Journal articles on the topic 'Melanoma cell proliferation'
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1
Schadendorf, D., A. Möller, B. Algermissen, M. Worm, M. Sticherling, and B. M. Czarnetzki. "IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor." Journal of Immunology 151, no. 5 (September 1, 1993): 2667–75. http://dx.doi.org/10.4049/jimmunol.151.5.2667.
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Abstract Normal melanocytes require a number of exogenous growth factors in contrast to most metastatic malignant melanomas. This investigation demonstrates that endogenously produced human IL-8 can act as an important growth factor for human melanoma cells. In the present study, six out of eight human melanoma cell lines tested secrete IL-8 protein into the culture supernatant. In two of these IL-8-secreting melanoma cell lines, SK-MEL 13 and SK-MEL 23, we have determined the IL-8 requirement for their proliferative capacity. These melanoma cell lines produced significant amounts of bioactive IL-8 as measured by the ELISA technique. Secretion of human IL-8 was inducible by IL-1 and by PMA. Human IL-8-specific mRNA was already detected in unstimulated melanoma cells. In addition, human IL-8-R mRNA could be detected for the first time in human melanoma cells. Exposure of the two melanoma cell lines in vitro to antisense oligonucleotides targeted against two different sites of human IL-8 mRNA-inhibited cell proliferation, colony formation in soft agar, and secretion of IL-8 protein into culture supernatant in a dose dependent fashion. Effects were reversible either by removal of the oligomers or by addition of exogenous IL-8 protein. In contrast, exposure to IL-8 sense probes or oligonucleotides in sense or antisense orientation specific for IL-7, TGF-alpha, TGF-beta, and MGSA had no such effect. A monospecific immune serum and two IL-8-specific mAb were also capable of inhibiting melanoma cell proliferation in the same manner. These results provide strong evidence for an autocrine IL-8 synthesis and for an IL-8-dependent proliferation in a subgroup of human melanomas. Furthermore, they suggest that IL-8 may play a role not only in immunomodulation but also in melanoma progression and metastatic spread.
2
Chen, Xianjin, Lili Chang, Yan Qu, Jinning Liang, Waishu Jin, and Xiujuan Xia. "Tea polyphenols inhibit the proliferation, migration, and invasion of melanoma cells through the down-regulation of TLR4." International Journal of Immunopathology and Pharmacology 31 (January 1, 2018): 039463201773953. http://dx.doi.org/10.1177/0394632017739531.
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Melanoma is the most common skin cancer and malignant melanoma which can cause skin cancer-related deaths. Toll-like receptor 4 (TLR4) had been reported to play an important role in melanoma, and tea polyphenol (TP) is regarded as an anticancer substance. However, the relationship between TP and TLR4 in melanoma is not well explored. Therefore, our aim is to figure out how TP has an influence on melanoma. Melanoma cell lines (B16F10 and A375) were treated with TP and lipopolysaccharides (LPS). Western blot assay was used to examine TLR4 expression, and MTT assay was conducted to assess proliferation. Wound healing assay was conducted to evaluate the migration of melanoma cells, and transwell assay was used to examine the melanoma cells’ invasiveness. Besides, in vivo experiments were practiced for TP function in mice with melanoma cells. TP inhibited the proliferation, migration and invasion ability of melanoma cells, which displayed a dosage and time dependence. TLR4 was highly expressed in melanoma cells compared with normal skin cells. TP could suppress TLR4 expression both in normal melanomas and in stimulated melanomas by TLR4 agonist LPS. Suppressing TLR4 in melanomas could inhibit cell function (proliferation, migration, and invasion), and blocking the expression of 67LR could abolish TP function on TLR4. TP can inhibit melanoma (B16F10) growth in vivo.
3
La, Ting, Lei Jin, Xiao Ying Liu, Ze Hua Song, Margaret Farrelly, Yu Chen Feng, Xu Guang Yan, et al. "Cylindromatosis Is Required for Survival of a Subset of Melanoma Cells." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 28, no. 4 (September 1, 2020): 385–98. http://dx.doi.org/10.3727/096504020x15861709922491.
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The deubiquitinase cylindromatosis (CYLD) functions as a tumor suppressor inhibiting cell proliferation in many cancer types including melanoma. Here we present evidence that a proportion of melanoma cells are nonetheless addicted to CYLD for survival. The expression levels of CYLD varied widely in melanoma cell lines and melanomas in vivo, with a subset of melanoma cell lines and melanomas displaying even higher levels of CYLD than melanocyte lines and nevi, respectively. Strikingly, although short hairpin RNA (shRNA) knockdown of CYLD promoted, as anticipated, cell proliferation in some melanoma cell lines, it reduced cell viability in a fraction of melanoma cell lines with relatively high levels of CYLD expression and did not impinge on survival and proliferation in a third type of melanoma cell lines. The decrease in cell viability caused by CYLD knockdown was due to induction of apoptosis, as it was associated with activation of the caspase cascade and was abolished by treatment with a general caspase inhibitor. Mechanistic investigations demonstrated that induction of apoptosis by CYLD knockdown was caused by upregulation of receptor-interacting protein kinase 1 (RIPK1) that was associated with elevated K63-linked polyubiquitination of the protein, indicating that CYLD is critical for controlling RIPK1 expression in these cells. Of note, microRNA (miR) profiling showed that miR-99b-3p that was predicted to target the 3-untranslated region (3-UTR) of the CYLD mRNA was reduced in melanoma cell lines with high levels of CYLD compared with melanocyte lines. Further functional studies confirmed that the reduction in miR-99b-3p expression was responsible for the increased expression of CYLD in a highly cell line-specific manner. Taken together, these results reveal an unexpected role of CYLD in promoting survival of a subset of melanoma cells and uncover the heterogeneity of CYLD expression and its biological significance in melanoma.
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Kang, Wesuk, Dabin Choi, Soyoon Park, and Taesun Park. "Carvone Decreases Melanin Content by Inhibiting Melanoma Cell Proliferation via the Cyclic Adenosine Monophosphate (cAMP) Pathway." Molecules 25, no. 21 (November 7, 2020): 5191. http://dx.doi.org/10.3390/molecules25215191.
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Melanin, which determines the color of the skin and hair, is initially synthesized to protect the skin from ultraviolet light; however, excessive melanin pigmentation caused by abnormal cell proliferation can result in various melanocytic lesions. Cyclic adenosine monophosphate (cAMP) is known to regulate cell cycle progression and consequently to inhibit the division of abnormally proliferating cells. In this work, we aimed to test whether carvone, a scent compound from plants, inhibits proliferation and subsequently reduces melanin content of melanoma cells and to determine whether its beneficial effects are mediated by the cAMP pathway. We found that carvone decreases melanin content and inhibits melanoma cell proliferation in a concentration-dependent manner. Meanwhile, it inhibited the activation of cell cycle-associated proteins such as cyclin-dependent kinase 1 (CDK1). Of note, the beneficial effects of carvone were abrogated by cAMP inhibition. Our findings indicate potential benefits of carvone for the treatment of melanomas and presumably other hyperpigmentation-related dermatological disorders such as melasmas, lentigines, and excessive freckles.
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Wellbrock, Claudia, and Richard Marais. "Elevated expression of MITF counteracts B-RAF–stimulated melanocyte and melanoma cell proliferation." Journal of Cell Biology 170, no. 5 (August 29, 2005): 703–8. http://dx.doi.org/10.1083/jcb.200505059.
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The protein kinase B-RAF is a human oncogene that is mutated in ∼70% of human melanomas and transforms mouse melanocytes. Microphthalmia-associated transcription factor (MITF) is an important melanocyte differentiation and survival factor, but its role in melanoma is unclear. In this study, we show that MITF expression is suppressed by oncogenic B-RAF in immortalized mouse and primary human melanocytes. However, low levels of MITF persist in human melanoma cells harboring oncogenic B-RAF, suggesting that additional mechanisms regulate its expression. MITF reexpression in B-RAF–transformed melanocytes inhibits their proliferation. Furthermore, differentiation-inducing factors that elevate MITF expression in melanoma cells inhibit their proliferation, but when MITF up-regulation is prevented by RNA interference, proliferation is not inhibited. These data suggest that MITF is an antiproliferation factor that is down-regulated by B-RAF signaling and that this is a crucial event for the progression of melanomas that harbor oncogenic B-RAF.
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Tsai, Alexander, and Eduardo Davila. "A multikinase inhibitor and DNA-PK inhibitor combination reduces tumor growth and alters the tumor microenvironment of B16 melanoma." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 213.2. http://dx.doi.org/10.4049/jimmunol.196.supp.213.2.
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Abstract Recent breakthroughs in targeted therapies and immunotherapies for melanoma have prolonged survival in certain patients. Yet, many patients are not candidates for targeted therapies and response rates to immunotherapies remain low. Thus, there is an unmet need to develop novel melanoma therapies that generate: the high response rates that are characteristic of targeted therapies, the durable responses often observed with immunotherapies, and can be used in a majority of melanoma patients. Therefore, a high-throughput approach evaluating nearly 2,000 compounds was taken to identify FDA-approved therapies that alter the expression of immunologically relevant molecules commonly found on human melanomas. Eight compounds were identified based on their ability to reduce melanoma proliferation without negatively impacting T cell proliferation and function. Studies examining the expression of immunosuppressive molecules on melanoma, melanoma proliferation, and T cell-melanoma co-cultures were used to select a multikinase inhibitor and DNA-PK inhibitor for further investigation. The compounds sensitized melanoma to T cell cytotoxicity which was associated with increased MHC class I and antigen expression. In mice with established B16 tumors, the therapeutic combination significantly reduced tumor growth while prolonging survival. Preliminary data suggests that the drug combination impacts the tumor microenvironment and alters various immune cells present in the tumor. Studies using alternative models of melanomas and additional therapeutic combinations are ongoing. These studies represent a proof of concept demonstrating the ability to repurpose drugs to immunosensitize tumors to T cell-based therapies.
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Lucas, Lauren M., Vipasha Dwivedi, Rania H. Mohamedelhassan, Erin L. Harrell, Connor M. Kelley, Elizabeth L. Knerr, Jessica A. Markham, and David J. Riese. "Abstract 4000: ERBB4 is sufficient and necessary for proliferation of BRAF WT melanoma cell lines." Cancer Research 82, no. 12_Supplement (June 15, 2022): 4000. http://dx.doi.org/10.1158/1538-7445.am2022-4000.
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Abstract Approximately 50% of metastatic melanomas possess wild-type (WT) BRAF alleles. These BRAF-WT tumors are a significant clinical problem, despite the fact that these tumors commonly possess mutations in NF1 or RAS genes, as there are no targeted therapeutics for these tumors. Here we demonstrate that ERBB4 is sufficient and necessary for proliferation of BRAF WT melanoma cell lines, suggesting that disrupting ERBB4 signaling may be effective against BRAF WT melanomas. ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, which includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are validated targets in a variety of solid tumors, whereas the roles that ERBB4 plays in human malignancies are ambiguous. Our previous in silico analyses of BRAF-WT tumor genomes in The Cancer Genome Atlas skin cutaneous melanoma (TCGA-SKCM) dataset suggest that ERBB4 mutation or overexpression cooperates with NF1 or RAS gene mutations to drive melanomas via activation of the PI3 kinase/AKT signaling pathway. These in silico analyses have also enabled us to prioritize the ERBB4 mutants found in BRAF-WT melanomas. We have tested this hypothesis using a panel of human BRAF-WT melanoma cell lines. We have shown that expression of wild-type ERBB4 causes increased clonogenic proliferation, whereas expression of a dominant-negative ERBB4 mutant (K751M) causes decreased clonogenic proliferation. These data indicate that ERBB4 is sufficient and necessary for clonogenic proliferation of BRAF-WT melanoma cell lines. Analgous studies are testing whether ERBB4 regulates anchorage independence in semi-solid medium and proliferation rates and saturation density in culture dishes. The BRAF-WT melanoma cell lines endogenously express ERBB4 ligands, EGFR, and ERBB2. Moreover, ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR and ERBB4-ERBB2 heterodimers are oncogenic. Thus, we are using gene silencing and pharmacologic tools to determine whether endogenous ERBB4 ligands, endogenous EGFR, or endogenous ERBB2 is required for the oncogenic activity of ERBB4. Furthermore, we are determining whether prioritized ERBB4 mutants found in BRAF-WT melanomas exhibit greater signaling and oncogenic activities than WT ERBB4. Consequently, these experiments will establish a functional role for ERBB4 mutations and expression in BRAF-WT melanomas and will identify potential strategies for disrupting oncogenic ERBB4 signaling in these tumors. Citation Format: Lauren M. Lucas, Vipasha Dwivedi, Rania H. Mohamedelhassan, Erin L. Harrell, Connor M. Kelley, Elizabeth L. Knerr, Jessica A. Markham, David J. Riese. ERBB4 is sufficient and necessary for proliferation of BRAF WT melanoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4000.
8
Wang, Shu Jing, Jia Liu, Fei Wang, Ning Chen, Shan Jiang, Lin Liu, Ying Zhao, and Xiao Dan Zhang. "Tumstatin 7 Peptide Affect Biological Activity of B16 Melanoma Cell." Advanced Materials Research 641-642 (January 2013): 915–18. http://dx.doi.org/10.4028/www.scientific.net/amr.641-642.915.
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To study the effect of biological activity of Tumstatin 7 peptide on the cell proliferation and apoptosis of B16 melanoma. Tumstatin 7 peptide was synthesized and its purity is 98.4532% by high-performance liquid chromatography. The effect of 7 peptide on B16 melanoma was observed by MTT, cell growth curve, the observation of the transmission electron microscope (TEM). 7 peptide can significantly inhibit B16 melanoma cell proliferation, showing dose- and time-dependent .Its IC50 was 72.53 μg/ml.The morphology of B16 melanoma cell was obviously changed by TEM, such as karyopyknosis and apoptotic bodies. So7 peptides can inhibit the proliferation of melanoma cells and promote melanoma cells apoptosis. It will be of great potential value to melanoma treatment.
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Henderson, Evita, and Curtis E. Margo. "Iris Melanoma." Archives of Pathology & Laboratory Medicine 132, no. 2 (February 1, 2008): 268–72. http://dx.doi.org/10.5858/2008-132-268-im.
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AbstractThe iris is the least common site of primary uveal melanoma. The prognosis of iris melanoma is better than that of melanoma of the ciliary body and choroid, but the reason for this difference is unclear. One possible explanation is that iris melanoma is smaller than its posterior segment counterparts at the time of diagnosis. Most iris melanomas are spindle cell types, according to a modified Callender classification system. There is evidence that the proliferation of melanocytes of the anterior iris surface (iris plaque) and diffuse stromal invasion may be risk factors for local recurrence and metastasis, respectively.
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Vital, Patrik da Silva, Murilo Bonatelli, Marina Pereira Dias, Larissa Vedovato Vilela de Salis, Mariana Tomazini Pinto, Fátima Baltazar, Silvya Stuchi Maria-Engler, and Céline Pinheiro. "3-Bromopyruvate Suppresses the Malignant Phenotype of Vemurafenib-Resistant Melanoma Cells." International Journal of Molecular Sciences 23, no. 24 (December 9, 2022): 15650. http://dx.doi.org/10.3390/ijms232415650.
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(1) BRAF mutations are associated with high mortality and are a substantial factor in therapeutic decisions. Therapies targeting BRAF-mutated tumors, such as vemurafenib (PLX), have significantly improved the overall survival of melanoma patients. However, patient relapse and low response rates remain challenging, even with contemporary therapeutic alternatives. Highly proliferative tumors often rely on glycolysis to sustain their aggressive phenotype. 3-bromopyruvate (3BP) is a promising glycolysis inhibitor reported to mitigate resistance in tumors. This study aimed to evaluate the potential of 3BP as an antineoplastic agent for PLX-resistant melanoma treatment. (2) The effect of 3BP alone or in combination with PLX on viability, proliferation, colony formation, cell death, migration, invasion, epithelial-mesenchymal marker and metabolic protein expression, extracellular glucose and lactate, and reactive species were evaluated in two PLX-resistant melanoma cell lines. (3) 3BP treatment, which was more effective as monotherapy than combined with PLX, disturbed the metabolic and epithelial-mesenchymal profile of PLX-resistant cells, impairing their proliferation, migration, and invasion and triggering cell death. (4) 3BP monotherapy is a potent metabolic-disrupting agent against PLX-resistant melanomas, supporting the suppression of the malignant phenotype in this type of neoplasia.
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Sun, Ming-xia, Qun An, La-mei Chen, and Ling Guo. "MIR-520f Regulated Itch Expression and Promoted Cell Proliferation in Human Melanoma Cells." Dose-Response 18, no. 2 (April 1, 2020): 155932582091845. http://dx.doi.org/10.1177/1559325820918450.
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Accumulating evidence suggests that abnormal expression and dysfunction of microRNA is involved in development of cancers. However, the function of miR-520f especially in human melanoma remains elusive. In the current study, the underlying function of miR-520f in human melanoma was investigated. Our study demonstrated that the miR-520f level in human melanoma cell lines and clinical tissues was increased. Overexpression of miR-520f promoted cell proliferation by using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation, anchorage-independent growth assay, and 5-bromo-2-deoxyuridine assays. Furthermore, we revealed that miR-520f could interact with circular RNA Itchy E3 ubiquitin protein ligase (ITCH) 3′-untranslated region and suppress ITCH expression in human melanoma cells. The inhibitory effect of miR-520f-in could be partially restored by knockdown of ITCH in human melanoma cells. In summary, this study provides novel insights into miR-520f act as a crucial role in the regulation of human melanoma cell growth via regulating ITCH, which might be a potential biomarker and therapeutic target of human melanoma.
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Wawszczyk, Joanna, Katarzyna Jesse, and Małgorzata Kapral. "Pterostilbene-Mediated Inhibition of Cell Proliferation and Cell Death Induction in Amelanotic and Melanotic Melanoma." International Journal of Molecular Sciences 24, no. 2 (January 6, 2023): 1115. http://dx.doi.org/10.3390/ijms24021115.
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Melanoma is one of the fastest-growing cancers worldwide. Treatment of advanced melanoma is very difficult; therefore, there is growing interest in the identification of new therapeutic agents. Pterostilbene is a natural stilbene that has been found to have several pharmacological activities. The aim of this study was to evaluate the influence of pterostilbene on the proliferation and apoptosis of human melanoma cells. Proliferation of pterostilbene-treated amelanotic (C32) and melanotic (A2058) melanoma cells was determined by BRDU assay. Flow cytometric analyses were used to determine cell cycle progression, and further molecular investigations were performed using real-time RT-qPCR. The expression of the p21 protein and the DNA fragmentation assay were determined by the ELISA method. The results revealed that pterostilbene reduced the proliferation of both amelanotic and melanotic melanoma cells. Pterostilbene induced apoptosis in amelanotic C32 melanoma cells, and this effect was mediated by an increase in the expression of the BAX, CASP9, and CASP9 genes; induction of caspase 3 activity; and DNA degradation. Pterostilbene did not affect the activation of apoptosis in the A2058 cell line. It may be concluded that pterostilbene has anticancer potential against human melanoma cells; however, more studies are still needed to fully elucidate the effects of pterostilbene on amelanotic and melanotic melanoma cells.
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Bartos, V., and A. Farkasova. "Spindle Cell Melanoma Harboring a Nodule of Epitheloid Cell Melanoma Component: A Study of a Diagnostically Challenging Case." Acta Medica Martiniana 21, no. 1 (March 1, 2021): 26–33. http://dx.doi.org/10.2478/acm-2021-0005.
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Abstract Background: Melanoma is a very heterogeneous human neoplasm. In addition to four major (conventional) histologic subtypes a number of uncommon variants do exist. Objective: An unusual case of a spindle cell melanoma (SCM) containing a demarcated nodule of conventional epitheliod cell melanoma component is described. Material and Methods: A 71-year-old man manifested with a protuberated ulcerated skin tumor arising on the right forearm. The resected biopsy was analyzed immunohistochemically with a variety of anti-human antibodies. Results: The tumor consisted of a highly cellular mass of spindle-shaped cells without any significant intratu-moral fibrosis. In addition, a nodule of epithelioid cell tumor component was present within the lesion. The spindle cell component showed a disperse reactivity for S100 protein and was negative for other melanocytic markers. It exhibited a very high mitotic activity and proliferation Ki-67 index. No melanin pigment was detected. In contrast, the epithelioid cell component was strongly positive for S100 protein, Melan-A/MART-1, HMB-45, and PNL-2. The mitotic and proliferation indices were much less pronounced and melanin deposits were visible. A diagnosis of a non-desmoplastic SCM harboring a nodule of epithelioid cell melanoma component was established. Conclusion: SCM often posses a diagnostic dilemma because its histomorphology is atypical and its immunohistochemical profile may differ from other subtypes of melanomas. The present paper points out this uncommon histopathological entity that may sometimes be encountered in dermatopathological practice and that requires more complex diagnostic approach.
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Silwal, Prashanta, and Seung-Kiel Park. "Adenine Inhibits B16-F10 Melanoma Cell Proliferation." Biomedical Science Letters 26, no. 3 (September 30, 2020): 179–85. http://dx.doi.org/10.15616/bsl.2020.26.3.179.
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Goodall, Jane, Claudia Wellbrock, Timothy J. Dexter, Karen Roberts, Richard Marais, and Colin R. Goding. "The Brn-2 Transcription Factor Links Activated BRAF to Melanoma Proliferation." Molecular and Cellular Biology 24, no. 7 (April 1, 2004): 2923–31. http://dx.doi.org/10.1128/mcb.24.7.2923-2931.2004.
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ABSTRACT Malignant melanoma, an aggressive and increasingly common cancer, is characterized by a strikingly high rate (70%) of mutations in BRAF, a key component of the mitogen-activated protein (MAP) kinase signaling pathway. How signaling events downstream from BRAF affect the underlying program of gene expression is poorly understood. We show that the Brn-2 POU domain transcription factor is highly expressed in melanoma cell lines but not in melanocytes or melanoblasts and that overexpression of Brn-2 in melanocytes results in increased proliferation. Expression of Brn-2 is strongly upregulated by Ras and MAP kinase signaling. Importantly, the Brn-2 promoter is stimulated by kinase-activating BRAF mutants and endogenous Brn-2 expression is inhibited by RNA interference-mediated downregulation of BRAF. Moreover, silent interfering RNA-mediated depletion of Brn-2 in melanoma cells expressing activated BRAF leads to decreased proliferation. The results suggest that the high levels of Brn-2 expression observed in melanomas link BRAF signaling to increased proliferation.
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Huang, Siyuan, Zhu Chen, Xiaoqiang Hou, Kuankuan Han, Bingshe Xu, Miao Zhang, Shukai Ding, Yongtao Wang, and Yingjun Yang. "Promotion of Melanoma Cell Proliferation by Cyclic Straining through Regulatory Morphogenesis." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11884. http://dx.doi.org/10.3390/ijms231911884.
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The genotype and phenotype of acral melanoma are obviously different from UV-radiation-induced melanoma. Based on the clinical data, mechanical stimulation is believed to be a potential cause of acral melanoma. In this case, it is desirable to clarify the role of mechanical stimulation in the progression of acral melanoma. However, the pathological process of cyclic straining that stimulates acral melanoma is still unclear. In this study, the influence of cyclic straining on melanoma cell proliferation was analyzed by using a specifically designed cell culture system. In the results, cyclic straining could promote melanoma cell proliferation but was inefficient after the disruption of cytoskeleton organization. Therefore, the mechanotransduction mechanism of promoted proliferation was explored. Both myosin and actin polymerization were demonstrated to be related to cyclic straining and further influenced the morphogenesis of melanoma cells. Additionally, the activation of mechanosensing transcription factor YAP was related to regulatory morphogenesis. Furthermore, expression levels of melanoma-involved genes were regulated by cyclic straining and, finally, accelerated DNA synthesis. The results of this study will provide supplementary information for the understanding of acral melanoma.
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Oria, Victor, Hongyi Zhang, Huifang Zhu, Gang Deng, Christopher Zito, Chetan Rane, Shenqi Zhang, et al. "19. PLEKHA5 REGULATES TUMOR GROWTH IN METASTATIC MELANOMA." Neuro-Oncology Advances 2, Supplement_2 (August 2020): ii3. http://dx.doi.org/10.1093/noajnl/vdaa073.009.
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Abstract Understanding the mechanisms behind melanoma brain metastasis, a disease that continues to portend a poor prognosis, will lead to the identification and development of novel drug targets. We previously identified PLEKHA5, a gene involved in brain development, as a novel molecule implicated in melanoma brain metastasis. Our aim was to further characterize the function of this protein in brain-tropic melanoma. We established stable loss- and gain-of-function cell lines to explore the underlying mechanisms of PLEKHA5-mediated tumor growth. The effect of PLEKHA5 expression silencing on proliferation and tumor growth was assessed using both in vitro systems and xenograft models of brain-tropic melanomas, respectively. The clinical relevance of PLEKHA5 dysregulation in brain metastasis was also investigated in two unique cohorts of melanoma patients with cerebrotropic disease and included analysis of matched cranial and extra-cranial specimens. Knock-down of PLEKHA5 in brain-tropic melanoma cells negatively regulated cell proliferation by inhibiting G1 to S cell cycle transition. This coincided with up-regulation of PDCD4, p21, and p27, as well as the downregulation of pRb protein, involved in the regulation of cell cycle. Conversely, the ectopic re-expression of PLEKHA5 had an inverse effect. Subcutaneous and direct cranial injections of PLEKHA5 knock-down cells in nude mice significantly inhibited tumor growth, while its overexpression upregulated the growth of tumors. This reduction in tumor growth in vivo might be attributed to decreased phosphorylation of Akt (S473) and mTOR (S2448), key mediators for tumor growth and survival. Our results demonstrate the role of PLEKHA5 as a mediator of melanoma brain metastasis. Our findings highlight the significance of PLEKHA5 as a possible regulator of cell cycle transition via crosstalk with the ubiquitin-proteasome and PI3K/AKT/mTOR signaling pathways, driving the proliferation and growth of brain-tropic melanomas. Our studies suggest that PLEKHA5 targeting should be further investigated for melanoma brain metastasis patient population.
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Osta, Erica, Harshita B. Gupta, Deyi Zhang, Anand Kornepati, Curtis A. Clark, and Tyler J. Curiel. "Tumor cell-intrinsic programmed death protein 1 expression and induction in human cancer cell lines." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 178.33. http://dx.doi.org/10.4049/jimmunol.200.supp.178.33.
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Abstract The programmed death protein 1 (PD-1) and ligand (PD-L1) axis inhibits T cell activation and reduces anti-tumor immunity. Most studies of the PD-1/PD-L1 axis test extrinsic, immune-dependent effects. However, tumor cell-intrinsic PD-L1 regulates immune-independent tumor mTOR signals, autophagy, and tumor initiating cell generation. Melanoma cell-intrinsic PD-1 regulates melanoma growth and mTOR. We tested PD-1 expression and induction in multiple human tumor cell lines. We detected PD-1 in human cell lines in vitro from ES2 ovarian cancer, VMM122 melanoma, and RT4 bladder cancer by flow cytometry, Western blot and RT-PCR. All lines were negative for the other PD-L1 receptor, CD80, by flow cytometry. Incubating lines with IFNα or IFNγ for 48 hours further augmented PD-1 expression as detected by flow, Western blot and RT-PCR. αPD-1 antibody (50 μg/ml) reduced proliferation of RT4 bladder cancer cells in vitro, demonstrating a direct PD-1 signal effect in these cells, and αPD-L1 similarly reduced in vitro proliferation. Interestingly, anti-PD-1 effects on reducing proliferation were similar: 41.5% reduction; p<0.0001. We used CRISPR/Cas9 to generate PD-L1KO RT4 cells. αPD-L1 did not reduce in vitro proliferation as expected, but unexpectedly, αPD-1 also had no anti-proliferative effect on PD-L1KO RT4 cells, suggesting a PD-L1/PD-1 interaction. In murine B16 melanoma, we generated PD-L1KO and PD-1KO cells using CRISPR/Cas9. Cell-intrinsic PD-L1 and PD-1 downregulate chemokine production. Among chemokines analyzed, PD-L1 suppressed CCL2 and CCL5, PD-1 suppressed CCL4 and CCL7, and both suppressed CCL3 and CXCL2. Understanding intrinsic PD-1 and PD-L1 effects on tumor cells can be exploited to improve cancer immunotherapy
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Moreno, Ana Carolina Ramos, Renata de Freitas Saito, Manoela Tiago, Renato Ramos Massaro, Roberta Liberato Pagni, Rafael Pegoraro, Patrícia da Cruz Souza, et al. "Melatonin inhibits human melanoma cells proliferation and invasion via cell cycle arrest and cytoskeleton remodeling." Melatonin Research 3, no. 2 (June 1, 2020): 194–209. http://dx.doi.org/10.32794/mr11250057.
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Among skin cancers,
melanoma has the highest mortality rate. The heterogeneous genetic melanoma
background leads to a tumor-propagating capacity particularly important in
maintaining therapeutic resistance, and tumor recurrence. The identification of
efficient molecules able to control melanoma progress represents an important
opportunity for new therapeutic strategies, particularly in combination with the
current standard-of-care treatments. In this context,
several studies have reported the antitumor effects of melatonin against
different types of cancer, including melanoma. Here,
we describe the underlying mechanisms associated with melatonin’s activity in
human melanoma cell lines, focusing on cell cycle and cytoskeleton
remodeling. Interestingly, while melatonin induced melanocyte
DNA replication, melanoma cells exhibited cell cycle arrest in the G1-phase.
This phenomenon was associated with cyclin-D1 downregulation or p21
overexpression. The efficacy of melatonin on melanoma cells survival and
proliferation was detected using the clonogenic assay, with a decrease in both
the number and size of colonies. Additionally, melatonin induced a dramatic
cytoskeleton remodeling in all melanoma cell lines, leading to a star-like
morphology or cell swelling. The role of melatonin on melanoma cytoskeleton was
associated with the actin disruption, with thinning and/or broken actin fibers,
and weak and/or loss of paxillin along stress fibers. These data support the
observed findings that melatonin impairs melanoma invasion in skin
reconstructed models. Together, our results suggest that melatonin could be
used to control melanoma growth and support basic and
clinical studies on melatonin as a promising immunometabolic
adjuvant for melanoma therapy.
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Nguyen, Hai Duong, You-Cheng Liao, Yuan-Soon Ho, Li-Ching Chen, Hui-Wen Chang, Tzu-Chun Cheng, Donald Liu, et al. "The α9 Nicotinic Acetylcholine Receptor Mediates Nicotine-Induced PD-L1 Expression and Regulates Melanoma Cell Proliferation and Migration." Cancers 11, no. 12 (December 11, 2019): 1991. http://dx.doi.org/10.3390/cancers11121991.
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Cigarette smoking is associated with an increased risk of melanoma metastasis. Smokers show higher PD-L1 expression and better responses to PD-1/PD-L1 inhibitors than nonsmokers. Here, we investigate whether nicotine, a primary constituent of tobacco, induces PD-L1 expression and promotes melanoma cell proliferation and migration, which is mediated by the α9 nicotinic acetylcholine receptor (α9-nAChR). α9-nAChR overexpression in melanoma using melanoma cell lines, human melanoma tissues, and assessment of publicly available databases. α9-nAChR expression was significantly correlated with PD-L1 expression, clinical stage, lymph node status, and overall survival (OS). Overexpressing or knocking down α9-nAChR in melanoma cells up- or downregulated PD-L1 expression, respectively, and affected melanoma cell proliferation and migration. Nicotine-induced α9-nAChR activity promoted melanoma cell proliferation through stimulation of the α9-nAChR-mediated AKT and ERK signaling pathways. In addition, nicotine-induced α9-nAchR activity promoted melanoma cell migration via activation of epithelial-mesenchymal transition (EMT). Moreover, PD-L1 expression was upregulated in melanoma cells after nicotine treatment via the transcription factor STAT3 binding to the PD-L1 promoter. These results highlight that nicotine-induced α9-nAChR activity promotes melanoma cell proliferation, migration, and PD-L1 upregulation. This study may reveal important insights into the mechanisms underlying nicotine-induced melanoma growth and metastasis through α9-nAChR-mediated carcinogenic signals and PD-L1 expression.
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Cullum, Richard L., Lauren M. Lucas, Jared I. Senfeld, John T. Piazza, Logan T. Neel, Kanupriya Whig, Ling Zhai, et al. "Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics." PLOS ONE 15, no. 12 (December 30, 2020): e0243901. http://dx.doi.org/10.1371/journal.pone.0243901.
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Whereas recent clinical studies report metastatic melanoma survival rates high as 30–50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2β) functions as a partial agonist at ErbB4. NRG2β/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z’ > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors.
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Lee, Cheol-Jung, Hyun-Jung An, Seung-Min Kim, Sun-Mi Yoo, Juhee Park, Ga-Eun Lee, Woo-Young Kim, et al. "FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation." Proceedings of the National Academy of Sciences 117, no. 1 (December 16, 2019): 584–94. http://dx.doi.org/10.1073/pnas.1909879116.
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In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3β-mediated STAT2 phosphorylation facilitated STAT2–FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.
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Souza Sobrinho, Celestino Prospero de, Alfredo Gragnani, Ivan Dunshee Abranches Oliveira Santos, Andrea Fernandes Oliveira, Monica Vanucci Nunes Lipay, and Lydia Masako Ferreira. "AZT on telomerase activity and cell proliferation in HS 839.T melanoma cells." Acta Cirurgica Brasileira 27, no. 12 (December 2012): 855–60. http://dx.doi.org/10.1590/s0102-86502012001200005.
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PURPOSE: To evaluate telomerase activity and proliferation of HS839.T melanoma cells, subjected to the action of AZT. METHODS: Cells were grown in triplicate, AZT at different concentrations: 50, 100 and 200μM, was added and left for 24 and 48 hours, and its effects were compared with the control group. Telomerase activity was detected by PCR and cell proliferation was evaluated by MTT. RESULTS: After 24 hours, there was no inhibition of cell proliferation or telomerase activity when compared to the control group. After 48 hours, there was a momentary decrease, suggesting that the cell lines used in this study are sensitive to AZT, but quickly recover both the enzyme activity and cell proliferation. CONCLUSION: The action of AZT on the melanoma cells studied, at the concentrations and times tested, did not inhibit telomerase activity nor affect cell proliferation.
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Hua, Huaikang, and Huifang Yang. "Centrosomal protein55 enhances melanoma cell proliferation, invasion and migration through PI3K/AKT signaling." Tropical Journal of Pharmaceutical Research 21, no. 10 (November 3, 2022): 2065–70. http://dx.doi.org/10.4314/tjpr.v21i10.4.
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Purpose: To investigate the role of centrosomal protein55 (CEP55) in melanoma.
Methods: The CEP55 expression in human melanoma cells and normal human melanocytes were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation was evaluated by colony formation and CCK8 assays, while cell cycle was assessed by flow cytometry. Transwell assay was used to investigate cell migration and invasion.
Results: The CEP55 protein expression was higher in A-2058 and A375 melanoma cells than in normal HEMn-LP cells. Overexpression of CEP55 increased melanoma cell viability and the number of melanoma cell colonies (p < 0.01), while CEP55 silencing reduced melanoma cell viability and proliferation. Overexpression of CEP55 promoted cell cycle (p < 0.01) via decreased p21 expression, but increased CyclinD1 and CDK1 expression. Knockdown of CEP55 enhanced p21 expression and reduced CyclinD1 and CDK1 expression to induce cell cycle arrest. Knockdown of CEP55 suppressed melanoma cell migration and invasion by downregulating p-AKT and p-PI3K.
Conclusion: Centrosomal protein55 functions as an oncogene in melanoma by activating PI3K/AKT signaling. Therefore, CEP55 might be a promising target for melanoma diagnosis and treatment.
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Kwan, Hiu Yee, Xiuqiong Fu, Bin Liu, Xiaojuan Chao, Chi Leung Chan, Huihui Cao, Tao Su, Anfernee Kai Wing Tse, Wang Fun Fong, and Zhi-Ling Yu. "Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway." Journal of Biological Chemistry 289, no. 44 (September 16, 2014): 30525–37. http://dx.doi.org/10.1074/jbc.m114.593210.
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Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY® FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt.
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Caré, A., A. Silvani, E. Meccia, G. Mattia, A. Stoppacciaro, G. Parmiani, C. Peschle, and M. P. Colombo. "HOXB7 constitutively activates basic fibroblast growth factor in melanomas." Molecular and Cellular Biology 16, no. 9 (September 1996): 4842–51. http://dx.doi.org/10.1128/mcb.16.9.4842.
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Homeobox (HOX) genes control axial specification during mammalian development and also regulate skin morphogenesis. Although selected HOX genes are variably expressed in leukemias and kidney and colon cancer cell lines, their relationship with the neoplastic phenotype remains unclear. In both normal development and neoplastic transformation, HOX target genes are largely unknown. We investigated the expression and function of HOXB cluster genes in human melanoma. The HOXB7 gene was constitutively expressed in all 25 melanoma cell lines and analyzed under both normal and serum-starved conditions, as well as in in vivo primary and metastatic melanoma cells; conversely, HOXB7 was expressed in proliferating but not quiescent normal melanocytes. Treatment of melanoma cell lines with antisense oligomers targeting HOXB7 mRNA markedly inhibited cell proliferation and specifically abolished expression of basic fibroblast growth factor (bFGF) mRNA. Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter. These novel findings indicate a key role for constitutive HOXB7 expression in melanoma cell proliferation via bFGF. The results also raise the possibility that growth factor genes are critical HOX target genes in other developmental and/or neoplastic cell systems.
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Brar, Sukhdev S., Thomas P. Kennedy, Anne B. Sturrock, Thomas P. Huecksteadt, Mark T. Quinn, A. Richard Whorton, and John R. Hoidal. "An NAD(P)H oxidase regulates growth and transcription in melanoma cells." American Journal of Physiology-Cell Physiology 282, no. 6 (June 1, 2002): C1212—C1224. http://dx.doi.org/10.1152/ajpcell.00496.2001.
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Malignant melanoma cells spontaneously generate reactive oxygen species (ROS) that promote constitutive activation of the transcription factor nuclear factor-κB (NF-κB). Although antioxidants and inhibitors of NAD(P)H oxidases significantly reduce constitutive NF-κB activation and suppress cell proliferation (11), the nature of the enzyme responsible for ROS production in melanoma cells has not been determined. To address this issue, we now have characterized the source of ROS production in melanoma cells. We report that ROS are generated by isolated, cytosol-free melanoma plasma membranes, with inhibition by NAD(P)H oxidase inhibitors. The p22phox, gp91phox, and p67phoxcomponents of the human phagocyte NAD(P)H oxidase and the gp91phoxhomolog NOX4 were demonstrated in melanomas by RT-PCR and sequencing, and protein product for both p22phoxand gp91phoxwas detected in cell membranes by immunoassay. Normal human epidermal melanocytes expressed only p22phoxand NOX4. Melanoma proliferation was reduced by NAD(P)H oxidase inhibitors and by transfection of antisense but not sense oligonucleotides for p22phoxand NOX4. Also, the flavoprotein inhibitor diphenylene iodonium inhibited constitutive DNA binding of nuclear protein to the NF-κB and cAMP-response element consensus oligonucleotides, without affecting DNA binding activity to activator protein-1 or OCT-1. This suggests that ROS generated in autocrine fashion by an NAD(P)H oxidase may play a role in signaling malignant melanoma growth.
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Reigstad, Agathe, Christina Frantzen Herdlevær, Emma Rigg, Tuyen Hoang, Ole Vidhammer Bjørnstad, Synnøve Nymark Aasen, Jasmin Preis, Claude Haan, Terje Sundstrøm, and Frits Thorsen. "CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells." PLOS ONE 17, no. 9 (September 9, 2022): e0273711. http://dx.doi.org/10.1371/journal.pone.0273711.
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Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18–2.6 μM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis.
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Jani, Aditi, Sandeep Chaudhary, Zorica Janjetovic, Mohammad A. Sherwani, Nabiha Yusuf, Andrzej Slominski, Mohammad Athar, and Craig Elmets. "2349 The role of interleukin-23 in human melanoma." Journal of Clinical and Translational Science 2, S1 (June 2018): 32. http://dx.doi.org/10.1017/cts.2018.135.
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OBJECTIVES/SPECIFIC AIMS: Interleukin-23 (IL-23) promotes differentiation of naïve T-cells into Th17 cells, which drive the pathogenesis of autoinflammatory conditions such as psoriasis. IL-23-neutralizing antibody therapies are now in use for treatment of psoriasis, with promising results. Studies in mice have shown that IL-23 plays a role in inhibiting the growth, progression, and metastasis of melanomas. Thus, therapeutic neutralization of IL-23 in patients may inadvertently increase their susceptibility to development of melanoma. In this study, we aim to characterize expression of IL-23 receptors (IL-23R) in human melanocytes and melanoma cells and tissue and to study the effect of IL-23 on growth, proliferation, and tumorigenicity of these cells. METHODS/STUDY POPULATION: IL-23R expression was characterized using immunofluorescence staining, Western blot, and flow cytometric analysis. Response of melanoma and melanocytes to recombinant IL-23 treatment will be studied through similar methods in addition to assays of cell proliferation and tumorigenicity. RESULTS/ANTICIPATED RESULTS: Preliminary immunofluorescence staining and flow cytometry results indicate that both human melanoma and primary melanocytes express IL-23 receptors. Western blot analysis showed that melanoma cell line A375 expressed nearly twice the amount of IL-23R versus normal melanocytes (p<0.05). Based on previous studies, we anticipate that addition of recombinant IL-23 to cultures of melanoma will reduce proliferative potential, and we expect similar addition to normal melanocytes will increase DNA repair mechanisms. DISCUSSION/SIGNIFICANCE OF IMPACT: In showing that human melanocytes and melanoma cells express IL-23 receptors, and potentially showing the inhibitory effect of IL-23 in the development of melanocytic neoplasms, our findings imply that using IL-23 neutralizing therapies may increase risk of developing melanoma, especially in patients who are already susceptible. As such, these therapies must be used with great care in these patients.
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Kaufmann, Simone, Silke Kuphal, Thomas Schubert, and Anja K. Bosserhoff. "Functional Implication of Netrin Expression in Malignant Melanoma." Analytical Cellular Pathology 31, no. 6 (January 1, 2009): 415–22. http://dx.doi.org/10.1155/2009/954172.
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Background: Malignant melanoma cells are known to have altered expression of genes supporting proliferation and invasion, however, the expression of molecules of the Netrin family of repellent factors has not been analyzed in melanomas until now.Results: Here, we show that Netrin-1 expression is strongly induced in melanoma cells compared to melanocytes in vivo and in vitro controlled at the transcriptional level via ETS-1. In addition, the expression of the netrin receptor UNC5B was induced and that of UNC5C was reduced in the tumor cells. In order to determine the functional relevance of Netrin-1 expression in malignant melanoma, Netrin expression in melanoma cells was reduced by siRNA attempts and primary human melanocytes were treated with recombinant Netrin-1. The cells showed no changes in proliferation or apoptosis, however, a strong reduction of migratory properties was observed in the melanoma cells after reduction of Netrin expression whereas melanocyte migration was strongly induced by treatment with Netrin.Conclusions: Our study suggests that Netrin-1 promotes melanoma cell invasion and migration and therefore has an important role in the progression of malignant melanoma.
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Chen, Xiangjun, Guozhen Gao, Sha Liu, Li Yu, Dexiong Yan, Xingwei Yao, Weijing Sun, Dezhi Han, and Hao Dong. "Long Noncoding RNA PVT1 as a Novel Diagnostic Biomarker and Therapeutic Target for Melanoma." BioMed Research International 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/7038579.
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Accumulating evidences indicated that plasmacytoma variant translocation 1 (PVT1) plays vital roles in several cancers. However, the expression, functions, and clinical values of PVT1 in melanoma are still unknown. In this study we measured the expression of PVT1 in clinical tissues and serum samples and explored the diagnostic value of PVT1 for melanoma and the effects of PVT1 on melanoma cell proliferation, cell cycle, and migration. Our results, combined with publicly available PVT1 expression data, revealed that PVT1 is upregulated in melanoma tissues compared with nonneoplastic nevi tissues. Serum PVT1 level is significantly increased in melanoma patients compared with age and gender-matched nonmelanoma controls with melanocytic nevus. Receiver operating characteristic curve analyses revealed that serum PVT1 level could sensitively discriminate melanoma patients from controls. Furthermore, serum PVT1 level indicted melanoma dynamics. Functional experiments showed that overexpression of PVT1 promotes melanoma cells proliferation, cell cycle progression, and migration, while depletion of PVT1 significantly inhibits melanoma cells proliferation, cell cycle progression, and migration. Collectively, our results indicate that PVT1 functions as an oncogene in melanoma and could be a potential diagnostic biomarker and therapeutic target for melanoma.
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Cui, Aili, Zhehu Jin, Zhonggao Gao, Mingji Jin, Lianhua Zhu, Lianhua Li, Chenglong Jin, and Yinghua An. "Downregulation of miR-493 promoted melanoma proliferation by suppressing IRS4 expression." Tumor Biology 39, no. 5 (May 2017): 101042831770164. http://dx.doi.org/10.1177/1010428317701640.
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Accumulating evidence indicated that aberrantly expressed microRNAs play critical roles in the initiation and progression of human cancers. However, the underlying functions of miR-493 in human melanoma remains unknown. Here, our study found that miR-493 expression was downregulated in human melanoma tissues and cells. Overexpression of miR-493 suppressed cell proliferation and cell cycle in human melanoma cell line A375. IRS4 was defined as a target for downregulation by miR-493 and was confirmed by luciferase assay. We also found that knockdown of IRS4 counteracted the proliferation promotion by miR-493 inhibitor. In summary, these results demonstrated that miR-493 acts as a tumor suppressor and inhibits cell proliferation and cell cycle in human melanoma by directly targeting IRS4.
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Wong, Ronald P. C., Almass-houd Aguissa-Touré, Aijaz A. Wani, Shahram Khosravi, Michal Martinka, Magdalena Martinka, and Gang Li. "Elevated expression of Rad18 regulates melanoma cell proliferation." Pigment Cell & Melanoma Research 25, no. 2 (January 12, 2012): 213–18. http://dx.doi.org/10.1111/j.1755-148x.2011.00948.x.
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Jin, Cheng, Dake Dong, Zhen Yang, Rushan Xia, Shiqin Tao, and Meishan Piao. "CircMYC Regulates Glycolysis and Cell Proliferation in Melanoma." Cell Biochemistry and Biophysics 78, no. 1 (December 6, 2019): 77–88. http://dx.doi.org/10.1007/s12013-019-00895-0.
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Tang, Liren, Mingwan Su, Yi Zhang, Wency Ip, Magdalena Martinka, Changzheng Huang, and Youwen Zhou. "Endothelin-3 Is Produced by Metastatic Melanoma Cells and Promotes Melanoma Cell Survival." Journal of Cutaneous Medicine and Surgery 12, no. 2 (March 2008): 64–70. http://dx.doi.org/10.2310/7750.2008.06164.
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Background: Endothelin-3 (ET-3) is an essential paracrine factor for the proliferation, migration, and survival of embryonic melanocytes during fetal development. Its expression is tightly regulated, being completely turned off in adult skin. Objective: In this study, results are presented that demonstrate abnormal expression of ET-3 by metastatic melanoma cells in both tissue biopsies and cell culture. Further, in vitro experiments showed that metastatic melanoma cells have the capacity to respond to ET-3 stimulation by increasing survival. Conclusion: Therefore, an abnormal autocrine stimulation pathway involving ET-3 is present in metastatic melanoma cells. Blocking this signal transduction pathway may prove useful for the treatment of metastatic melanoma.
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Lucas, Lauren M., Richard L. Cullum, Jared I. Senfeld, Laura J. Cook, Mackenzie H. Harris, David Z. Kaufmann, Cristina C. Rael, et al. "Abstract A19: Discovery and characterization of selective and nonselective inhibitors of ErbB4 signaling: Putative targeted melanoma therapeutics." Cancer Research 80, no. 19_Supplement (October 1, 2020): A19. http://dx.doi.org/10.1158/1538-7445.mel2019-a19.
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Abstract Introduction: Gain-of-function mutations in the gene that encodes the ErbB4 receptor tyrosine kinase have been found in a significant fraction of melanoma samples. Melanoma cell lines that harbor some of these mutations are dependent on ErbB4 for proliferation. However, there is a scarcity of therapeutics for treating these ErbB4-dependent melanomas. Our drug discovery approach is based on the observation that the Q43L mutant of the ErbB4 agonist Neuregulin 2beta (NRG2b) functions as a partial agonist/antagonist at ErbB4. NRG2b/Q43L stimulates ErbB4 tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and competitively antagonizes agonist stimulation of ErbB4-dependent cell proliferation. ErbB4 partial agonists that function as antagonists at ErbB4 may hold promise as targeted therapeutics for ErbB4-dependent melanomas. Experimental Procedures: Automated, high-throughput phospho-ErbB4 sandwich ELISA and ErbB4-dependent proliferation assays were developed and deployed to identify 19 small-molecule compounds that stimulate ErbB4 tyrosine phosphorylation, yet inhibit ErbB4-dependent cell proliferation. These compounds were prioritized on the basis of their potency, efficacy, and specificity for inhibition of ErbB4-dependent proliferation. Traditional immunoblotting approaches specific to candidate proteins have been deployed to identify targets for hit molecules of interest. Data: The single high-priority candidate (AU-05) inhibits agonist-induced ErbB4-dependent cellular proliferation with an IC50 of 6.8 uM, but inhibits IL3-dependent proliferation with an IC50 of ~2100 uM, suggesting that AU-05 possesses specificity for ErbB4-dependent proliferation. In contrast, AU-39 potently inhibits both ErbB4-dependent cell proliferation with an IC50 of 1.05 nM and IL3-dependent cellular proliferation with an IC50 of 2.61 nM. We have hypothesized that AU-39 targets the PI3K/Akt signaling pathway, which lies downstream of both ErbB4 and the IL3 receptor. We are testing this hypothesis in part by examining the effects of AU-39 on agonist-induced ErbB4 and IL3 receptor coupling to phosphorylation of Akt and other components of the PI3K/Akt pathway. Conclusions: AU-05 is a starting point for the development of specific ErbB4 inhibitors, whereas AU-39 is a candidate inhibitor of the PI3K/Akt signaling pathway. The inhibition of ErbB4-dependent cellular proliferation by these molecules justifies further development of both molecules. Citation Format: Lauren M. Lucas, Richard L. Cullum, Jared I. Senfeld, Laura J. Cook, Mackenzie H. Harris, David Z. Kaufmann, Cristina C. Rael, Darby C. Taylor, John T. Piazza, Logan T. Neel, Ram B. Gupta, Allan E. David, David J. Riese II. Discovery and characterization of selective and nonselective inhibitors of ErbB4 signaling: Putative targeted melanoma therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A19.
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Piérard, G. E. "Cell Proliferation in Cutaneous Malignant Melanoma: Relationship with Neoplastic Progression." ISRN Dermatology 2012 (January 11, 2012): 1–12. http://dx.doi.org/10.5402/2012/828146.
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The establishment of the diagnosis of cutaneous malignant melanoma (CMM) always calls for histopathological confirmation. Further to the recognition of the CMM aspects, immunohistochemistry is helpful, in particular, in determining the size of the replicative compartment and the activity in each of the cell cycle phases (G1, S, G2, M). The involvement of cancer stem cells and transient amplifier cells in CMM genesis is beyond doubt. The proliferation activity is indicative of the neoplastic progression and is often related to the clinical growth rate of the neoplasm. It allows to distinguish high-risk CMM commonly showing a high growth rate, from those CMMs of lower malignancy associated with a more limited growth rate. The recruitment and progression of CMM cells in the cell cycle of proliferation depend on mitogen-activated protein kinase (MAPK) pathway and result from a loss of control normally involving a series of key regulatory cyclins. In addition, the apoptotic pathways potentially counteracting any excess in proliferative activity are out of the dependency of specific regulatory molecular mechanisms. Key molecular components involved in the deregulation of the growth fraction, the cell cycle phases of proliferation, and apoptosis are presently described in CMM.
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Lee, John A. H. "The Determination of Melanoma Stage at Diagnosis." Dermatology Research and Practice 2010 (2010): 1–3. http://dx.doi.org/10.1155/2010/839829.
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The rising proportion of melanomas diagnosed at an early pathologic stage is commonly ascribed to better public education. However in the US SEER program of cancer registration it has been found that the rates forin situmelanomas are closely related by a log linear relationship to the incidence of invasive melanomas and that this relationship is unrelated to calendar year or gender or patient age. This relationship is sufficiently strong to leave little room for other factors. The relationship may be different in populations with different melanoma rates and responses to them. It is suggested that the results are due to variations within populations of individual response to melanoma cell proliferation.
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Glenn, Sean, Sarabjot Pabla, Shumei Kato, Erik Van Roey, Jeffrey M. Conroy, Yirong Wang, Mary Nesline, et al. "Inflammation and cell proliferation signatures: Implications for response to immune checkpoint inhibition therapies." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): 67. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.67.
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67 Background: Progress in unraveling the complex tumor immune microenvironment (TIME) has aided our understanding of the host immune response to ICI therapies. To gain further insight, we associate a 160-gene tumor inflammation signature (TIS) with cell proliferation status and response to ICI. Methods: 242 FFPE tumor samples from lung, RCC and melanoma were evaluated by RNA-seq to measure expression levels of 394 immune related genes. TIS (weak, moderate, strong) and cell proliferation status (poor, moderate, high) were determined by algorithmic analysis of selected gene pathways. All cases were evaluated for association with ORR to ICIs using RECIST criterion. Furthermore, 13 pre-post ICI treated biopsy pairs were studied to understand the dynamics of these signatures following treatment. Results: In both weakly and moderately inflamed tumors, ORR was highest in moderately proliferative tumors 32.6% (15/46) and 37.8% (14/37), respectively (Table). Surprisingly, in strongly inflamed tumors, both highly and moderately proliferative tumors had a high response rate of 55% (11/20) and 43.2% (16/37), whereas poorly proliferative tumors have a significantly lower response rate of 12.5% (3/24; p= 0.03). 6 of 13 pre-post ICI treated cases demonstrated increased inflammation post treatment, with 83% (5/6) demonstrating concurrent decrease in cell proliferation. Conclusions: Together, TIS and cell proliferation predict response to ICI in NSCLC, RCC and melanoma. The data suggests that in strongly inflamed and highly proliferative tumors, the cell proliferation signal could be attributed to antigen stimulated T-cell proliferation, whereas in other categories of inflammation, moderately proliferative tumors contain signal from both immune cells and tumor cells. Further studies are required to determine the relationship between these signatures in hot and cold tumors. [Table: see text]
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Collard, Marianne, George Chen, Hyeon Jeong Lee, Zhicong Chen, Ji-Xen Cheng, Muzhou Wu, and Rhoda Alani. "Mitochondrial Fatty Acid Oxidation Is Not Vital for Melanoma Cell Proliferation and Migration." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 314. http://dx.doi.org/10.1093/cdn/nzaa044_013.
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Abstract Objectives Melanoma, the 5th most common cancer in the US, is the most aggressive form of skin cancer. Excess adiposity is associated with an increased risk of melanoma in males, and a high-fat diet promotes melanoma tumor growth in mice. Our group found that lipid droplet (LD) content increases with melanoma cell aggressiveness and that fatty acid uptake inhibition reduces cell proliferation and migration; however, the function of these lipids in melanoma is unknown. Since lipids can be used to produce energy by fatty acid oxidation (FAO), we sought to determine whether melanoma cells were using FAO to maintain aggressiveness. Methods Gene expression microarray was used to identify differences in gene expression, which was confirmed by RT-qPCR. WM983A, WM983B, 1205Lu and A375 human melanoma cells were treated with 5 µM Etomoxir and cell proliferation, migration, and respiration were quantified using the Quant-iT™ PicoGreen™ dsDNA Assay Kit, Boyden Chamber transwell migration, and Seahorse XFe96 Flux Analyzer, respectively. Results The most significantly altered genes expressed between four invasive, lipid-rich and four non-invasive, lipid-poor melanoma cells pertained to fatty acid metabolism. Carnitine palmitoyltransferase 1A (CPT1a), the rate limiting enzyme in mitochondrial FAO (mFAO), mRNA was increased in lipid-rich cells compared to the lipid-poor cells (p < 0.05, n = 6–7), indicating that melanoma cells may use LD lipids for mFAO. To determine the importance of mFAO to melanoma cells, we inhibited mFAO with etomoxir, an irreversible CPT1 inhibitor. Treatment of lipid-rich 1205Lu and A375 cells or lipid-poor WM983A and WM983B cells with etomoxir for 4 days had no effect on cell proliferation. Extracellular flux analysis of cells with or without etomoxir showed no difference in ATP production, indicating that melanoma cells do not use mFAO to generate energy under normal conditions. In motile cells, etomoxir reduced lipid-rich A375 cell migration by 8.8% (p = 0.05, n = 2). Conclusions Lipids play a role in melanoma aggressiveness; however, our results indicate that mFAO of lipids is not vital to melanoma cell proliferation or migration. Further studies are required to understand the implication of excess adiposity and circulating lipids in melanoma development and progression. Funding Sources Institutional Department Fund
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Shi, Quan, Qi He, and Jing Wei. "MicroRNA-342 Prohibits Proliferation and Invasion of Melanoma Cells by Directly Targeting Zinc-Finger E-Box-Binding Homeobox 1." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 26, no. 9 (October 17, 2018): 1447–55. http://dx.doi.org/10.3727/096504018x15193823766141.
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As documented in numerous studies, microRNAs (miRNAs) play key roles in various biological processes associated with melanoma occurrence and development. In this study, we found that miRNA-342 (miR-342) was significantly downregulated in melanoma tissues and cell lines. Additionally, the ectopic expression of miR-342 prohibited the cell proliferation and invasion of melanoma. Moreover, zinc-finger E-box-binding homeobox 1 (ZEB1) was identified as a direct target gene of miR-342 in melanoma. Similar with the results induced by miR-342 overexpression, ZEB1 knockdown attenuated cell proliferation and invasion in melanoma. Furthermore, the restoration of ZEB1 expression reversed the suppressive effects of miR-342 on the proliferation and invasion of melanoma cells. These findings suggest that miR-342 may play tumor-suppressing roles in melanoma, at least partially, by directly inhibiting ZEB1 expression. Therefore, miR-342 may be developed as a potential candidate for the treatment of patients with this aggressive type of cancer.
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Jiang, Zhongming, Yuexiang Yan, Juan Dong, and Lingling Duan. "PD-1 expression on uveal melanoma induces tumor proliferation and predicts poor patient survival." International Journal of Biological Markers 35, no. 3 (July 18, 2020): 50–58. http://dx.doi.org/10.1177/1724600820943610.
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Introduction: Uveal melanoma is one of the most common primary intraocular malignant tumors with poor prognosis and limited treatments. Programmed cell death receptor-1 (PD-1) blockade represents the primary treatment strategy of immune checkpoint inhibition; however, there is a lack of studies on whether PD-1 expression in primary (ocular) uveal melanoma affects tumor progression. Methods: PD-1 expression in 82 cases of primary (ocular) uveal melanoma was detected by immunohistochemistry. The clinical significance of PD-1 expression was evaluated using univariate and multivariate analysis. PD-1 overexpression and knockdown studies were conducted in C918 and Mum-2B cell lines to analyze the effect of PD-1 expression on tumor cell proliferation and intracellular cell signaling transduction. real-time qPCR (RT-qPCR) and western blot analysis were performed to investigate the gene expression level. CCK8 assays were performed to examine the cell proliferation ability. Results: High expression of primary (ocular) intratumor PD-1 was associated with poor patient survival. Moreover, PD-1 expression was correlated with the largest tumor diameter. PD-1 expression and optic nerve invasion were independent prognostic risk factors. PD-1 overexpression in uveal melanoma cell lines promoted tumor cell proliferation, while knockdown of PD-1 inhibited cell proliferation capacity. Conclusion: Our study established the role of PD-1 in the progression of uveal melanoma and provided a new potential treatment selection for uveal melanoma.
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Walczak, Katarzyna, Ewa Langner, Anna Makuch-Kocka, Monika Szelest, Karolina Szalast, Sebastian Marciniak, and Tomasz Plech. "Effect of Tryptophan-Derived AhR Ligands, Kynurenine, Kynurenic Acid and FICZ, on Proliferation, Cell Cycle Regulation and Cell Death of Melanoma Cells—In Vitro Studies." International Journal of Molecular Sciences 21, no. 21 (October 26, 2020): 7946. http://dx.doi.org/10.3390/ijms21217946.
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Tryptophan metabolites: kynurenine (KYN), kynurenic acid (KYNA) and 6-formylindolo[3,2-b]carbazole (FICZ) are considered aryl hydrocarbon receptor (AhR) ligands. AhR is mainly expressed in barrier tissues, including skin, and is involved in various physiological and pathological processes in skin. We studied the effect of KYN, KYNA and FICZ on melanocyte and melanoma A375 and RPMI7951 cell toxicity, proliferation and cell death. KYN and FICZ inhibited DNA synthesis in both melanoma cell lines, but RPMI7951 cells were more resistant to pharmacological treatment. Tested compounds were toxic to melanoma cells but not to normal human adult melanocytes. Changes in the protein level of cyclin D1, CDK4 and retinoblastoma tumor suppressor protein (Rb) phosphorylation revealed different mechanisms of action of individual AhR ligands. Importantly, all tryptophan metabolites induced necrosis, but only KYNA and FICZ promoted apoptosis in melanoma A375 cells. This effect was not observed in RPMI7951 cells. KYN, KYNA and FICZ in higher concentrations inhibited the protein level of AhR but did not affect the gene expression. To conclude, despite belonging to the group of AhR ligands, KYN, KYNA and FICZ exerted different effects on proliferation, toxicity and induction of cell death in melanoma cells in vitro.
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Tong, Yang, and Lei Jin. "miR-590-5p Targets Skp2 to Inhibit the Growth and Invasion of Malignant Melanoma Cells." Disease Markers 2022 (July 7, 2022): 1–9. http://dx.doi.org/10.1155/2022/8723725.
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Skp2 participates in the regulation of cell growth cycle and promotes the growth of tumor cells. It was speculated that miR-590-5p could regulate the expression of Skp2 and have therapeutic effects on malignant melanin. In this study, the expression of Skp2 was detected by qRT-PCR and Western blot (WB), and the targeted binding between miR-590-5p and Skp2 was verified by dual luciferase reporting assay. Subsequently, cell proliferation activity was detected by CCK8, cell invasion was detected by Transwell, and cell apoptosis was detected by mitochondrial membrane potential assay. The results indicate that Skp2 is highly expressed in melanoma cells and inhibits the proliferation and invasion of melanoma cells. However, miR-590-5p can bind to Skp2 in a targeted manner. miR-590-5p is underexpressed in melanoma cells, and its overexpression can inhibit Skp2 expression and proliferation and invasion of melanoma cells. Our results showed that miR-590-5p could inhibit melanoma cell development by targeting Skp2. This study provides more therapeutic targets for the treatment of melanoma.
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Shirley, Stephanie H., Kristine von Maltzan, Paige O. Robbins, and Donna F. Kusewitt. "Melanocyte and Melanoma Cell Activation by Calprotectin." Journal of Skin Cancer 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/846249.
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Calprotectin, a heterodimer of S100A8 and S100A9, is a proinflammatory cytokine released from ultraviolet radiation-exposed keratinocytes. Calprotectin binds to Toll-like receptor 4, the receptor for advanced glycation end-products, and extracellular matrix metalloproteinase inducer on target cells to stimulate migration. Melanocytes and melanoma cells produce little if any calprotectin, but they do express receptors for the cytokine. Thus, keratinocyte-derived calprotectin has the potential to activate melanocytes and melanoma cells within the epidermis in a paracrine manner. We examined the ability of calprotectin to stimulate proliferation and migration in normal human melanocytes and melanoma cellsin vitro. We first showed, by immunofluorescence and quantitative RT-PCR, that the melanocytic cells employed expressed a calprotectin receptor, the receptor for advanced end-products. We then demonstrated that calprotectin significantly enhanced proliferation, migration, and Matrigel invasion in both normal human melanocytes and melanoma cells. Thus, calprotectin is one of the numerous paracrine factors released by ultraviolet radiation-exposed keratinocytes that may promote melanomagenesis and is a potential target for melanoma prevention or therapy.
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Evans, Jadon, Aaron Jones, Elliott Blumenthal, and Tanya Soule. "Anti-proliferation of Melanoma Cells and Immune Stimulation by the Cyanobacterial Indole-alkaloid Scytonemin." Fine Focus 7, no. 1 (December 3, 2021): 54–63. http://dx.doi.org/10.33043/ff.7.1.54-63.
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Under the stress of ultraviolet radiation some cyanobacteria synthesize scytonemin, a protective pigment against DNA photodamage. In addition to photoprotection, scytonemin has been shown to have an anti-proliferative effect on various types of malignant cells. In this study the effect of scytonemin on melanoma and spleen cells was assessed both in vitro using tissue cultures and in vivo in mice models. Melanoma and spleen cells were exposed to 0.08 to 10 μM of scytonemin, and cell proliferation was measured using tritiated thymidine uptake. The data suggest that scytonemin acts as an inhibitor for melanoma cells in a concentration-dependent manner while enhancing the proliferation of spleen cells, suggesting that it can potentially augment the immune response. Furthermore, mice injected with melanoma cells and scytonemin produced fewer tumors than mice that did not receive scytonemin, although the data were not significant. This study adds to the growing body of research that scytonemin may be beneficial as a future anticancer agent to prevent tumor cell growth.
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Cordiali-Fei, Paola, Marcella Mottolese, Raffaele Tecce, Piergiorgio Natali, and Soldano Ferrone. "Accessory cell function of human melanoma cells in mitogen-induced T cell proliferation." Cellular Immunology 116, no. 1 (October 1988): 149–62. http://dx.doi.org/10.1016/0008-8749(88)90217-1.
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Yi, Xin, Jia yong Liu, Jie Dai, Jun Guo, Cong ying Wu, Lu Si, Lili Mao, and Zhong Hui Qi. "Characterization of mechano-microenvironment of acral melanoma and its potential impact on tumor cell invasion." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e21062-e21062. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e21062.
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e21062 Background: Acral melanoma is the main subtype in Asia, and tends to be insensitive to conventional and novel therapies compared with cutaneous melanomas. It has been proved that biomechanical alterations inside the tumor microenvironment significantly affect tumor progression in breast, pancreatic and other cancers(Hepatology. 2016 July ; 64(1): 261–275; Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXXI) . Hence, we hypothesized that the biomechanical microenvironment plays critical roles in proliferation and invasion in acral melanoma. In this study, the main purpose is to observe whether melanoma cells have the same ability called “durotaxis” as other tumors, which to respond to a gradient of extracellular stiffness and migrate in a directed fashion. Methods: In this study, the stiffness was compared between the acral melanoma tissue and the normal tissue by using the atomic force microscope (AFM) with fresh samples and the freezing microtome sectioning specimen (J. Matthew Barnes et al., Nature Cell Biology 2018.) . A stiffness gradient polyacrylamide hydrogel system was constructed to observe how the acral melanoma cells response. Using automated tracking (Curr Protoc Cell Biol. ; 76: 12.12.1–12.12.16.) of positional data for large sample size of single migrating cells to systematically analyze polarized melanoma cell migration in response to stiffness gradient. Results: The results showed that 1) all the acral melanoma cell lines tested displayed strong anti-durotactic migratory response, which was in accordance with the AFM measurement that the melanoma microenvironment gradually softened; 2) Acral melanoma cells tend to move toward softer areas on gradient gels, which is contrary to the migration behavior of most other tumor cells. Conclusions: In this study, we presented the different migratory pattern of acral melanoma cells. It may illustrate the invasion mechanism for aral melanoma cells. It could also herald that extracellular matrix may be a potential therapeutic target in acral melanomas.
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Lim, Jonathan, Yuet Kwan, Michelle Tan, Melissa Teo, Shunsuke Chiba, Walter Wahli, and Xiaomeng Wang. "The Role of PPARβ/δ in Melanoma Metastasis." International Journal of Molecular Sciences 19, no. 10 (September 20, 2018): 2860. http://dx.doi.org/10.3390/ijms19102860.
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Background: Peroxisome proliferator–activated receptor (PPAR) β/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARβ/δ has been linked to carcinogenesis and was reported to inhibit melanoma cell proliferation, anchorage-dependent clonogenicity and ectopic xenograft tumorigenicity. However, PPARβ/δ’s role in tumour progression and metastasis remains controversial. Methods: In the present studies, the consequence of PPARβ/δ inhibition either by global genetic deletion or by a specific PPARβ/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models. Results: Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparβ/δ−/− mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparβ/δ−/− mice as demonstrated in the same animal model. Conclusion: These results indicated a protective role of PPARβ/δ in melanoma progression and metastasis.
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Song, Minjung, Dong Ki Park, and Hye-Jin Park. "Antrodia camphorataGrown on Germinated Brown Rice Suppresses Melanoma Cell Proliferation by Inducing Apoptosis and Cell Differentiation and Tumor Growth." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/321096.
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Antrodia camphoratagrown on germinated brown rice (CBR) was prepared to suppress melanoma development. CBR extracts were divided into hexane, EtOAc, BuOH, and water fractions. Among all the fractions, EtOAc fraction showed the best suppressive effect on B16F10 melanoma cell proliferation by CCK-8 assay. It also showed the increased cell death and the changed cellular morphology after CBR treatment. Annexin V-FITC/PI, flow cytometry, and western blotting were performed to elucidate anticancer activity of CBR. The results showed that CBR induced p53-mediated apoptotic cell death of B16F10. CBR EtOAc treatment increased melanin content and melanogenesis-related proteins of MITF and TRP-1 expressions, which supports its anticancer activity. Its potential as an anticancer agent was further investigated in tumor-xenografted mouse model. In melanoma-xenografted mouse model, melanoma tumor growth was significantly suppressed under CBR EtOAc fraction treatment. HPLC analysis of CBR extract showed peak of adenosine. In conclusion, CBR extracts notably inhibited B16F10 melanoma cell proliferation through the p53-mediated apoptosis induction and increased melanogenesis. These findings suggest that CBR EtOAc fraction can act as an effective anticancer agent to treat melanoma.