/8075285.
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Objective. The goal of this work was to look at the expression and probable role of exosomal long noncoding RNA (lncRNA) GAS5 in gestational diabetes mellitus (GDM), as well as forecast the importance of its interaction with neuropeptides in the progression of the disease. Methods. We divided 44 pregnant women visiting the obstetric outpatient clinics at the Affiliated Hospital of Guilin Medical College from January 2021 to December 2021 into healthy and GDM groups. We measured the expression levels of the lncRNA GAS5 in peripheral blood using PCR and compared the expression levels between the 2 groups. The Gene Expression Omnibus (GEO) database and the R software were used to analyse the differences in the genes expressed in the amniotic fluid cells in the GDM and normal groups. catRAPID was used to identify potential target proteins for GAS5. Key neuropeptide-related proteins and potential target proteins of GAS5 were extracted, and protein interaction networks were mapped. AlphaFold 2 was used to predict the structure of the target protein. The ClusPro tool was used to predict protein-protein interactions. ZDOCK was used to further confirm the protein–nucleic acid docking. Results. The lncRNA GAS5 was downregulated in the peripheral blood of pregnant women with GDM compared with normal pregnant women. The subcellular localization sites of GAS5 were the nucleus, cytoplasm, and ribosome; in addition, GAS5 was present in exosomes. Intercellular interactions, including neuropeptide receptors, were increased in the amniotic fluid cells of patients with GDM. Venn diagram analysis yielded seven neuropeptide-related proteins and three GAS5 target proteins. Among them, HERC5/TAC1 interacted and GAS5 docked well with HERC5. Conclusion. The lncRNA GAS5 in the peripheral blood exosomes in patients with GDM may be a new target for the detection of GDM, and the interaction between GAS5 and HERC5/TAC1 may be involved in the pathogenesis of GDM.
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Xagorari, Marieta, Antonios Marmarinos, Lydia Kossiva, Margarita Baka, Dimitrios Doganis, Marina Servitzoglou, Maria Tsolia, Andreas Scorilas, Margaritis Avgeris, and Dimitrios Gourgiotis. "Overexpression of the GR Riborepressor LncRNA GAS5 Results in Poor Treatment Response and Early Relapse in Childhood B-ALL." Cancers 13, no. 23 (December 1, 2021): 6064. http://dx.doi.org/10.3390/cancers13236064.
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Glucocorticoids (GCs) remain the cornerstone of childhood acute lymphoblastic leukemia (chALL) therapy, exerting their cytotoxic effects through binding and activating of the glucocorticoid receptor (GR). GAS5 lncRNA acts as a potent riborepressor of GR transcriptional activity, and thus targeting GAS5 in GC-treated chALL could provide further insights into GC resistance and support personalized treatment decisions. Herein, to study the clinical utility of GAS5 in chALL prognosis and chemotherapy response, GAS5 expression was quantified by RT-qPCR in bone marrow samples of chB-ALL patients at diagnosis (n = 164) and at end-of-induction (n = 109), treated with ALL-BFM protocol. Patients’ relapse and death were used as clinical end-points for survival analysis. Bootstrap analysis was performed for internal validation, and decision curve analysis assessed the clinical net benefit for chALL prognosis. Our findings demonstrated the elevated GAS5 levels in blasts of chALL patients compared to controls and the significantly higher risk for short-term relapse and poor treatment outcome of patients overexpressing GAS5, independently of their clinicopathological data. The unfavorable prognostic value of GAS5 overexpression was strongly validated in the high-risk/stem-cell transplantation subgroup. Finally, multivariate models incorporating GAS5 levels resulted in superior risk stratification and clinical benefit for chALL prognostication, supporting personalized prognosis and precision medicine decisions in chALL.
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Tang, Rui, Yung-Chun Wang, Xiaohan Mei, Ning Shi, Chenming Sun, Ran Ran, Gui Zhang, et al. "LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling." American Journal of Physiology-Cell Physiology 319, no. 1 (July 1, 2020): C105—C115. http://dx.doi.org/10.1152/ajpcell.00059.2020.
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Transforming growth factor-β (TGF-β)-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (lncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-β-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-β and in resident fibroblasts from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-β-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound mothers against decapentaplegic homolog 3 (Smad3) and promoted Smad3 binding to Protein phosphatase 1A (PPM1A), a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-β-treated fibroblasts. In addition, GAS5 inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGF-β/Smad3 signaling, which provides a rationale for an lncRNA-based therapy to treat fibrotic diseases.
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Li, Junnan, Wei Gao, Zhonghui Zhao, Yannan Li, Lixuan Yang, Wei Wei, Feifei Ren, et al. "Ginsenoside Rg1 Reduced Microglial Activation and Mitochondrial Dysfunction to Alleviate Depression-Like Behaviour Via the GAS5/EZH2/SOCS3/NRF2 Axis." Molecular Neurobiology 59, no. 5 (March 1, 2022): 2855–73. http://dx.doi.org/10.1007/s12035-022-02740-7.
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AbstractGinsenoside Rg1 is the principal active ingredient in ginseng. The antidepressant effects of Rg1 have been validated; however, the specific underlying mechanism of this effect needs further research. Rats were subjected to the chronic restraint stress (CRS) depression model. Rg1, or a positive control drug, was administered to the rats. Depression-like behaviours were evaluated through behavioural experiments. Cytokine, mRNA, protein, ATP, and mitochondria DNA levels were detected using the indicated methods. Lentivirus-packaged plasmids were injected into the rat brain for GAS5 overexpression or knockdown. In vitro mitochondrial dysfunction was evaluated by detecting mitochondrial reactive oxygen species and mitochondrial membrane potential. Direct interaction between GAS5 and EZH2 was validated by RNA immunoprecipitation and RNA pull-down assay. The enrichment of EZH2 and H3K27me3 was evaluated through chromatin immunoprecipitation quantitative real-time PCR. Rg1 treatment alleviated depression-like behaviours, microglial activation, and mitochondrial dysfunction in CRS rats. Similarly, GAS5 knockdown revealed a similar protective effect of Rg1 treatment. GAS5 overexpression in the rat brain compromised the protective effect of Rg1 treatment. Moreover, Rg1 treatment or GAS5 knockdown attenuated microglial activation and mitochondrial dysfunction in vitro. Mechanically, GAS5 was suppressed SOCS3 and NRF2 expression by facilitating EZH2-mediated transcriptional repression. Rg1 attenuated microglial activation and improved mitochondrial dysfunction in depression by downregulating GAS5 expression. Mechanically, GAS5 might regulate microglial activation and mitochondrial dysfunction via the epigenetic suppression of NRF2 and SOCS3.
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Han, Man-Hoon, Jee Hyun Lee, Gyeonghwa Kim, Eunhye Lee, Yu Rim Lee, Se Young Jang, Hye Won Lee, et al. "Expression of the Long Noncoding RNA GAS5 Correlates with Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease." Genes 11, no. 5 (May 13, 2020): 545. http://dx.doi.org/10.3390/genes11050545.
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Background: Advanced liver fibrosis is the most important prognostic factor in nonalcoholic fatty liver disease (NAFLD). The long noncoding RNA (lncRNA), growth arrest-specific transcript 5 (GAS5), is associated with the inhibition of liver fibrogenesis, and its levels are decreased in cirrhotic liver. Methods: We analyzed 51 patients with NAFLD, the diagnosis of which was confirmed by liver biopsy. Expression of GAS5 in both the liver and plasma of the patients was analyzed using a quantitative real-time polymerase chain reaction according to the fibrosis stage. Results: Plasma GAS5 expression was significantly higher in patients with advanced fibrosis than in those without. As the fibrosis progressed, GAS5 expression in plasma increased, with the exception of that in cirrhotic livers. Plasma levels of GAS5 were lower in patients with cirrhosis than in those with advanced fibrosis. Conclusion: Elevated circulating levels of the lncRNA GAS5 are associated with the progression of liver fibrosis prior to the development of cirrhosis.
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Lei, Yan, Li Jing-jing, Zhang Ke-nan, Tian Qing-zhong, and Li Jin. "A tumor suppressive role of lncRNA GAS5 in human colorectal cancer." Open Life Sciences 11, no. 1 (January 1, 2016): 105–9. http://dx.doi.org/10.1515/biol-2016-0014.
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AbstractObjectiveIt is already known that long non-coding RNA growth arrest-specific 5 (GAS5) is downregulated in human colorectal cancer (CRC) cells inhibiting cell proliferation. We further analyzed its involvement in cell cycle distribution and apoptosis induction.MethodsWe measured the expression level of GAS5 in CRC tissues and cell lines with the corresponding non-tumoral cells. We also analyzed the roles of GAS5 in modulation of cell growth, cell cycle distribution and apoptosis by the CCK-8 method and flow cytometry. Western blots were performed to evaluate the protein level of cyclin D1 and p21 after overexpression of GAS5ResultsGAS5 expression was significantly reduced in CRC samples and cell lines. Overexpression of GAS5 induced cell growth arrest and induced cell apoptosis in vitro. Meanwhile, we found that the growth suppressive role of GAS5 might be attributed to the inhibition of G1-S phase transition, reflected by the downregulation of cyclin D1 and upregulation of p21.ConclusionOur results demonstrate that GAS5 is a crucial tumor suppressor in human CRC cells.
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Keenan, Christine R., Michael J. Schuliga, and Alastair G. Stewart. "Pro-inflammatory mediators increase levels of the noncoding RNA GAS5 in airway smooth muscle and epithelial cells." Canadian Journal of Physiology and Pharmacology 93, no. 3 (March 2015): 203–6. http://dx.doi.org/10.1139/cjpp-2014-0391.
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The long noncoding RNA (lncRNA) GAS5 has been found to act as a decoy for the glucocorticoid receptor (GR), thus implicating GAS5 as a potential regulator of glucocorticoid sensitivity and resistance. Airway smooth muscle (ASM) cells and airway epithelial cells (AEC) play an important role in the pathogenesis and persistence of asthma and other chronic airways diseases. These airway structural cell types are also important cellular targets of the anti-inflammatory actions of glucocorticoids. In this study, we sought to examine the relevance of GAS5 to glucocorticoid sensitivity and resistance in ASM and AEC. We provide the first evidence that pro-inflammatory mediators up-regulate GAS5 levels in both airway epithelial and smooth muscle cells, and that decreasing GAS5 levels can enhance glucocorticoid action in AEC.
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Weng, Wei-Chun, Chih-Jung Chen, Pei-Ni Chen, Shian-Shiang Wang, Ming-Ju Hsieh, and Shun-Fa Yang. "Impact of Gene Polymorphisms in GAS5 on Urothelial Cell Carcinoma Development and Clinical Characteristics." Diagnostics 10, no. 5 (April 28, 2020): 260. http://dx.doi.org/10.3390/diagnostics10050260.
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Urothelial cell carcinoma (UCC) is the commonest malignant tumor of the urinary tract and the second most common kidney cancer malignancy. Growth arrest-specific 5 (GAS5), a long noncoding RNA, is encoded by the GAS5 gene and plays a critical role in cellular growth arrest and apoptosis. In the current study, two single nucleotide polymorphisms (SNPs) in the GAS5 gene, rs145204276 and rs55829688, were selected to investigate correlations between these single SNPs and susceptibility to UCC. A total of 430 UCC cases and 860 ethnically matched healthy controls were included. SNP rs145204276 and SNP rs55829688 were determined using a TaqMan genotyping assay. Logistic regression models demonstrated that female patients with UCC carrying the rs145204276 GAS5 Ins/Del or Del/Del genotype had a 3.037-fold higher risk of larger tumor status (95% confidence interval 1.259–7.324) than did rs145204276 wild type (Ins/Ins) carriers (p = 0.011). The Cancer Genome Atlas validation cohort analysis demonstrated that the expression of GAS5 in female patients with bladder urothelial carcinoma (BLCA) with larger tumor size was much lower than that in patients with a smaller tumor size (p = 0.041). Kaplan-Meier curve analysis and the log–rank test revealed that female patients with BLCA and lower GAS5 expression had poorer overall survival than those with higher GAS5 expression. In conclusion, genetic variations in GAS5 rs145204276 may serve as a critical predictor of the clinical status of female patients with UCC.
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Li, Lexing, Chunxiao Huang, Yulong He, Zhan Sang, Guoquan Liu, and Hanchuan Dai. "Knockdown of Long Non-Coding RNA GAS5 Increases miR-23a by Targeting ATG3 Involved in Autophagy and Cell Viability." Cellular Physiology and Biochemistry 48, no. 4 (2018): 1723–34. http://dx.doi.org/10.1159/000492300.
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Background/Aims: Autophagy is a process of evolutionarily conservative degradation, which could maintain cellular homeostasis and cope with various types of stress. LncRNAs are considered as competing endogenous RNAs (ceRNAs) contributing to autophagy. GAS5 has been suggested as a new potential factor to mediate autophagy pathway and the underlying mechanism remains to be further confirmed. This study was taken to identify the effect of GAS5/miR-23a/ATG3 axis on autophagy and cell viability. Methods: The western blotting assay was used to detecte the protein levels of LC3, mTOR, Beclin-1, ATG3, ATG5-ATG12 complex and p62. The mRNA level of Pre-miR-23a, Pri-miR-23a, miR-23a, GAS5, LC3, mTOR and ATG3 were quantified by real-time RT-PCR. Dual-luciferase reporter assays were performed to confirm the direct binding of miR-23a and ATG3 or GAS5. Cell viability was evaluated by CCK-8 and flow cytometry. Results: We showed that miR-23a could directly suppress ATG3 expression in 293T cells, which suggested that ATG3 was identified as a target of miR-23a. MiR-23a mimics could restrain LC3 II, Beclin1 levles and ATG5-ATG12 complex formation. Meanwhile, miR-23a also increased the expression of mTOR and p62. Notably, there was a putative miR-23a-binding site in GAS5. MiR-23a overexpression might suppress the GAS5 expression, but the repressive effect was abolished by mutation of binding sites. Importantly, overexpression of GAS5 could inhibit the mature miR-23a and has no effect on miR-23a precursors. Knockdown of GAS5 suppressed the expression of LC3 II, ATG3 and ATG5-ATG12 complex formation, whereas p62 and mTOR levels were promoted. The further results showed that miR-23a overexpression and GAS5 inhibition both significantly suppressed cell viability and promoted the apoptosis rate following LPS stimulation, and knockdown of miR-23a exhibited the opposite effects. Conclusions: Our study revealed that down-regulation GAS5 attenuated cell viability and inhibited autophagy through ATG3-dependent autophagy by regulating miR-23a expression. The results suggested that GAS5/miR-23a/ATG3 axis might be a novel regulatory network contributing to a better understanding of regulation on autophagy program and cell viability.
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Lei, Jin, Xiao Zhang, Rui Tan, Yu Li, Kai Zhao, and Hongquan Niu. "Levels of lncRNA GAS5 in Plasma of Patients with Severe Traumatic Brain Injury: Correlation with Systemic Inflammation and Early Outcome." Journal of Clinical Medicine 11, no. 12 (June 9, 2022): 3319. http://dx.doi.org/10.3390/jcm11123319.
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Scientific efforts continue to concentrate on elucidating the complex molecular mechanisms underlying traumatic brain injury (TBI), and recent reports suggest that epigenetic regulation including long non-coding RNA (lncRNA) is involved. The present study aimed to investigate the plasma concentration of a long non-coding RNA, named growth arrest-specific 5 (GAS5), in a group of 45 patients with severe TBI (sTBI), and to analyze the correlations of GAS5 with TBI onset, injury severity, systemic inflammation, and early outcome of the patients. It was found that plasma GAS5 levels were substantially increased in sTBI patients compared with the relative controls (p < 0.001). Further, significantly higher expression of plasma GAS5 was observed in patients with a Glasgow Coma Scale (GCS) score of less than five (p = 0.002) or unfavorable outcome at discharge (p < 0.001). Circulating GAS5 expression had a negative correlation with GCS score (r = −0.406, p = 0.006), and positive correlations with white blood cell count (r = 0.473, p = 0.001), neutrophil count (r = 0.502, p < 0.001), and neutrophil/lymphocyte ratio (NLR) (r = 0.398, p = 0.007). Univariate and multivariate logistic regression analyses revealed that GCS score (OR = 0.318, 95% CI 0.132–0.767, p = 0.011) and GAS5 (OR = 2.771, 95% CI 1.025–7.494, p = 0.045) were the two independent predictors for early outcome of patients. The receiver operating characteristic (ROC) curves showed good prognostic values of GCS score (AUC = 0.856, 95% CI: 0.719–0.943) and GAS5 expression (AUC = 0.798, 95% CI: 0.651–0.903). Importantly, the combined use of them can improve the prognostic ability of TBI with an AUC of 0.895 (95% CI: 0.767–0.966). Collectively, our study indicated that the levels of lncRNA GAS5 in circulation were elevated following severe TBI and correlated well with injury severity and inflammatory parameters. In addition, GAS5 as well as GCS scores may have the potential to predict the early outcome of TBI patients.
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Liu, Yuan, Yi-Fang Li, Jia Liu, Zhi-Gang Deng, Li Zeng, and Wei-Bing Zhou. "Long Noncoding RNA GAS5 Targeting miR-221-3p/Cyclin-Dependent Kinase Inhibitor 2B Axis Regulates Follicular Thyroid Carcinoma Cell Cycle and Proliferation." Pathobiology 88, no. 4 (2021): 289–300. http://dx.doi.org/10.1159/000513338.
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<b><i>Introduction:</i></b> Follicular thyroid carcinoma (FTC) is more aggressive than the most common papillary thyroid carcinoma (PTC). However, the current research on FTC is less than PTC. Here, we investigated the effects of long noncoding RNA (lncRNA) GAS5 and miR-221-3p in FTC. <b><i>Methods:</i></b> Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect GAS5 and miR-221-3p expression in the FTC tissues and cells. Cell proliferation was assessed by CCK8 and EdU assays. Flow cytometry was performed to determine the cell cycle. The dual-luciferase reporter assay was employed to validate the binding relationship of GAS5/miR-221-3p and miR-221-3p/cyclin-dependent kinase inhibitor 2B (CDKN2B). Western blot was conducted to measure the protein level of CDKN2B. <b><i>Results:</i></b> Our results displayed that GAS5 was downregulated, while miR-221-3p was upregulated in FTC tissues and cells. What’s more, overexpression of GAS5 or miR-221-3p inhibition induced G0/G1 phase arrest and inhibited cell proliferation of FTC cells. GAS5 acted as a sponge of miR-221-3p, and CDKN2B was a target gene of miR-221-3p. Additionally, GAS5 inhibited cell cycle and proliferation of FTC cells via reducing miR-221-3p expression to enhance CDKN2B expression. <b><i>Conclusion:</i></b> GAS5 induced G0/G1 phase arrest and inhibited cell proliferation via targeting miR-221-3p/CDKN2B axis in FTC. Thus, GAS5 may be a potential therapeutic target for the treatment of FTC.
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Gu, Juan, Yueping Wang, Xuedong Wang, Daoping Zhou, Xinguo Wang, Ming Zhou, and Zhimin He. "Effect of the LncRNA GAS5-MiR-23a-ATG3 Axis in Regulating Autophagy in Patients with Breast Cancer." Cellular Physiology and Biochemistry 48, no. 1 (2018): 194–207. http://dx.doi.org/10.1159/000491718.
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Background/Aims: An increasing body of evidence shows that long noncoding RNAs (lncRNAs) are involved in many different cancers. In this study, we aimed to investigate the competing endogenous RNA (ceRNA)-dependent mechanism by which the lncRNA GAS5 contributes to the development of breast cancer. Methods: A total of 68 breast cancer patients were enrolled, and breast cancer and adjacent normal tissues were collected. The human breast cancer cell lines MDA-MB-231, MDA-MB-453, BT549, SK-BR-3 and MCF-7 and human breast cell line MCF10A were utilized in this study. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were performed to detect expression of relative factors. RNA immunoprecipitation (RIP) was used to evaluate the relationship between GAS5 and miR-23a, and a dual luciferase reporter gene assay was employed to assess the relationship between ATG3 and miR-23a. A subcutaneous xenograft nude mouse model was generated to examine the role of GAS5 and its regulatory pathway in autophagy. Results: GAS5 levels were frequently decreased in breast cancer tissues and cell lines, and its relatively low expression was closely related to a larger tumour size, advanced tumour-node-metastasis (TNM) stage and estrogen receptor-negative (ER-) breast cancer tissues. More importantly, we found that GAS5 promoted autophagy, with enhanced autophagosome formation after GAS5 overexpression. GAS5 was found to act as a microRNA sponge in a pathway that included miR-23a and its target gene ATG3. The GAS5-miR-23a-ATG3 axis significantly regulated autophagy in vivo and in vitro. Conclusions: In summary, we report that the GAS5-miR-23a-ATG3 axis can be regarded as a key regulator of autophagy pathways in breast cancer; it may constitute a promising biomarker and therapeutic target in the future.
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Wang, Yaqi, Mengzhen Xue, Fangqi Xia, Leiqi Zhu, Dengke Jia, Yan Gao, Luoying Li, et al. "Long Non-Coding RNA GAS5 in Age-Related Diseases." Current Medicinal Chemistry 29, no. 16 (May 2022): 2863–77. http://dx.doi.org/10.2174/0929867328666211027123932.
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Abstract: Aging refers to a natural process and a universal phenomenon in all cells, tissues, organs, and the whole organism. Long non-coding RNAs (lncRNAs) are non-coding RNAs with a length of 200 nucleotides. LncRNA growth arrest-specific 5 (lncRNA GAS5) is often down-regulated in cancer. The accumulation of lncRNA GAS5 has been found to be able to inhibit cancer growth, invasion, and metastasis while enhancing the sensitivity of cells to chemotherapy drugs. LncRNA GAS5 can be a signaling protein, which is specifically transcribed under different triggering conditions. Subsequently, it is involved in signal transmission in numerous pathways as a signal node. LncRNA GAS5, with a close relationship to multiple miRNAs, was suggested to be involved in the signaling pathway under three action modes (i.e., signal, bait, and guidance). LncRNA GAS5 was found to be involved in different age-related diseases (e.g., rheumatoid arthritis, type 2 diabetes, atherosclerosis, osteoarthritis, osteoporosis, multiple sclerosis, cancer, etc.). This study mainly summarized the regulatory effect exerted by lncRNA GAS5 on age-related diseases.
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Cheng, Ying, Xin Dai, Ti Yang, Nan Zhang, Zhenzhong Liu, and Yiguo Jiang. "Low Long Noncoding RNA Growth Arrest-Specific Transcript 5 Expression in the Exosomes of Lung Cancer Cells Promotes Tumor Angiogenesis." Journal of Oncology 2019 (May 2, 2019): 1–13. http://dx.doi.org/10.1155/2019/2476175.
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Angiogenesis plays a key role in the development and progression of lung cancer. Recent studies have found that tumor cells can stimulate angiogenesis by secreting exosomes, which contain many long noncoding RNAs (lncRNAs), some of which are important for the development of lung cancer. However, the roles and mechanisms of exosomal lncRNAs in lung cancer angiogenesis have not yet been reported. In this study, lung cancer in mice was induced by urethane; we found that growth arrest specific 5 (GAS5) was lowly expressed in the serum exosomes and lung cancer tissues of mice with lung cancer. And there was a significant positive correlation between GAS5 expression in serum exosomes and lung cancer tissues. Furthermore, GAS5 was lowly expressed in human lung cancer tissues, lung cancer cells, and cells culture supernatant exosomes. The exosomes of lung cancer cells promoted human umbilical vein endothelial cells (HUVECs) proliferation and tube formation and inhibited their apoptosis. GAS5 overexpression in lung cancer cells increased GAS5 level in cell culture supernatant exosomes. And the exosomes of lung cancer cells containing high GAS5 level inhibited HUVECs proliferation and tube formation and increased their apoptosis. In addition, we found that GAS5 competitively bound miRNA-29-3p with phosphatase and tensin homolog (PTEN), upregulating PTEN mRNA and protein expression, and inhibited level of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3K) and serine/threonine kinase 1 (AKT) phosphorylation in HUVECs. Overall, our results suggest that exosomal GAS5 could be a new therapeutic target for lung cancer which inhibits angiogenesis.
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Kaur, Jesminder, Nur’ain Salehen, Anwar Norazit, Amirah Abdul Rahman, Nor Azian Abdul Murad, Nik Mohd Afizan Nik Abd Rahman, and Kamariah Ibrahim. "Tumor Suppressive Effects of GAS5 in Cancer Cells." Non-Coding RNA 8, no. 3 (May 28, 2022): 39. http://dx.doi.org/10.3390/ncrna8030039.
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In recent years, long non-coding RNAs (lncRNAs) have been shown to play important regulatory roles in cellular processes. Growth arrests specific transcript 5 (GAS5) is a lncRNA that is highly expressed during the cell cycle arrest phase but is downregulated in actively growing cells. Growth arrests specific transcript 5 was discovered to be downregulated in several cancers, primarily solid tumors, and it is known as a tumor suppressor gene that regulates cell proliferation, invasion, migration, and apoptosis via multiple molecular mechanisms. Furthermore, GAS5 polymorphism was found to affect GAS5 expression and functionality in a cell-specific manner. This review article focuses on GAS5’s tumor-suppressive effects in regulating oncogenic signaling pathways, cell cycle, apoptosis, tumor-associated genes, and treatment-resistant cells. We also discussed genetic polymorphisms of GAS5 and their association with cancer susceptibility.
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Kanabe, Belan O., Mehmet Ozaslan, Sherwan Ahmed Aziz, Mustafa S. Al-Attar, İbrahim Halil Kılıç, and Rozhgar A. Khailany. "Expression patterns of LncRNA-GAS5 and its target APOBEC3C gene through miR-103 in breast cancer patients." Cellular and Molecular Biology 67, no. 3 (November 25, 2021): 5–10. http://dx.doi.org/10.14715/cmb/2021.67.3.2.
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Early diagnosis of breast cancer can increase the survivability of the patients and the patient’s quality of life. There is growing evidence demonstrating the active role of LncRNA-GAS5 and miR-103 in cancer biology. APOBEC enzymes are important players in immunity and may contribute to carcinogenesis. Mutation and expression alteration in the APOBEC gene family was found to have a strong correlation with breast cancer risk. This study aimed to evaluate the expression level of lncRNA-GAS5 and its target APOBEC3C in women with breast cancer through expression evaluation of miR-103. Moreover, the interaction between lncRNA-GAS5 and miR-103 was studied. In the present study, forty paired tumor and normal samples classified based on breast cancer subtypes and clinical features of patients were analyzed using gene expression studies. Immunohistochemical analysis of the gene products was performed to classify tumors. The RNA samples were extracted from breast tissue. Real-time PCR was conducted for APOBEC3C and Lnc-RNA GAS5 expression. In addition, miR-103a miScript Primer Assay was utilized for the expression of miR-103-5p. It was revealed that the expression level of APOBEC3C and lncRNA-GAS5 were significantly down-regulated; however, the miRNA-103 expression level was significantly up-regulated. GAS5 expression was positively correlated with APOBEC3C expression and negatively correlated with miR-103 expression. In conclusion, we observed down-regulation of APOBEC3C and LncRNA-GAS5 and up-regulation of miRNA 103 in breast cancer patients. The expression of GAS5 may provide a new potential treatment target for breast cancer. To clarify the role of these molecules in the cellular signaling pathways, further studies are required.
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Patel, Rekha S., Sabrina Impreso, Ashley Lui, Gitanjali Vidyarthi, Paul Albear, and Niketa A. Patel. "Long Noncoding RNA GAS5 Contained in Exosomes Derived from Human Adipose Stem Cells Promotes Repair and Modulates Inflammation in a Chronic Dermal Wound Healing Model." Biology 11, no. 3 (March 11, 2022): 426. http://dx.doi.org/10.3390/biology11030426.
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Chronic recalcitrant wounds result from delayed or slowed healing processes. Underlying inflammation is a substantial risk factor for impaired dermal wound healing and often leads to chronic wound-related sequelae. Human adipose stem cells (hASCs) have shown tremendous potential in regenerative medicine. The goal of this project was to improve the outcome of chronic wounds by harvesting the exosomes from hASCs for therapeutic intervention. The results demonstrate that long noncoding RNA GAS5 is highly enriched in hASC exosomes and, further, that GAS5 is central to promoting wound repair in vitro. To evaluate the outcome of wound healing in a chronic low-grade inflammatory environment, lipopolysaccharide-treated HDF cells were evaluated for their response to hASC exosome treatment. Ingenuity pathway analysis identified inflammation pathways and genes affected by exosomes in a GAS5-dependent manner. Using siRNA to deplete GAS5 in HDF, the results demonstrated that Toll-like receptor 7 (TLR7) expression levels were regulated by GAS5. Importantly, the results demonstrate that GAS5 regulates inflammatory pathway genes in a chronic inflammation environment. The results presented here demonstrate that hASC exosomes are a viable therapeutic that accelerate the healing of chronic recalcitrant wounds.
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Chen, Hongwei, Chuan He, Yan Liu, Xiaolin Li, Chaoju Zhang, Qunyan Qin, and Qixiong Pang. "LncRNA-GAS5 Inhibits Expression of miR 103 and Ameliorates the Articular Cartilage in Adjuvant-Induced Arthritis in Obese Mice." Dose-Response 18, no. 4 (October 1, 2020): 155932582094271. http://dx.doi.org/10.1177/1559325820942718.
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We explored whether long noncoding RNA growth arrest-specific transcript 5 (LncRNA-GAS5) small interfering RNA (siRNA) reduced cartilage destruction in obese mice with adjuvant-induced arthritis. We studied the effects of LncRNA-GAS5 siRNA on the polyarthritis index; hind paw swelling; and the serum levels of certain biochemicals, cytokines, and oxidative stress parameters. We measured the expression levels of matrix metalloproteinases (MMP)-13, NF-κB, fibroblast growth factor (FGF) 21, p38, Akt, and PI3K in cartilage via Western blotting and quantitative reverse transcription PCR. Long noncoding RNA-GAS5 siRNA reduced joint swelling; the serum levels of arthritis-associated biochemicals, cytokines, and oxidative stress markers; and cartilage MMP-13, NF-κB, FGF21, p38, Akt, and PI3K levels. Cartilage miR-103 expression was reduced. Histopathologically, LncRNA-GAS5 siRNA ameliorated the pathological changes of cartilage. Long noncoding RNA-GAS5 siRNA prevented cartilage destruction by inhibiting miR-103 expression.
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Williams, Gwyn T., Mirna Mourtada-Maarabouni, and Farzin Farzaneh. "A critical role for non-coding RNA GAS5 in growth arrest and rapamycin inhibition in human T-lymphocytes." Biochemical Society Transactions 39, no. 2 (March 22, 2011): 482–86. http://dx.doi.org/10.1042/bst0390482.
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Non-coding RNA GAS5 (growth arrest-specific transcript 5) is a 5′-TOP (5′-terminal oligopyrimidine tract) RNA, whose translation, and consequently also stability, is controlled by the mTOR (mammalian target of rapamycin) pathway. GAS5 was identified by functional expression cloning and is necessary and sufficient for normal growth arrest in both leukaemic and untransformed human T-lymphocytes. GAS5 is also required for the inhibitory effects of rapamycin and its analogues on T-cells. The striking functional effects of GAS5 may be mediated through the snoRNAs (small nucleolar RNAs) encoded in its introns and/or through the unusual folding of the mRNA itself, which sequesters, and therefore inhibits, the glucocorticoid receptor.
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Misovic, Miroslav, Predrag Aleksic, Dejan Kostic, Miodrag Vukovic, Bojan Radojicic, Nemanja Rancic, and Bojana Cikota-Aleksic. "The levels of circulating long non-coding RNA GAS5 in prostate cancer patients: Single center study." Vojnosanitetski pregled, no. 00 (2022): 75. http://dx.doi.org/10.2298/vsp220412075m.
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Background/Aim. Prostate cancer (PCa) is second occurring carcinoma that affect males population. Although PCa incidence rates are high, most cases has favorable prognosis, with comfortable long term life quality. This study was aimed to assess distinction of lncRNA GAS5 plasma levels between healthy individuals and patients with PCa, and also between PCa patients with different prognostic scores. Methods. The present study included a total of 40 patients with PCa and a control group of 20 healthy individuals. PCa patients were divided into two subgroups (20 patients each) based on the prognostic criteria of American Joint Committee on Cancer. The patient data were collected and analysed. GAS5 levels were quantified using Real-time PCR metod. Statistical analysis was conducted using the IBM SPSS Statistics 26.0 computer program (IBM, USA, 2019). Results. The relative quantification of GAS5 expression levels shows downregulation in PCa patients compared to healthy individuals, however the difference was marginaly statistically significant (p = 0.056). With further analysis of the given results, we have concluded that the expression level of GAS5 was not significantly different in the first patient subgroup and the healthy individuals (p = 0.268). Patients from second subgroup had significantly lower plasma levels of GAS5 than healthy individuals (p = 0.033). Levels of GAS5 expression between patients with favorable prognosis (Group 1) than in the patients with worse prognostic score (Group 2), did not indicate the statistical significance (p = 0.275). In both Group 1 (p = 0.805) and Group 2 (p = 0.454), the plasma levels of GAS5 were not significantly different in comparing to the age (? 65 vs > 65 years). Conclusion. One of the main objective in PCa researching is identifying novel and more efficient biomarkers. Conducted research provides strong evidence about the significance of lncRNAs in PCa, as well as the correlation of decreased expression of GAS5 and poor prognosis in various tumours.