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Passam, Freda H., Angelina Lay, Alexander Dupuy, Jessica Tieng, Lejla Hagimola, Jessica Maclean, Marc Ellis, and Philip Hogg. "Protein Disulphide Isomerase 6 (PDIA6) Attenuates Platelet Endoplasmic Reticulum Stress and Secretion in a Mouse Model." Blood 138, Supplement 1 (November 5, 2021): 3138. http://dx.doi.org/10.1182/blood-2021-152307.
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Abstract Background: Platelet hyperreactivity involves increased secretion of their granule content which promotes platelet aggregation and thrombosis. Platelet hyperreactivity is observed in conditions such as diabetes mellitus and is associated with decreased cardioprotective effect from antiplatelet agents in this patient group. Diabetes is associated with increased endoplasmic reticulum (ER) stress from hyperglycemia and hyperlipidemia. Protein disulphide isomerase 6 (PDIA6) is an endoplasmic reticulum protein which folds nascent proteins by reduction and oxidation of their disulphide bonds. PDIA6 has been shown to inhibit downstream ER stress pathways by inhibiting the phosphorylation of IRE-1 in fibroblasts (Eletto, Mol Cell, 2014). We hypothesized that ER stress pathways are functional in platelets and that PDIA6 may inhibit ER stress pathways leading to platelet secretion. Methods: We generated conditional PDIA6 knockout mice (PF4Cre+ Pdia6 fl/fl) (CKO) in the megakaryocyte/platelet lineage by CRISPR-Cas9 technology (Fig.1A). Megakaryopoiesis and haemostasis was assessed by bone marrow histology, coagulation assays, platelet aggregation and tail bleeding studies. We induced ER stress of purified platelets by incubation with thapsigargin and tunicamycin. Activation of the PERK and IRE1 pathways was measured by Western blot. Thrombosis was assessed in vitro by microfluidic devices and in vivo by electrolytic injury of the carotid artery. Results: PDIA6 CKO mice displayed a mild macrothrombocytopenia: the mean (+/-SD) platelet count in Pf4Cre+/Pdia6fl/fl was 775 +/- 98 x10 3/ul compared with 874 +/- 55 x10 3/ul in Pdia6fl/fl (p<0.005). The median platelet volume was 6.3 fL in Pf4Cre+/Pdia6fl/fl compared with 5.7 fL in Pdia6fl/fl (p<0.005). Megakaryopoiesis was normal at baseline. However, PDIA6 CKO mice showed significant upregulation of intracellular platelet PDIs including PDIA1, PDIA3 and PDIA4. PDIA6 deficient platelets displayed significant increase of disulphide reductase activity and the generation of free thiols on the platelet surface. Activation of the PERK and IRE-1 pathway at baseline and after induction of ER stress was increased in PDIA6 deficient platelets (Figure 1B, C). There was striking hypersecretion of PDIA1 (Figure 1D) and α-granule proteins (Figure 1E, F) in response to shear and stimulation with thrombin. PDIA6 CKO mice displayed a prothrombotic phenotype with increased platelet adhesion to fibrinogen under shear (500 s-1) and decreased time to carotid artery occlusion (mean+/SD: 10.8 +/-3.2 min in Pf4Cre+/Pdia6fl/fl compared with 15.3 +/-5.2 min in Pdia6fl/fl, n=8-10, p<0.05). Conclusion: We have identified a role for platelet PDIA6 in attenuating platelet ER stress and secretion. This opens avenues for further study into the role of platelet PDIs in conditions with increased ER stress, such as obesity and diabetes. Figure 1: PDIA6 deficient platelets have increased endoplasmic reticulum (ER) stress and are hypersecretory. A. Western blot of PDIA6 protein in platelets from Pf4Cre+/Pdia6fl/fl mice and control mice (Pdia6fl/fl) showing efficient deletion of PDIA6 in platelets. B. PDIA6 deficient platelets have increased phosphorylation of pEIF2a (PERK phosphorylation pathway) at baseline and after induction of ER stress by thapsigargin, representative image. C. Normalized band intensity (peIF2a/beta actin) in platelets treated with DMSO control or thapsigargin. D. Increased secretion of thiol isomerase PDIA1. E. alpha granule proteins: platelet factor 4 (PF4) and F. von Willebrand factor (vWF) from PDIA6 deficient platelets compared with controls after stimulation with thrombin 0.5 U/ml. n=3-5 Pf4Cre+/Pdia6fl/fl (red boxes) and n=3-5 Pdia6fl/fl mice (grey boxes). Columns are presented as mean+/-SD, *p<0.05, ** p<0.001 by Mann Whitney. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Cheng, He-Peng, Qian Liu, Yang Li, Xiao-Dong Li, and Chao-Yang Zhu. "The Inhibitory Effect of PDIA6 Downregulation on Bladder Cancer Cell Proliferation and Invasion." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 25, no. 4 (April 14, 2017): 587–93. http://dx.doi.org/10.3727/096504016x14761811155298.
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Protein disulfide isomerases A6 (PDIA6) belongs to the PDI family. Recently, PDIA6 was found to have a close association with various cancers. However, there has been little investigation into the biological functions of PDIA6 in bladder cancer (BC). In this study, we explored the expression pattern and functional significance of PDIA6 in BC. We found that PDIA6 was overexpressed in BC tissues and cell lines. The in vitro study showed that PDIA6 downregulation significantly inhibited BC proliferation and invasion. In addition, the in vivo experiment demonstrated that PDIA6 downregulation decreased the volume, weight, and metastasis of tumors. Furthermore, PDIA6 downregulation reduced the protein expression of β-catenin, cyclin D1, and c-Myc and thus suppressed the Wnt/β-catenin signaling pathway. In conclusion, we suggest that PDIA6 could be targeted for the treatment of BC.
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Kim, Tae-Wan, Hyang-Hwa Ryu, Song-Yuan Li, Chun-Hao Li, Sa-Hoe Lim, Woo-Youl Jang, and Shin Jung. "PDIA6 regulation of ADAM17 shedding activity and EGFR-mediated migration and invasion of glioblastoma cells." Journal of Neurosurgery 126, no. 6 (August 2016): 1829–38. http://dx.doi.org/10.3171/2016.5.jns152831.
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OBJECTIVEIn patients with glioblastoma, local invasion of tumor cells causes recurrence and shortens survival. The goal of this study was to determine whether protein disulfide isomerase (PDI) A6 regulates migration and invasion of glioblastoma cells and the associated factors.METHODSU87MG cells were treated with either PDIA6 or ADAM17 small interfering RNA (siRNA) fragments or with both types of siRNA fragments, and expression was confirmed by reverse transcription–polymerase chain reaction and Western blot. Migration and invasion were assessed using a wound-healing assay, a Matrigel assay, and an organotypic culture system. After the U87MG cells were treated with siRNAs and epidermal growth factor receptor (EGFR) inhibitors, the expression of matrix metalloproteinase–2 (MMP-2), membrane Type 1-matrix metalloproteinase (MT1-MMP), integrin, phosphorylated focal adhesion kinase (pFAK), and phosphorylated EGFR (pEGFR) was detected by Western blotting and zymography.RESULTSU87MG cell migration and invasion increased significantly after inhibition of PDIA6. The MMP-2 activation ratio and ADAM17 activity (as a sheddase of the proligand) increased, and expression of pEGFR, pFAK, integrin α5β3, and MT1-MMP was induced, compared with control levels. Furthermore, heparin-binding epidermal growth factor (EGFR signaling ligand) was highly expressed in PDIA6-knockdown cells. After siPDIA6-transfected U87MG cells were treated with EGFR signaling inhibitors, expression of pFAK, MMP-2, and MT1-MMP decreased and invasion decreased significantly. Simultaneous double-knockdown of PDIA6 and ADAM17 reduced pEGFR and pFAK expression, compared with control levels.CONCLUSIONSThe authors propose that inhibiting PDIA6 could transduce EGFR signaling by activating and inducing ADAM17 during migration and invasion of U87MG glioblastoma cells. The results of this study suggest that PDIA6 is an important component of EGFR-mediated migration and invasion of U87MG cells. This is the first report of the effects of PDIA6 on migration and invasion in glioblastoma.
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Shen, Chien-Heng, Shui-Yi Tung, Wen-Shih Huang, Kam-Fai Lee, Yung-Yu Hsieh, Meng Chiao Hsieh, Cheng-Nan Chen, and Hsing-Chun Kuo. "Comparative Proteomic Identification of Protein Disulphide Isomerase A6 Associated with Tert-Butylhydroperoxide-Induced Liver Injury in Rat Hepatocytes." Cellular Physiology and Biochemistry 45, no. 5 (2018): 1915–26. http://dx.doi.org/10.1159/000487968.
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Background/Aims: Oxidants are important human toxicants. They have been implicated in the occurrence and development of liver diseases. Increased intracellular tert-butylhydroperoxide (t-BHP) may be critical for oxidant toxicity, and is commonly used for evaluating mechanisms involving oxidative stress, but the method remains controversial. Methods: Primary cultures of hepatocytes as well as human Hep G2 and mouse FL83B liver cells were obtained. Cell viability was measured by annexin V–FITC/propidium iodide and DAPI staining to determine the effects of t-BHP treatment on acute liver injury. A proteomic assay provided information that was used to identify the differentially expressed proteins following t-BHP treatment; immunohistochemistry and western blotting were performed to detect the expression of PDIA6 activity in apoptotic and endoplasmic reticulum (ER) stress pathways. Results: Our results demonstrate that t-BHP treatment of liver cells increased cell cytotoxicity and the generation of reactive oxygen species. This treatment also increased the level of PDIA6; this was validated in vitro and in vivo based on a comparison of t-BHP-treated and -untreated groups. Treatment of mouse liver FL83B cells with t-BHP activated caspase 3, increased the expression of apoptotic molecules, caused cytochrome c release, and induced Bcl-2, Bax and IRE1α/TRAF2 complex formation. t-BHP-dependent induction of apoptosis was accompanied by sustained phosphorylation of the IRE1α/ASK1/JNK1/2/p38 pathways and PDIA6 expression. Furthermore, t-BHP induced liver FL83B cell viability and apoptosis by upregulating the levels of PDIA6; this process could be involved in the activation of the IRE1α/ASK1/JNK1/2/p38 signalling pathways. Conclusions: We conclude that t-BHP induced an apoptosis cascade and ER stress in hepatocytes by upregulation of PDIA6, providing a new mechanism underlying the effects of t-BHP on liver injury.
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Ramos, F. S., L. T. R. Serino, C. M. S. Carvalho, R. S. Lima, C. A. Urban, I. J. Cavalli, and E. M. S. F. Ribeiro. "PDIA3 and PDIA6 gene expression as an aggressiveness marker in primary ductal breast cancer." Genetics and Molecular Research 14, no. 2 (2015): 6960–67. http://dx.doi.org/10.4238/2015.june.26.4.
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Vieujean, S., S. Hu, E. Bequet, C. Salée, C. Massot, N. Bletard, N. Pierre, et al. "P013 Potential Role of Epithelial Protein Disulphide Isomerases in Crohn’s Disease Fibrosis." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S134—S135. http://dx.doi.org/10.1093/ecco-jcc/jjab076.142.
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Abstract Background Intestinal fibrosis is a common complication of Crohn’s disease (CD) characterized by an accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. In in-vitro experiments, this myofibroblastic differentiation is elicited by a whole series of factors among which transforming growth factor-β1 (TGF-β1) seems to play a key role. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser-capture microdissection in normal and fibrotic zones of resected ileal CD strictures (13 zones collected in 5 patients). The pro-fibrotic role of selected epithelial proteins was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model. Results Proteomic study revealed an endoplasmic reticulum (ER) stress proteins increase in the epithelium of CD ileal fibrotic strictures, including Anterior gradient protein 2 homolog (AGR2), Protein disulphide isomerase A6 (PDIA6) and Endoplasmic reticulum resident protein 44 (ERP44) which are 3 protein disulphide isomerases. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2, PDIA6, ERP44 as well as TGF-β1 intracellular expression and their secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin (Tm), led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. The application of blocking agents for AGR2, PDIA6, ERP44 or TGF-β1 in the supernatant of these Tm-pre-conditioned HT-29 cells, attenuated the myofibroblastic differentiation induced by this supernatant, suggesting a pro-fibrotic role of these secreted epithelial proteins. Conclusion The development of CD fibrotic strictures may involve ER stress in epithelial cells, releasing a whole set of proteins into their environment, including AGR2, PDIA6, ERP44 as well as TGF-β1, which could exercise a pro-fibrotic role through a paracrine action.
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Tufo, G., A. W. E. Jones, Z. Wang, J. Hamelin, N. Tajeddine, D. D. Esposti, C. Martel, et al. "The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma." Cell Death & Differentiation 21, no. 5 (January 24, 2014): 685–95. http://dx.doi.org/10.1038/cdd.2013.193.
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Zhou, Ping, Lakshmanan K. Iyer, Hani Hassoun, James E. Hoffman, Heather Landau, and Raymond L. Comenzo. "Cyclin D1 Overexpression In Clonal Plasma Cells In Systemic AL Amyloidosis Is Associated with Differential Expression of Protein Quality Control Genes and Bias In Clonal Germline IgVL donor Gene Use." Blood 116, no. 21 (November 19, 2010): 4043. http://dx.doi.org/10.1182/blood.v116.21.4043.4043.
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Abstract Abstract 4043 Cyclin D1 (CCND1) overexpression in AL plasma cells (PC) is associated with patient characteristics such as production of free immunoglobulin (Ig) light chains (FLC) without an intact M-protein (that is, without partner Ig heavy chains), increased cardiac biomarkers and shorter survival (Amyloid 2010;17(S1):61a; Blood 2008;111:4700; Haematologica 2009;94:380). The molecular ramifications of CCND1 overexpression within AL PC clones have not been described. To study these associations, we used CD138+ AL PC from 69 untreated AL patients at diagnosis for (1) gene expression profiling (GEP, Affymetrix U133A 2.0) (n=16), (2) qRT-PCR to validate GEP findings (n=53), and (3) clonal IgVL germline donor gene identification (n=69) by established methods (Blood 2008;111:549; Blood 2001;98:714). By GEP, all cases displayed significant overexpression of the appropriate isotypic IgVL constant region gene, confirming the preponderance of clonal AL PC. Five cases were CCND1hi and 11 CCND1lo, and a supervised analysis of CCND1hi vs CCND1lo transcriptomes showed that in CCND1hi PC among the most down-regulated genes were IGHG1, IGHG3 and CCND2 while among the most up-regulated ones (after CCND1) were FAM129A, WARS, SEC63, PDIA6 and SEL1L. By RT-PCR all 53 cases used for qRT-PCR displayed prominent amplification of spliced and unspliced XBP1, confirming PC derivation. By qRT-PCR, median CCND1 expression was 1.51 (range, 0–19.36) with 27 cases above (CCND1hi) and 26 below the median (CCND1lo) with clear-cut quartile differences (25% 0.02, 75% 4.78). We examined PDIA6 and SEL1L expression by qRT-PCR, and found that both correlated with CCND1 expression (PDIA6, P=0.018, r=0.452; SEL1L, P=0.038, r=0.395). In addition, PDIA6 and SEL1L values above and below the CCND1 median differed significantly (P=0.01, P=0.04). The genes up-regulated in CCND1hi cases are involved in endoplasmic reticulum (ER) and protein control processes: WARS in protein production, FAM129A in autophagy, SEC63 in ER protein transport, PDIA6 in catalysis of disulfide bonds and SEL1L in modifying misfolded proteins and channeling them to cytosolic proteasomes. We then identified the clonal IgVL germline donor genes in the CCND1hi (n=32) and CCND1lo (n=37) AL PC clones. We knew that CCND1hi clones displayed biased Ig light chain restriction with 10/12 κ and 22/57 λ cases being CCND1hi (p=0.009, Fisher's exact). Surprisingly, we also identified biased λ family use as only 6/27 λ1 and λ2 cases were CCND1hi compared to 16/30 λ3 and λ6 cases (P=0.03). Overall these results confirm that CCND1hi AL PC clones express significantly higher levels of important ER protein quality control genes than CCND1lo clones, possibly due to CCND1hi AL PC clones adapting to the production of FLC without partner Ig heavy chains. Moreover, CCND1hi AL PC clones display a biased clonal IgVL germline donor gene repertoire, raising questions about the origin of CCND1hi clones since germline gene selection is an early and CCND1 overexpression likely a late event in malignant clonal PC emergence. Disclosures: No relevant conflicts of interest to declare.
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Gorasia, Dhana G., Nadine L. Dudek, Helena Safavi-Hemami, Rochelle Ayala Perez, Ralf B. Schittenhelm, Philippa M. Saunders, Sheena Wee, Jon E. Mangum, Michael J. Hubbard, and Anthony W. Purcell. "A prominent role of PDIA6 in processing of misfolded proinsulin." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1864, no. 6 (June 2016): 715–23. http://dx.doi.org/10.1016/j.bbapap.2016.03.002.
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Özenver, Nadire, and Thomas Efferth. "Identification of Prognostic and Predictive Biomarkers and Druggable Targets among 205 Antioxidant Genes in 21 Different Tumor Types via Data-Mining." Pharmaceutics 15, no. 2 (January 28, 2023): 427. http://dx.doi.org/10.3390/pharmaceutics15020427.
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(1) Background: Oxidative stress is crucial in carcinogenesis and the response of tumors to treatment. Antioxidant genes are important determinants of resistance to chemotherapy and radiotherapy. We hypothesized that genes involved in the oxidative stress response may be valuable as prognostic biomarkers for the survival of cancer patients and as druggable targets. (2) Methods: We mined the KM Plotter and TCGA Timer2.0 Cistrome databases and investigated 205 antioxidant genes in 21 different tumor types within the context of this investigation. (3) Results: Of 4347 calculations with Kaplan–Meier statistics, 84 revealed statistically significant correlations between high gene expression and worse overall survival (p < 0.05; false discovery rate ≤ 5%). The tumor types for which antioxidant gene expression was most frequently correlated with worse overall survival were renal clear cell carcinoma, renal papillary cell carcinoma, and hepatocellular carcinoma. Seventeen genes were clearly overexpressed in tumors compared to their corresponding normal tissues (p < 0.001), possibly qualifying them as druggable targets (i.e., ALOX5, ALOX5AP, EPHX4, G6PD, GLRX3, GSS, PDIA4, PDIA6, PRDX1, SELENOH, SELENON, STIP1, TXNDC9, TXNDC12, TXNL1, TXNL4A, and TXNRD1). (4) Conclusions: We concluded that a sub-set of antioxidant genes might serve as prognostic biomarkers for overall survival and as druggable targets. Renal and liver tumors may be the most suitable entities for this approach.
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Paglia, Giuliano, Lorenzo Antonini, Laura Cervoni, Rino Ragno, Manuela Sabatino, Marco Minacori, Elisabetta Rubini, and Fabio Altieri. "A Comparative Analysis of Punicalagin Interaction with PDIA1 and PDIA3 by Biochemical and Computational Approaches." Biomedicines 9, no. 11 (October 25, 2021): 1533. http://dx.doi.org/10.3390/biomedicines9111533.
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In a previous work, it was shown that punicalagin, an active ingredient of pomegranate, is able to bind to PDIA3 and inhibit its disulfide reductase activity. Here we provide evidence that punicalagin can also bind to PDIA1, the main expressed form of protein disulfide isomerase (PDI). In this comparative study, the affinity and the effect of punicalagin binding on each protein were evaluated, and a computational approach was used to identify putative binding sites. Punicalagin binds to either PDIA1 or PDIA3 with a similar affinity, but the inhibition efficacy on protein reductase activity is higher for PDIA3. Additionally, punicalagin differently affects the thermal denaturation profile of both proteins. Molecular docking and molecular dynamics simulations led to propose a punicalagin binding mode on PDIA1 and PDIA3, identifying the binding sites at the redox domains a’ in two different pockets, suggesting different effects of punicalagin on proteins’ structure. This study provides insights to develop punicalagin-based ligands, to set up a rational design for PDIA3 selective inhibitors, and to dissect the molecular determinant to modulate the protein activity.
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Kong, Xianghui, Hanhan Yao, Jianfeng Ren, Wenfang Dai, Zhihua Lin, Chenghua Li, and Yinghui Dong. "PDIA6 involves the thermal stress response of razor clam, Sinonovacula constricta." Fish & Shellfish Immunology 131 (December 2022): 766–74. http://dx.doi.org/10.1016/j.fsi.2022.10.055.
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Freitas, C. P., I. Clemente, T. Mendes, and C. Novo. "Trichinella spiralis: genome database searches for the presence and immunolocalization of protein disulphide isomerase family members." Journal of Helminthology 90, no. 1 (December 5, 2014): 62–67. http://dx.doi.org/10.1017/s0022149x14000807.
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AbstractThe formation of nurse cells in host muscle cells duringTrichinella spiralisinfection is a key step in the infective mechanism. Collagen trimerization is set up via disulphide bond formation, catalysed by protein disulphide isomerase (PDI). InT. spiralis, some PDI family members have been identified but no localization is described and no antibodies specific forT. spiralisPDIs are available. In this work, computational approaches were used to search for non-described PDIs in theT. spiralisgenome database and to check the cross-reactivity of commercial anti-human antibodies withT. spiralisorthologues. In addition to a previously described PDI (PDIA2), endoplasmic reticulum protein (ERp57/PDIA3), ERp72/PDIA4, and the molecular chaperones calreticulin (CRT), calnexin (CNX) and immunoglobulin-binding protein/glucose-regulated protein (BIP/GRP78), we identified orthologues of the human thioredoxin-related-transmembrane proteins (TMX1, TMX2 and TMX3) in the genome protein database, as well as ERp44 (PDIA10) and endoplasmic reticulum disulphide reductase (ERdj5/PDIA19). Immunocytochemical staining of paraffin sections of muscle infected byT. spiralisenabled us to localize some orthologues of the human PDIs (PDIA3 and TMX1) and the chaperone GRP78. A theoretical three-dimensional model forT. spiralisPDIA3 was constructed. The localization and characteristics of the predicted linear B-cell epitopes and amino acid sequence of the immunogens used for commercial production of anti-human PDIA3 antibodies validated the use of these antibodies for the immunolocalization ofT. spiralisPDIA3 orthologues. These results suggest that further study of the role of the PDIs and chaperones during nurse cell formation is desirable.
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Eletto, Daniela, Davide Eletto, Sarah Boyle, and Yair Argon. "PDIA6 regulates insulin secretion by selectively inhibiting the RIDD activity of IRE1." FASEB Journal 30, no. 2 (October 20, 2015): 653–65. http://dx.doi.org/10.1096/fj.15-275883.
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Bequet, E., C. Salée, N. Bletard, S. Vieujean, C. Massot, F. Fonzé, H. Sarter, et al. "P194 Characterization of Protein Disulfide Isomerases in adult and pediatric Crohn’s Disease and association with inflammation and fibrosis." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i347. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0324.
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Abstract Background Evolution of Crohn's disease (CD) is often marked by fibrostenotic complications and available biotherapies cannot prevent or treat intestinal fibrosis. The pathophysiological mechanisms of intestinal fibrosis are multiple and poorly understood. The intestinal epithelium probably plays a key role. The endoplasmic reticulum stress (ERS) is involved in the pathophysiology of IBD and in fibrosis. Protein disulfide isomerases (PDIs) take part in the ER stress response, but their precise roles and associations with CD remain poorly characterized. We investigated the distribution of selected PDIs within the ileum and colon of adult and pediatric patients with inflammatory or stenosing CD. Methods Tissues from 72 pediatric and 47 adult CDs, and 26 pediatric and 48 adult patients without IBD were included from 4 tertiary hospitals. The degree of fibrosis and inflammatory infiltrate were evaluated. The distribution of 4 PDIs (AGR2, BiP, PDIA6, ERP44) within the tissues was studied by immunohistochemistry (IHC) using a semiquantitative scoring scale (0 to 4). Statistical tests used were ANOVA or Kruskal-Wallis (with post hoc test), T-Student and Mann-Whitney. Results The clinical characteristics of the patients included are described in Table 1. The PDIs provide an IHC signal which was mainly epithelial. The distribution of PDIs differed according to the segment studied (colon or ileum), the age of CD onset, location in the epithelium (surface, median crypt, or bottom of crypt), and the normal, inflammatory, and/or fibrotic features of the tissues. In the ileum of adult and pediatric CDs, the distribution of AGR2 was significantly higher in the epithelium adjacent to fibro-inflammatory tissues (p<0.01). In pediatric cases, AGR2 increased significantly with the fibrosis grade within the surface epithelium of the ileum (Fig. 1). The distributions of the other PDIs (BiP, ERP44 and PDIA6) were rather influenced by the inflammatory infiltrates and varied in adult and pediatric CD. The distribution of BiP was significantly higher in tissues with acute and/or chronic inflammation and independent from fibrosis. In adults, the distribution of PDIA6 in the colonic epithelium was significantly higher in CD cases compared to non-CD cases. Conclusion Our results suggest that the studied PDIs may have different roles in the ERS response within the intestinal epithelium in adult and pediatric CD. These PDIs need to be functionally explored further to better understand their specific involvement in inflammation and fibrosis in CD. The increase of AGR2 in fibro-inflammatory tissues, not observed with other PDIs, suggests a specific link between AGR2 and intestinal fibrosis.
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Yan, Chao, Xiaolei Song, Su Wang, Jinhai Wang, and Lu Li. "Knockdown of PDIA6 Inhibits Cell Proliferation and Enhances the Chemosensitivity in Gastric Cancer Cells." Cancer Management and Research Volume 12 (November 2020): 11051–62. http://dx.doi.org/10.2147/cmar.s267711.
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Gao, Huijun, Bing Sun, Hailu Fu, Xinming Chi, Faming Wang, Xiaoyu Qi, Jun Hu, and Shujuan Shao. "PDIA6 promotes the proliferation of HeLa cells through activating the Wnt/β-catenin signaling pathway." Oncotarget 7, no. 33 (July 22, 2016): 53289–98. http://dx.doi.org/10.18632/oncotarget.10795.
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Bang, J. I., D. W. Bae, Y. S. Kwon, G. K. Deb, B. H. Choi, T. H. Kwon, A. N. Ha, et al. "34 DIFFERENTIALLY EXPRESSED PROTEINS OF EARLY-STAGE PLACENTA DERIVED FROM CLONED CAT EMBRYOS USING PROTEOMICS ANALYSIS." Reproduction, Fertility and Development 24, no. 1 (2012): 129. http://dx.doi.org/10.1071/rdv24n1ab34.
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We have previously demonstrated that differentially expressed proteins affect abnormal development and function of cloned term placenta. This is associated with cloned fetus morbidity and mortality. We also frequently observed loss of the cloned fetus and failed development during early pregnancy periods. To confirm the pattern of important gene expression in cloned placenta during pre- and post-implantation, we investigated expression pattern of proteins in early stage (21 days) domestic cat placentas of cloned embryo transfer (CEP; n = 2) and artificial insemination (CP; n = 4) derived pregnancy. The differentially expressed proteins were investigated by 2-DE and MALDI-TOF/MS. Twenty-three proteins were up- and down-regulated at least 1.5-fold in the CEP (P < 0.05) compared with the CP. Differentially expressed proteins were analysed using PDQest program and statistically analysed by 1-way ANOVA using the SPSS software. In CEP, 13 proteins were up-regulated, such as 78-kDa glucose-regulated protein (GRP78), annexin A2 (ANXA2), protein DJ-1 (DJ1), adenylate kinase isoenzyme 1 (AK1), protein disulfide-isomerase A3 (PDIA3), heat shock protein β-1 (HSPB1), actin, cytoplasmic 1 (ACTB), serum albumin (ALB), protein disulfide-isomerase A6 (PDIA6), G protein-regulated inducer of neurite outgrowth 1 (GRIN1) and triosephosphate isomerase (TIM). In contrast, 10 proteins were down-regulated, such as vinculin (VCL), triosephosphate isomerase (TIM), heterogeneous nuclear ribonucleoprotein H (hnRNPH), tropomyosin α-4 (TPM4), 60-kDa heat shock protein, mitochondrial (Hsp60), serum albumin (ALB), calumenin (CALU), keratin type 1 (CK1) and prohibitin (PHB). To validate the identified proteins in the CEP compared with the CP, we investigate a peptide sequences using MALDI-TOF/TOF tandem mass spectrometry. The sequence information obtained a high ions score from NCBI and Swiss-Prot databases. In conclusion, we did identify abnormal expression of proteins that might be associated with impaired development of CEP, which may endanger the cloned fetus during early pregnancy. This work was partly supported by the BK21 program and the KOSEF (10525010001-05N2501-00110) and the Next-generation BioGreen21 program (No. PJ007990012011).
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Groenendyk, J., Z. Peng, E. Dudek, X. Fan, M. J. Mizianty, E. Dufey, H. Urra, et al. "Interplay Between the Oxidoreductase PDIA6 and microRNA-322 Controls the Response to Disrupted Endoplasmic Reticulum Calcium Homeostasis." Science Signaling 7, no. 329 (June 10, 2014): ra54. http://dx.doi.org/10.1126/scisignal.2004983.
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Ma, Yihui, Peiyi Xia, Zhengyang Wang, Jingjing Xu, Lan Zhang, and Yanan Jiang. "PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of β-catenin and PD-L1." Neoplasia 23, no. 9 (September 2021): 912–28. http://dx.doi.org/10.1016/j.neo.2021.07.004.
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Sha, Zhen-Xia, Hong Liu, Qi-Long Wang, Yang Liu, Yang Lu, Min Li, and Song-Lin Chen. "Channel catfish (Ictalurus punctatus) protein disulphide isomerase, PDIA6: Molecular characterization and expression regulated by bacteria and virus inoculation." Fish & Shellfish Immunology 33, no. 2 (August 2012): 220–28. http://dx.doi.org/10.1016/j.fsi.2012.04.014.
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Bai, Yuxin, Xuefeng Liu, Xiaoyu Qi, Xuan Liu, Fang Peng, Huimin Li, Hailu Fu, et al. "PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway." EBioMedicine 42 (April 2019): 311–25. http://dx.doi.org/10.1016/j.ebiom.2019.03.045.
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Kiouptsi, Klytaimnistra, Stefanie Finger, Venkata S. Garlapati, Maike Knorr, Moritz Brandt, Ulrich Walter, Philip Wenzel, and Christoph Reinhardt. "Hypoxia evokes increased PDI and PDIA6 expression in the infarcted myocardium of ex-germ-free and conventionally raised mice." Biology Open 8, no. 1 (November 29, 2018): bio038851. http://dx.doi.org/10.1242/bio.038851.
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Li, Shenjie, Wei Xiang, Junjie Tian, Haorun Wang, Shuiwang Hu, Ke Wang, Ligang Chen, Changren Huang, and Jie Zhou. "Bone Marrow-Derived Mesenchymal Stem Cells Differentially Affect Glioblastoma Cell Proliferation, Migration, and Invasion: A 2D-DIGE Proteomic Analysis." BioMed Research International 2021 (February 11, 2021): 1–13. http://dx.doi.org/10.1155/2021/4952876.
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Bone marrow-derived mesenchymal stem cells (BM-MSCs) display high tumor tropism and cause indirect effects through the cytokines they secrete. However, the effects of BM-MSCs on the biological behaviors of glioblastoma multiforme remain unclear. In this study, the conditioned medium from BM-MSCs significantly inhibited the proliferation of C6 cells ( P < 0.05 ) but promoted their migration and invasion ( P < 0.05 ). Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) proteomic analysis revealed 17 proteins differentially expressed in C6 cells exposed to the BM-MSC-conditioned medium including five upregulated proteins and 12 downregulated proteins. Among these, six differentially expressed proteins (Calr, Set, Oat, Npm1, Ddah1, and Tardbp) were closely related to cell proliferation and differentiation, and nine proteins (Pdia6, Sphk1, Anxa4, Vim, Tuba1c, Actr1b, Actn4, Rap2c, and Tpm2) were associated with motility and the cytoskeleton, which may modulate the invasion and migration of tumor cells. Above all, by identifying the differentially expressed proteins using proteomics and bioinformatics analysis, BM-MSCs could be genetically modified to specifically express tumor-suppressive factors when BM-MSCs are to be used as tumor-selective targeting carriers in the future.
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Chen, Jianmei, Ziyi Wu, Ruxue Chen, Zhihui Huang, Xuelei Han, Ruimin Qiao, Kejun Wang, Feng Yang, Xin-Jian Li, and Xiu-Ling Li. "Identification of Genomic Regions and Candidate Genes for Litter Traits in French Large White Pigs Using Genome-Wide Association Studies." Animals 12, no. 12 (June 19, 2022): 1584. http://dx.doi.org/10.3390/ani12121584.
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The reproductive traits of sows are one of the important economic traits in pig production, and their performance directly affects the economic benefits of the entire pig industry. In this study, a total of 895 French Large White pigs were genotyped by GeneSeek Porcine 50K SNP Beadchip and four phenotypic traits of 1407 pigs were recorded, including total number born (TNB), number born alive (NBA), number healthy piglets (NHP) and litter weight born alive (LWB). To identify genomic regions and genes for these traits, we used two approaches: a single-locus genome-wide association study (GWAS) and a single-step GWAS (ssGWAS). Overall, a total of five SNPs and 36 genomic regions were identified by single-locus GWAS and ssGWAS, respectively. Notably, fourof all five significant SNPs were located in 10.72–11.06 Mb on chromosome 7, were also identified by ssGWAS. These regions explained the highest or second highest genetic variance in the TNB, NBA and NHP traits and harbor the protein coding gene ENSSSCG00000042180. In addition, several candidate genes associated with litter traits were identified, including JARID2, PDIA6, FLRT2 and DICER1. Overall, these novel results reflect the polygenic genetic architecture of the litter traits and provide a theoretical reference for the following implementation of molecular breeding.
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Souza-Neto, Francisco V., Sara Jiménez-González, Beatriz Delgado-Valero, Raquel Jurado-López, Marie Genty, Ana Romero-Miranda, Cristina Rodríguez, María Luisa Nieto, Ernesto Martínez-Martínez, and Victoria Cachofeiro. "The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats." Antioxidants 10, no. 8 (August 11, 2021): 1274. http://dx.doi.org/10.3390/antiox10081274.
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We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP; 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6; 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP; 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p < 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10−6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role.
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Cesarman, Ethel, Mikhail Roshal, Jonathan Reichel, Wagner Florian, Bhavneet Binder, Sakellarios Zairis, Jouliana Sadek, Joshua Brody, Raul Rabadan, and Sandeep Dave. "RNA Sequencing of Hodgkin Lymphoma Reed-Sternberg Cells Uncovers a Plasma Cell Signature and Escape from NK Cell Recognition." Blood 134, Supplement_1 (November 13, 2019): 549. http://dx.doi.org/10.1182/blood-2019-131163.
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Introduction: Previous gene expression profiling studies of classical Hodgkin lymphoma (cHL) have been confined to cell lines and microdissected HRS cells from tissue biopsies given the difficulty of isolating sparse Hodgkin and Reed-Sternberg (HRS) cells from reactive background tissue. We previously used flow sorting to separate HRS cells from fresh or viably frozen cHL biopsies, and performed the first full exome sequencing of HRS cells. Here we report use of the same cell separation approach to examine the HRS cell transcriptome using RNA sequencing. Methods: We used flow cytometric cell sorting and low-input RNA sequencing to generate full transcriptome data from viable primary HRS cells, along with intratumor B cells. Nine primary cases of cHL and four cell lines were assessed for RNA expression, expressed mutations, cell type of origin, signaling pathways, gene fusions and pathogen identification. We used immunohistochemistry to evaluate expression of PDIA6 and CD48 in the 9 cases sequenced and a tissue microarray containing 16 additional cases of cHL. Flow cytometry for CD48 was performed in two cell lines and 5 primary cases. Results: Clustering show that primary HRS cells have a transcriptional profile that is unique, and different from that of intratumoral B cells, as well as cHL cell lines. Comparison of HRS cells with normal cellular subsets indicated plasma cell differentiation, suggesting that the cell of origin is a B cell on its way to becoming a plasma cell. Clustering with B cells showed much lower similarity. Consistent with plasma cell differentiation, we uncovered an unfolded protein response UPR) signature, shared with plasma cell neoplasms and, to a lesser extent, activated B cell (ABC) diffuse large B cell lymphoma, but not other B cell lymphoma types, including primary mediastinal B cell lymphoma (PMBCL). Among other UPR response genes, PDIA6 showed strong downregulation at the RNA level (2.4 logFC, p=9.4E-17). This finding was validated by immunohistochemistry for PDIA6, which showed strong positivity in the HRS cells of all 25 cases examined, confirming that this is a common feature of cHL, including nodular sclerosis and mixed cellularity subtypes. Top upregulated genes included those involved in oncogenesis (HGF/MET, NFkB/apoptosis inhibition), stem cell differentiation (homeobox genes MEIS1 and PBX1), and mitotic checkpoints, mitotic spindle formation and DNA repair, possibly explaining the unique nuclear morphology of HRS cells. Downregulation of MHC-1 and MHC-2 driven antigen processing and presentation was confirmed, and so was overexpression of PDL1 (CD274). Importantly, we detected loss of SLAM family receptors, which serve as activation signals for NK cells providing an additional mechanism for tumor immune evasion. One of these is CD48 (-2.63 logFC, p=1.56E-05), which was confirmed to be strongly downregulated. This finding was confirmed by immunohistochemistry (25 cases) and flow cytometry (2 cell lines and 5 primary cases) on the expanded sample set. Given that only some cHL cases are associated with EBV infection, it has been speculated that other viruses are involved in negative cases. However, our analysis did not reveal additional viruses in the HRS cells. Conclusions: Our data indicate that cHL more closely resembles plasma cells than B cells, and plasma cell malignancies than other lymphomas. The salient feature of plasmacytic differentiation is a UPR, which is seen in HRS cells and multiple myeloma. In contrast, UPR is not a feature of primary mediastinal B cell lymphoma, which is thought to be the DLBCL most similar to cHL clinically, immunophenotypically and in terms of gene expression patterns. We also provide an integrated view of potential immune evasion mechanisms by HRS cells that potentially explain lack of anti-tumor T or innate response. These include lack of antigen presentation due to B2M mutations, overexpression of PDL1 and PDL2, immunosuppressive cytokine secretion and, for the first time, a demonstration of lack of NK activating receptors of the SLAM family. Lack of SLAM family receptors may explain lack of NK cells clearance of HRS cells in the face of MHC-I downregulation. It has long been suspected that cHL is a tumor where there likely exists a previously undiscovered virus in addition to EBV, but RNA sequencing failed to reveal additional infectious transcripts in the HRS cells. Disclosures Roshal: Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services. Brody:Kite Pharma: Research Funding; Celldex Therapeutics: Research Funding; Genentech: Research Funding; Acerta Pharma: Research Funding; Oncovir, Inc.: Research Funding; BMS: Research Funding; Merck: Research Funding. Dave:Data Driven Bioscience: Equity Ownership.
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Al‐Fadhli, Fatima M., Manal Afqi, Mona Hamza Sairafi, Makki Almuntashri, Essa Alharby, Ghadeer Alharbi, Firoz Abdud Samad, et al. "Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal‐onset diabetes." Clinical Genetics 99, no. 5 (February 17, 2021): 694–703. http://dx.doi.org/10.1111/cge.13930.
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Direito, Inês, Liliana Monteiro, Tânia Melo, Daniela Figueira, João Lobo, Vera Enes, Gabriela Moura, et al. "Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance." Cancers 13, no. 13 (June 26, 2021): 3195. http://dx.doi.org/10.3390/cancers13133195.
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The protein quality control network, including autophagy, the proteasome and the unfolded protein response (UPR), is triggered by stress and is overactive in acquired antiestrogen therapy resistance. We show for the first time that the aggresome load correlates with apoptosis and is increased in antiestrogen-sensitive cells compared to endocrine-resistant variants. LC-MS/MS analysis of the aggregated proteins obtained after 4OH-tamoxifen and Fulvestrant treatment identified proteins with essential function in protein quality control in antiestrogen-sensitive cells, but not in resistant variants. These include the UPR modulators RTCB and PDIA6, as well as many proteasome proteins such as PSMC2 and PSMD11. RTCB is a tRNA and XBP1 ligase and its aggregation induced by antiestrogens correlated with impaired XBP1s expression in sensitive cells. Knock down of RTCB was sufficient to restore sensitivity to tamoxifen in endocrine-resistant cells and increased the formation of aggresomes, leading to apoptotic cell death. Analysis of primary human breast cancer samples and their metastases appearing after endocrine treatment showed that RTCB is only localized to aggresomes in the primary tumors, while total aggresomes, including aggregated RTCB, were significantly reduced in the metastases. Therefore, different protein aggregation patterns may indicate loss of function of essential proteins resulting in enhanced protein aggregation that can be used to identify antiestrogen-resistant breast cancer cells and improve the response to antiestrogenic therapy.
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Herr, Ingrid, Heiner Sähr, Zhefu Zhao, Libo Yin, Georg Omlor, Burkhard Lehner, and Jörg Fellenberg. "MiR-127 and miR-376a act as tumor suppressors by in vivo targeting of COA1 and PDIA6 in giant cell tumor of bone." Cancer Letters 409 (November 2017): 49–55. http://dx.doi.org/10.1016/j.canlet.2017.08.029.
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Kullmann, Maximilian, Ganna V. Kalayda, Malte Hellwig, Sandra Kotz, Ralf A. Hilger, Sabine Metzger, and Ulrich Jaehde. "Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance." Journal of Inorganic Biochemistry 153 (December 2015): 247–52. http://dx.doi.org/10.1016/j.jinorgbio.2015.08.028.
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Shide, Kotaro, Takuro Kameda, Ayako Kamiunten, Yoshinori Ozono, Yuki Tahira, Masaaki Sekine, Masaya Ono, et al. "The Role of Calreticulin in Normal Hematopoiesis and Neoplastic Hematopoiesis of Myeloproliferative Neoplasms." Blood 134, Supplement_1 (November 13, 2019): 309. http://dx.doi.org/10.1182/blood-2019-130034.
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Mutations in the Calreticulin (CALR) gene were identified in cases of myeloproriferative neoplasms (MPNs), and various functions of the CALR mutant protein are being elucidated. On the other hand, few data are available on the role of CALR in the hematopoietic system. The knockout (KO) mice of Calr are impaired in expression of transcription factors necessary for cardiac development and are embryonic lethal. To clarify the role of CALR in normal hematopoiesis and MPN pathogenesis, we generated hematopoietic cell-specific Calr KO mice. Mice carrying floxed allele targeted exons 4-7 of Calr (Calrf/+ mice) and Calr heterozygous KO mice (Calr+/− mice) (Tokuhiro et al., Sci Rep 2015) were crossed with Mx1-Cre transgenic mice and obtained mice with three genotypes; Mx1-cre;Calr+/+, Mx1-cre;Calr+/−, and Mx1-cre;Calrf/−. Floxed alleles were then deleted by intraperitoneal injection with polyinosinic: polycytidilic acid. No differences were found in the peripheral blood (PB) leukocyte count, hemoglobin levels, or platelet count among the three genotypes of mice. The proportions of Mac1+ or Gr1+ myeloid lineage cells, B220+ B cells, and CD3+ T cells among the three groups were comparable. In the bone marrow (BM), cell pellet from Mx1-cre;Calrf/− mice appeared anemic and the proportion of CD71+/Ter119+ erythroid cells and the number of CFU-E were significantly lower in Mx1-cre;Calrf/− BM cells compared to the other two genotypes of BM cells. On the other hand, no difference was found in other mature cells such as myeloid, T, B, or CD41+ megakaryocytes (Mks) in BM. As for HSCs and progenitors, Mx1-cre;Calrf/− mice exhibited a higher proportion of MPP and GMP compared to the other two genotypes of mice. We found no difference in other progenitor compartments including long- and short-term HSCs among the three groups. In contrast to the minor effect on BM and PB cells, The spleen weight in Mx1-cre;Calrf/− mice was about 2-fold heavier than that in Mx1-cre;Calr+/+ mice. In spleens from Mx1-cre;Calrf/− mice, the border between the white and red pulp was obscured. Mks and maturing myeloid cells had markedly infiltrated into the red pulp. In FACS analysis, mature myeloid cells, erythroid cells, and Mks were significantly increased in spleens from Mx1-cre;Calrf/− mice compared to those from the other two genotypes of mice. HSCs and most types of myeloid progenitors were also increased in the spleen. Hematopoiesis in the spleen may compensate for the reduced erythropoiesis in the BM, as no anemia was seen in Mx1-cre;Calrf/− mice. No onset of leukemia or myelofibrosis was observed, and no difference in survival was seen among the three groups following observation for 2 years. As CALR plays a role as a chaperone in the endoplasmic reticulum (ER) during protein synthesis, we searched for proteins with expression that was reduced by Calr deficiency. The quantitative differences of proteins in Mac1+/Gr1+ BM cells between Mx1-cre;Calrf/− and Mx1-cre;Calr+/+ mice were compared using proteomics analysis by 2DICAL, a shotgun proteomics analysis system (Ono et al. Cellular Proteomics 2006). We found that only a few proteins, including myeloperoxidase and CALR itself, were reduced, and conversely, many proteins were increased by the absence of CALR. List of differentially upregulated proteins higher than those in WT samples were analyzed using Metascape (http://metascape.org) to determine enriched pathways. The most enriched cluster was "protein processing in the ER", and 19 out of 76 upregulated (>1.8-fold) proteins were included in this cluster. In real-time PCR analysis, we confirmed that ER chaperon genes (BiP, Grp94, Hsp40, Pdia3, Pdia4, Pdia6) and genes involved in ER-related degradation (Trap, Bap31, Derl1, p97) were significantly upregulated in Mx1-cre;Calrf/− myeloid cells. These observations suggested that chaperone dysfunction due to Calr deficiency is compensated by upregulation of unfolded protein response (UPR) pathway. In summary, Calr deficiency induced erythroid hypoplasia in the BM, and induced splenomegaly and extramedullary hematopoiesis. This suggests that the amount of WT CALR expression remaining in CALR mutant cells may modify the phenotype of MPN patients. Absence of myeloperoxidase protein and upregulation of UPR pathway in myeloid cells from Calr KO mice indicates that CALR plays a significant role as a chaperone also in hematopoiesis and that CALR deficient cells are exposed to ER stress. Disclosures No relevant conflicts of interest to declare.
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Pinto, Rute D., Ana R. Moreira, Pedro J. B. Pereira, and Nuno M. S. dos Santos. "Two thioredoxin-superfamily members from sea bass (Dicentrarchus labrax, L.): Characterization of PDI (PDIA1) and ERp57 (PDIA3)." Fish & Shellfish Immunology 35, no. 4 (October 2013): 1163–75. http://dx.doi.org/10.1016/j.fsi.2013.07.024.
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Kibitov, A., A. Rakitko, E. Kasyanov, D. Yermakovich, A. Kibitov, G. Rukavishnikov, V. Ilinsky, et al. "Genome-wide association study of depression symptoms using online self-questionnaires in the Russian population cohort: preliminary results." European Psychiatry 65, S1 (June 2022): S327. http://dx.doi.org/10.1192/j.eurpsy.2022.832.
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Introduction Depression is a chronic, recurrent mental disorder with a moderate level of genetic impact. Modern GWAS of depression require extra-large sample sizes and new effective, clinically sensitive, objective and simple to fill online phenotyping tools for population studies are necessary today. Objectives Aim: to test online phenotyping tools based on clinical and psychometric instruments to evaluate depressive symptoms in population cohort for using in GWAS Methods Participants: 2610 Russian-speaking respondents- clients of Genotek Ltd., provider of genetic testing services in Russian Federation. The online survey included HADS-D (Hospital Anxiety and Depression Scale - depression subscale), original questionnaire adapted for self-report from major depression DSM-5 criteria, questions about sex and age. Three research phenotypes were defined: quantitative “HADS-D score” and two categorical “HADS-D depression” (cut-off 8 points) - 20.63 %, “DSM depression” 16.73 %. DNA samples obtained from saliva were genotyped on Illumina Infinium GSA v1.0/v2.0/v3.0 microarrays. GWAS analysis was performed independently for each of the research phenotypes. Results None of the signals reached genome-wide significance (p value 10-8), but some signals with subthreshold significance were identified including four signals in the genes encoding proteins: “DSM_Depression”: rs2131596 in GRIP1 (p=3.682e-06,β=0.6965), rs11158021 in SAMD4A (p=2.841e-06, β=0.6762), “HADS-D Depression”: rs2425793 in CDH22 (p=4.408e-07, β=1.539), rs36006890 in PDIA6 (p = 6.529e-07, β=1.549). Conclusions Preliminary results of the first GWAS of depression symptoms in the Russian population are acceptable and confirm the accuracy of the research strategy using online phenotyping tools based on clinical and psychometric instruments and provide basis for further studies. Disclosure The study was supported by Russian Science Foundation Grant # 20-15-00132
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Zhou, zhaoming, Mingyao Lai, Jiangfen Zhou, Qingjun Hu, Ruyu Ai, shaoqun Li, Cheng Zhou, and Linbo Cai. "TAMI-11. INCREASED M1 MACROPHAGE INFILTRATION CORRELATED WITH POOR PROGNOSIS OF WHO IV GLIOMAS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi200. http://dx.doi.org/10.1093/neuonc/noab196.795.
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Abstract BACKGROUND Gliomas are the malignancy with a poor prognosis. Our previous database mining study demonstrated that M1 macrophage infiltration predicted the survival of GBM patients. Here in this study, we further explored the findings. METHODS RNA-seq was performed on 90 WHO IV glioma tissue samples. The sequencing data was investigated with xCell for the cell infiltration levels, and the M1 macrophage infiltration was further analyzed for the prognostic prediction effect with overall survival (OS) data. Differentially expressed genes (DEGs) were calculated between groups and the hub genes were determined by the MCC models in Cytoscape. The survival risk score (SRS) calculating models were established by several machine learning methods, including the least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM), and linear discriminant analysis (LDA). RESULTS Compared with M1 macrophages none infiltration, WHO IV gliomas with M1 macrophages infiltration was associated with poor prognosis, and this result remained significant in multivariate analyses (hazard ratio [HR], 0.219; 95% CI, 0.047–0.723; P = 0.035). Protein-to-protein (PPI) network analysis of top 200 up-regulated DEGs determined 10 hub genes (P4HB, PDIA6, LAMB1, PRKCSH, CSF1, LAMB2, LGALS1, RCN1, CALU, and TNC). Further analysis determined that the 10 hub genes were enriched in the ECM-receptor interaction signaling pathway, and six out of the ten gene expressions were confirmed by immunohistochemistry staining. Based on the 6 genes, a survival risk score (SRS) was established by machine learning methods. SRS was able to distinguish the high-risk and low-risk WHO IV gliomas with an AUC = 0.80 [95% CI: 0.74 – 0.86, P < 0.01]. CONCLUSIONS M1 macrophage infiltration was an unfavorable prognostic biomarker for WHO IV gliomas. ECM-receptor interaction signaling pathway was involved in M1 macrophage infiltration. Hub genes in the signaling pathway could be the potential therapeutic targets for WHO IV gliomas.
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Herrero, Ana B., Quwaider Dalia, Luis Antonio Corchete Sanchez, Ramon Garcia-Sanz, and Norma Gutierrez. "FAM46C Controls Antibody Production By the Polyadenylation of Ig mRNAs and Inhibits Cell Migration in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 1880. http://dx.doi.org/10.1182/blood-2018-99-111787.
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Abstract FAM46C, which is frequently mutated in multiple myeloma (MM), has recently been shown to encode a non-canonical poly(A) polymerase (ncPAP). However, its target mRNAs and its role in MM pathogenesis remain largely unknown. Using CRISPR-Cas9 technology and gene expression analysis we found that inactivation of FAM46C in MM downregulates immunoglobulins (Igs) and several mRNAs encoding ER-resident proteins, including some involved in unfolded protein response (UPR), such as PDIA6, ERP44 and EDEM2, and others that affect glycosylation, such as SSR4, AGA and DDOST. We also found that FAM46C knockout cells exhibited lower ER stress than controls after treatment with tunicamycin, as indicated by RT-PCR analysis of spliced/unspliced forms of XBP1 mRNA. Interestingly, we show that FAM46C expression is induced during PC differentiation and that Ig mRNAs encoding secretory heavy and light chains are direct substrates of the ncPAP, as revealed by poly(A) tail-length determination assays. The absence of the ncPAP results in Ig mRNA poly(A) tail-shortening, leading to a reduction in mRNA and protein abundance. On the other hand, loss of FAM46C upregulated metastasis-associated lncRNA MALAT1 and results in a sharp increase in the migration ability of MM cells. This phenotype depends mainly on the activation of PI3K/Rac1 signaling in FAM46C knockout cells since treatment with specific inhibitors substantially reduces cell mobility. This finding may have significant therapeutic implications. In conclusion, our results identify, for the first time, Ig mRNAs as targets of FAM46C, reveal an important function of this protein during PC maturation to increase antibody production, and suggest that its role as a tumor suppressor might be related with the inhibition of cell migration in MM. Disclosures Garcia-Sanz: Affimed: Research Funding.
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Fellenberg, Jörg, Heiner Sähr, Pierre Kunz, Zhefu Zhao, Li Liu, Diana Tichy, and Ingrid Herr. "Restoration of miR-127-3p and miR-376a-3p counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells by targeting COA1, GLE1 and PDIA6." Cancer Letters 371, no. 1 (February 2016): 134–41. http://dx.doi.org/10.1016/j.canlet.2015.10.039.
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Liu, Yang, Hua He, Zimu Song, Zheng Liu, and Kai Zhu. "Lin-28 Homolog B-Activated Protein Disulfide Isomerase A4 Regulates Cell Proliferation, Migration and Invasion of Glioma." Journal of Biomaterials and Tissue Engineering 12, no. 10 (October 1, 2022): 1972–80. http://dx.doi.org/10.1166/jbt.2022.3129.
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The goal of this study is to elucidate the role of protein disulfide isomerase A4 (PDIA4) in glioma, as well as its regulatory mechanism. Cell transfection was performed to adjust the expression level of PDIA4 and RNA-binding protein lin-28 homolog B (LIN28B). The expression of PDIA4 in human astrocytes and glioma cell lines was determined by quantitative real-time PCR and western blot. CCK-8, colony formation, Transwell and wound-healing assays were applied to determine the capabilities of cells to proliferate, invade and migrate. The connection between PDIA4 and LIN28B was demonstrated by RNA immunoprecipitation (RIP) and RNA pull down assays. As a result, PDIA4 was elevated in glioma. PDIA4 depletion hugely suppressed cell proliferative ability, which was characterized by the reduced cell viability and colony formation, and declined contents of PCNA and Ki67. Meanwhile, PDIA4 knockdown repressed the cell capabilities to migrate and invade, accompanied with downregulated MMP2 and MMP9. LIN28N was also found to be upregulated in glioma cells, and was verified to bind with PDIA4 and positively regulate PDIA4 expression. Additionally, LIN28B overexpression partly hindered the suppressive impacts of PDIA4 knockdown on cell abilities to proliferate, migrate and invade. In conclusion, this study delineates that LIN28B-mediated PDIA4 plays a critical role in the progression of glioma.
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Chen, Jiaxuan, Kirill S. Lobachev, Brian J. Grindel, Mary C. Farach-Carson, Sharon L. Hyzy, Khairat B. El-Baradie, Rene Olivares-Navarrete, Maryam Doroudi, Barbara D. Boyan, and Zvi Schwartz. "Chaperone Properties of Pdia3 Participate in Rapid Membrane Actions of 1α,25-Dihydroxyvitamin D3." Molecular Endocrinology 27, no. 7 (July 1, 2013): 1065–77. http://dx.doi.org/10.1210/me.2012-1277.
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Abstract Protein disulfide isomerase family A, member 3 (Pdia3) mediates many of the plasma membrane (PM)-associated rapid responses to 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3). It is not well understood how Pdia3, which is an endoplasmic reticulum (ER) chaperone, functions as a PM receptor for 1α,25(OH)2D3. We mutated 3 amino acids (K214 and R282 in the calreticulin interaction site and C406 in the isomerase catalytic site), which are important for Pdia3's ER chaperone function, and examined their role in responses to 1α,25(OH)2D3. Pdia3 constructs with and without the ER retention signal KDEL were used to investigate the PM requirement for Pdia3. Finally, we determined whether palmitoylation and/or myristoylation were required for Pdia3-mediated responses to 1α,25(OH)2D3. Overexpressing the Pdia3 R282A mutant in MC3T3-E1 cells increased PM phospholipase A2-activating protein, Rous sarcoma oncogene (c-Src), and caveolin-1 but blocked increases in 1α,25(OH)2D3-stimulated protein kinase C (PKC) seen in cells overexpressing wild-type Pdia3 (Pdia3Ovr cells). Cells overexpressing Pdia3 with K214A and C406S mutations had PKC activity comparable to untreated controls, indicating that the native response to 1α,25(OH)2D3 also was blocked. Overexpressing Pdia3[−KDEL] increased PM localization and augmented baseline PKC, but the stimulatory effect of 1α,25(OH)2D3 was comparable to that seen in wild-type cultures. In contrast, 1α,25(OH)2D3 increased prostaglandin E2 in Pdia3[±KDEL] cells. Although neither palmitoylation nor myristoylation was required for PM association of Pdia3, myristoylation was needed for PKC activation. These data indicate that both the chaperone functional domains and the subcellular location of Pdia3 control rapid membrane responses to 1α,25(OH)2D3.
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Hellewell, Andrew L., Kate J. Heesom, Mark A. Jepson, and Josephine C. Adams. "PDIA3/ERp57 promotes a matrix-rich secretome that stimulates fibroblast adhesion through CCN2." American Journal of Physiology-Cell Physiology 322, no. 4 (April 1, 2022): C624—C644. http://dx.doi.org/10.1152/ajpcell.00258.2021.
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The matricellular glycoprotein thrombospondin-1 (TSP1) has complex roles in the extracellular matrix (ECM) and at cell surfaces, but relatively little is known about its intracellular associations prior to secretion. To search for novel intracellular interactions of TSP1 in situ, we carried out a biotin ligase-based TSP1 interactome screen and identified protein disulfide isomerase A3 (PDIA3/ERp57) as a novel candidate binding protein. In validation, TSP1 and PDIA3 were established to bind in vitro and to colocalize in the endoplasmic reticulum of human dermal fibroblasts (HDF). Loss of PDIA3 function, either by pharmacological inhibition in HDF or in Pdia3−/− mouse embryo fibroblasts ( Pdia3−/− MEFs), led to alterations in the composition of cell-derived extracellular matrix, involving changed abundance of fibronectin and TSP1, was correlated with reduced cell spreading, altered organization of F-actin, and reduced focal adhesions. These cellular phenotypes of Pdia3−/− MEFs were normalized by exposure to conditioned medium (WTCM) or extracellular matrix (WTECM) from wild-type (WT)-MEFs. Rescue depended on PDIA3 activity in WT-MEFs and was not prevented by immunodepletion of fibronectin. Heparin-binding proteins in WTCM were found to be necessary for rescue. Comparative quantitative tandem-mass-tag proteomics and functional assays on the heparin-binding secretomes of WT-MEFs and Pdia3−/− MEFs identified multiple ECM and growth factor proteins to be downregulated in the CM of Pdia3−/− MEFs. Of these, cell communication network 2 (CCN2) was identified to be necessary for the adhesion-promoting activity of WTCM on Pdia3−/− MEFs and to bind TSP1. Thus, PDIA3 coordinates fibroblast production of an ECM-rich, proadhesive microenvironment, with implications for PDIA3 as a translational target.
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Mo, Hui-Qin, Fu-Ju Tian, Xiao-Ling Ma, Yu-Chen Zhang, Cheng-Xi Zhang, Wei-Hong Zeng, Yan Zhang, and Yi Lin. "PDIA3 regulates trophoblast apoptosis and proliferation in preeclampsia via the MDM2/p53 pathway." Reproduction 160, no. 2 (August 2020): 293–305. http://dx.doi.org/10.1530/rep-20-0156.
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Protein disulfide isomerase 3 (PDIA3) is a chaperone protein that modulates the folding of newly synthesized glycoproteins, has isomerase and redox activity, and has been implicated in the pathogenesis of many diseases. However, the role of PDIA3 in pregnancy-associated diseases remains largely unknown. Our present study reveals a key role for PDIA3 in the biology of placental trophoblasts from women with preeclampsia (PE). Immunohistochemistry and Western blot analysis revealed that PDIA3 expression was decreased in villous trophoblasts from women with PE compared to normotensive pregnancies. Further, using a Cell Counting Kit-8 assay, flow cytometry, and 5-ethynyl-2’-deoxyuridine (EdU) staining, we found that siRNA-mediated PDIA3 knockdown significantly promoted apoptosis and inhibited proliferation in the HTR8/SVneo cell line, while overexpression of PDIA3 reversed these effects. Furthermore, RNA sequencing and Western blot analysis demonstrated that knockdown of PDIA3 inhibited MDM2 protein expression in HTR8 cells, concurrent with marked elevation of p53 and p21 expression. Conversely, overexpression of PDIA3 had the opposite effects. Immunohistochemistry and Western blot further revealed that MDM2 protein expression was downregulated and p21 was increased in trophoblasts of women with PE compared to women with normotensive pregnancies. Our findings indicate that PDIA3 expression is decreased in the trophoblasts of women with PE, and decreased PDIA3 induces trophoblast apoptosis and represses trophoblast proliferation through regulating the MDM2/p53/p21 pathway.
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Zhang, Jing, Hui Li, Huling Li, Dandan Lin, Xiaoyan Wang, and Kai Wang. "Expression and Prognostic Significance of PDIA3 in Cervical Cancer." International Journal of Genomics 2022 (November 11, 2022): 1–25. http://dx.doi.org/10.1155/2022/4382645.
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To investigate the expression of protein disulfide isomerase A3 (PDIA3/ERP57) in cervical cancer and its clinical prognostic significance as well as its function and possible action mechanism in the progression of cervical cancer. Based on TIMER2.0 database, the human protein map (Human Protein Atlas) was used to determine the expression level of PDIA3 protein for the analysis of PDIA3 expression in 39 The Cancer Genome Atlas (TCGA) tumors. The PDIA3 expression in cervical cancer tissues in the TCGA and Genotype-Tissue Expression databases was further verified based on the GEPIA2 database to analyze the relationship between the PDIA3 expression and the pathological stage of cervical cancer patients. Immunohistochemistry was used to detect the PDIA3 expression in cervical cancer tissue microarray, including 111 cancer tissue samples and 24 adjacent cancer tissue samples, and the relationship between PDIA3 protein expression and clinical characteristics of patients with cervical cancer was analyzed. The Kaplan–Meier method and log-rank test were used for survival analysis. Based on the cBioPortal database, the Spearman’s and Pearson’s methods were used to analyze the correlation between PDIA3 expression and DNA methylation. The correlation between PDIA3 expression and the infiltration levels of each immune cell in cervical cancer was evaluated. The STRING was used to construct protein interaction network. Based on LinkedOmics database, the Spearman’s method was used to analyze the co-expressed genes of PDIA3 in TCGA cervical cancer. The gene ontology functional enrichment analysis was performed on Top 50 differentially co-expressed genes based on DAVID database. The PDIA3 expression in cervical cancer tissues was significantly higher than that in normal tissues, which ( F = 2.74 , PR (>F) = 0.0436) was significantly increased with the progression of tumor stage, and PDIA3 showed strong immunoreactivity in cervical cancer tissues. In cervical cancer patients, overall survival ( P = 0.014 ), disease-specific survival ( P = 0.013 ), disease-free interval ( P = 0.023 ), and progression-free interval ( P = 0.001 ) in those with high expression of PDIA3 were significantly lower than those with low expression, suggesting that high expression of PDIA3 was associated with poor prognosis. In cervical cancer, high expression of PDIA3 was associated with DNA methylation and negatively correlated with B cell memory ( r = − 0.132 , P = 0.021 ), T cell regulatory ( r = − 0.127 , P = 0.026 ), monocytes ( r = − 0.204 , P = 0 ), and macrophages M2 ( r = − 0.142 , P = 0.013 ), whereas positively correlated with levels of NK cell activated ( r = 0.162 , P = 0.005 ) and mast cells activated ( r = 0.119 , P = 0.037 ). The genes positively correlated with PDIA3 expression included HSPA5 and PPIB, which were mainly enriched in biological processes, such as endoplasmic reticulum (ER) protein folding and ER stress response. PDIA3 can be used as a marker of poor prognosis of cervical cancer. The expression level of PDIA3 is closely related to the survival and prognosis of cervical cancer patients, DNA methylation, and immune cell infiltration.
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Peña, Esther, Gemma Arderiu, and Lina Badimon. "Protein disulphide-isomerase A2 regulated intracellular tissue factor mobilisation in migrating human vascular smooth muscle cells." Thrombosis and Haemostasis 113, no. 04 (July 2015): 891–902. http://dx.doi.org/10.1160/th14-09-0776.
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SummaryProtein-disulphide isomerase family (PDI) are an ER-stress protein that controls TF-procoagulant activity but its role in HVSMC migration and coronary artery disease remains to be elucidated. We aimed to investigate whether in human coronary smooth muscle cells (HVSMC) the ER-stress protein-disulphide isomerase family A member 2 (PDIA2) regulates tissue factor (TF) polarisation during migration and atherosclerotic remodeling. PDIA2 and TF were analysed by confocal microscopy, silenced by small interfering RNAs (siRNA) and their function analysed by transwell and migration assays in vitro and in vivo. PDIA2and TF co-localise in the front edge of motile HVSMC. Silencing PDIA2, as well as silencing TF, reduces migration. PDIA2 silenced cells show increased TF-rich microparticle shedding. In vivo cell-loaded plug implants in nude mice of PDIA2 silenced HVSMC together with microvascular endothelial cells showed a significant impairment in mature microvessel formation. PDIA2 and TF are found in remodelled atherosclerotic plaques but not in healthy coronaries. In conclusion, we demonstrate that TF is chaperoned by PDIA2 to the HVSMC membrane and to the cell migratory front. Absence of PDIA2 impairs TF intracellular trafficking to its membrane docking favoring its uncontrolled release in microparticles. TF-regulated HVSMC migration and microvessel formation is under the control of the ER-protein PDIA2.
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Song, Danyang, Meng Guo, Kaichu Wu, Jianyu Hao, Yongzhan Nie, and Daiming Fan. "Silencing of ER-resident oxidoreductase PDIA3 inhibits malignant biological behaviors of multidrug-resistant gastric cancer." Acta Biochimica et Biophysica Sinica 53, no. 9 (August 7, 2021): 1216–26. http://dx.doi.org/10.1093/abbs/gmab101.
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Abstract Glycosylation is a common posttranslational modification of proteins, which plays a role in the malignant transformation, growth, progression, chemoresistance, and immune response of tumors. Disulfide isomerase family A3 (PDIA3) specifically acts on newly synthesized glycoproteins to promote the correct folding of sugar chains. Studies have shown that PDIA3 participates in multidrug-resistant gastric cancer (MDR-GC). In this study, we performed western blot analysis and immunohistochemistry to identify PDIA3 expression. Cell proliferation was assessed by CCK-8 assay. Transwell assays were used to detect the migration and invasion abilities of cells. Immunoprecipitation coupled to mass spectrometry (IP-MS) analysis was employed to identify PDIA3-interacting proteins and the associated pathways in MDR-GC cells. Glycoprotein interactions and translocation were detected by immunofluorescence assay. The results showed that PDIA3 knockdown significantly inhibited the proliferation, invasion, and migration abilities of MDR-GC cells. Kyoto Encyclopedia of Genes and Genomes analysis of the IP-MS results showed that PDIA3 was closely associated with focal adhesion pathways in MDR-GC cells. Additionally, important components of focal adhesion pathways, including fibronectin-1 (FN1) and integrin α5 (ITGA5), were identified as pivotal PDIA3-binding glycoproteins. Knockdown of PDIA3 altered the cellular locations of FN1 and ITGA5, leading to abnormal accumulation. In conclusion, our results suggest that knockdown of PDIA3 inhibited the malignant behaviors of MDR-GC cells and influenced the translocation of FN1 and ITGA5.
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Zhang, Jing, Kai Wang, Tuersun Hainisayimu, and Hui Li. "Pan-Cancer Analysis of PDIA3: Identifying It as a Potential Biomarker for Tumor Prognosis and Immunotherapy." Oxidative Medicine and Cellular Longevity 2022 (August 22, 2022): 1–42. http://dx.doi.org/10.1155/2022/9614819.
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Protein disulfide isomerase A3 (PDIA3) is a kind of thiol oxidoreductase with a wide range of functions, and its expression is elevated in a variety of tumors, which is closely related to the invasion and metastasis of tumor cells, and has a significant impact on the immunogenicity of tumor cells. Although more and more studies have shown that PDIA3 plays an important role in the occurrence and development of many tumors, there is no systematic pan-cancer study on PDIA3. Therefore, in this study, the differential expression of PDIA3 in 33 kinds of tumors was analyzed to explore its ability to regulate tumor immunity as a biomarker and evaluate its role in different cancer onset stages or clinical prognosis. In this paper, by analyzing the multilevel data including 33 kinds of cancers in the databases of Cancer Genome Atlas (TCGA), UCSC Xena, Cancer Cell Encyclopedia (CCLE), Genotypic Tissue Expression (GTEx), Human Protein Atlas (HPA), cBioPortal, and GDC; the differential expression level of PDIA3 in different types of malignant tumors and its relationship with prognosis and the potential correlation between PDIA3 expression and microsatellite instability (MSI), tumor mutation load (TMB), mismatch repair gene (MMR), DNA methylation level, and immune infiltration level were analyzed with bioinformatics. The results showed that PDIA3 was highly expressed in 19 types of cancers, but downregulated only in THCA. Next, PDIA3 in different tumors was positively or negatively correlated with patient outcome, Kaplan-Meier survival analysis showed that PDIA3 plays an important role in the prognosis of patients with KIRP, KICH, and CESC and may be used as a prognostic biomarker, and the methylation level of PDIA3 promoter region was closely related to patient outcome in eight tumors. The expression level of PDIA3 was correlated with TMB in 13 tumors and MSI in 9 tumors. Among them, the expression level of PDIA3 in THYM has the strongest correlation with TMB, and the expression level of PDIA3 in READ has the strongest correlation with MSI. In addition, the expression of PDIA3 in eight kinds of tumors, including BRCA, HNSC, THYM, LGG, LUAD, LUSC, PRAD, and THCA, had the highest correlation with the infiltration degree of immune cells, and the expression of PDIA3 had the highest correlation with the infiltration degree of 11 kinds of immune cells, including regulatory T cell and macrophages. And LGG is the tumor most likely to be affected by the tumor microenvironment to affect its development and prognosis. To sum up, this study suggests that PDIA3 plays an important role in the occurrence and development of KIRP, KICH, and CESC and in the immunotherapeutic response of THYM, READ, and LGG and can be used as a prognostic biomarker for these tumors.
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Stojak, Marta, Magdalena Milczarek, Anna Kurpinska, Joanna Suraj-Prazmowska, Patrycja Kaczara, Kamila Wojnar-Lason, Joanna Banach, et al. "Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells." Cancers 12, no. 10 (October 2, 2020): 2850. http://dx.doi.org/10.3390/cancers12102850.
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Cancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial migration. For comparison, the role of PDIA1 in proliferation, migration, cell cycle and apoptosis was also assessed. Pharmacological inhibitor, bepristat 2a and PDIA1 silencing were used to inhibit PDIA1. Inhibition of PDIA1 by bepristat 2a markedly decreased the adhesion of breast cancer cells to collagen type I, fibronectin and human lung microvascular endothelial cells. Transendothelial migration of breast cancer cells across the endothelial monolayer was also inhibited by bepristat 2a, an effect not associated with changes in ICAM-1 expression or changes in cellular bioenergetics. The silencing of PDIA1 produced less pronounced anti-adhesive effects. However, inhibiting extracellular free thiols by non-penetrating blocker p-chloromercuribenzene sulphonate substantially inhibited adhesion. Using a proteomic approach, we identified that β1 and α2 integrins were the most abundant among all integrins in breast cancer cells as well as in lung microvascular endothelial cells, suggesting that integrins could represent a target for PDIA1. In conclusion, extracellular PDIA1 plays a major role in regulating the adhesion of cancer cells and their transendothelial migration, in addition to regulating cell cycle and caspase 3/7 activation by intracellular PDIA1. PDIA1-dependent regulation of cancer–endothelial cell interactions involves disulphide exchange and most likely integrin activation but is not mediated by the regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells.
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Chiavari, Marta, Gabriella Maria Pia Ciotti, Francesco Canonico, Fabio Altieri, Pedro Miguel Lacal, Grazia Graziani, Pierluigi Navarra, and Lucia Lisi. "PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation." International Journal of Molecular Sciences 21, no. 21 (November 3, 2020): 8214. http://dx.doi.org/10.3390/ijms21218214.
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The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played by the endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3), the modulation of which has been reported in a variety of cancers. Moreover, by using The Cancer Genome Atlas database, we found that overexpression of PDIA3 correlated with about 55% reduction of overall survival of glioma patients. Therefore, we analyzed the expression of ERp57/PDIA3 using specimens obtained after surgery from 18 GB patients. Immunohistochemical analysis of tumor samples revealed ERp57/PDIA3 expression in GB cells as well as in GAMs. The ERp57/PDIA3 levels were higher in GAMs than in the microglia present in the surrounding parenchyma. Therefore, we studied the role of PDIA3 modulation in microglia–glioma interaction, based on the ability of conditioned media collected from human GB cells to induce the activation of microglial cells. The results indicated that reduced PDIA3 expression/activity in GB cells significantly limited the microglia pro-tumor polarization towards the M2 phenotype and the production of pro-inflammatory factors. Our data support a role of PDIA3 expression in GB-mediated protumor activation of microglia.
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Diaz Cruz, Maria Araceli, Sandra Karlsson, Ferenc Szekeres, Maria Faresjö, Dan Lund, and Dennis Larsson. "Differential expression of protein disulfide-isomerase A3 isoforms, PDIA3 and PDIA3N, in human prostate cancer cell lines representing different stages of prostate cancer." Molecular Biology Reports 48, no. 3 (March 2021): 2429–36. http://dx.doi.org/10.1007/s11033-021-06277-1.
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AbstractProstate cancer (PCa) is a highly heterogeneous and unpredictable progressive disease. Sensitivity of PCa cells to androgens play a central role in tumor aggressiveness but biomarkers with high sensitivity and specificity that follow the progression of the disease has not yet been verified. The vitamin D endocrine system and its receptors, the Vitamin D Receptor (VDR) and the Protein Disulfide-Isomerase A3 (PDIA3), are related to anti-tumoral effects as well as carcinogenesis and have therefore been suggested as potential candidates for the prevention and therapy of several cancer forms, including PCa. In this study, we evaluated the mRNA expression of VDR and PDIA3 involved in vitamin D signaling in cell lines representing different stages of PCa (PNT2, P4E6, LNCaP, DU145 and PC3). This study further aimed to evaluate vitamin D receptors and their isoforms as potential markers for clinical diagnosis of PCa. A novel transcript isoform of PDIA3 (PDIA3N) was identified and found to be expressed in all PCa cell lines analyzed. Androgen-independent cell lines showed a higher mRNA expression ratio between PDIA3N/PDIA3 contrary to androgen-dependent cell lines that showed a lower mRNA expression ratio between PDIA3N/PDIA3. The structure of PDIA3N differed from PDIA3. PDIA3N was found to be a N-truncated isoform of PDIA3 and differences in protein structure suggests an altered protein function i.e. cell location, thioredoxin activity and affinity for 1,25(OH)2D3. Collectively, PDIA3 transcript isoforms, the ratio between PDIA3N/PDIA3 and especially PDIA3N, are proposed as candidate markers for future studies with different stages of PCa progression.
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Yao, Lijun, Reyka G. Jayasinghe, Tianjiao Wang, Julie O'Neal, Ruiyang Liu, Michael P. Rettig, Chia-Feng Tsai, et al. "Myeloma Cell Associated Therapeutic Protein Discovery Using Single Cell RNA-Seq Data." Blood 136, Supplement 1 (November 5, 2020): 4–5. http://dx.doi.org/10.1182/blood-2020-142205.
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Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity. In an effort to identify potential myeloma-specific target antigens, we performed an unbiased search for genes with specific expression in plasma and/or B cells using single-cell RNA-sequencing (scRNAseq) of 53 bone marrow samples taken from 42 patients. By comparing >40K plasma cells to >97K immune cells across our cohort, we were able to identify a total of 181 plasma cell-associated genes, including 65 that encode cell-surface proteins and 116 encoding intracellular proteins. Of particular interest is that the plasma cells from each patient were shown to be transcriptionally distinct with unique sets of genes expressed defining each patient's malignant plasma cells. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to B-Cell receptor (BCR) signaling, protein transport, and endoplasmic reticulum (ER) stress, involving genes such as DERL3, HERPUD1, PDIA4, PDIA6, RRBP1, SSR3, SSR4, TXNDC5, and UBE2J1. To note, our strategy successfully captured several of the most promising MM therapeutic targets currently under pre-clinical and clinical trials, including TNFRSF17(BCMA), SLAMF7, and SDC1 (CD138). Among these, TNFRSF17 showed very high plasma cell expression, with concomitant sharp exclusion of other immune cell types. To ascertain tissue specificity of candidate genes outside of the bone marrow, we analyzed gene and protein expression data from the Genotype-Tissue Expression (GTEx) portal and Human Protein Atlas (HPA). We found further support for several candidates (incl. TNFRSF17,SLAMF7, TNFRSF13B (TACI), and TNFRSF13C) as being both exclusively and highly expressed in lymphoid tissues. While several surface candidates were not found to be lymphocyte-restricted at the protein level, they remain relevant considerations as secondary targets for bi-specific immunotherapy approaches currently under development. To further investigate potential combinatorial targeting, we examine sample-level patterns of candidate co-expression and mutually-exclusive expression using correlation analysis. As the majority of our detected plasma cell-specific genes encode intracellular proteins, we investigated the potential utility of these epitopes as therapeutic targets via MHC presentation. Highly expressed candidates include MZB1, SEC11C, HLA-DOB, POU2AF1, and EAF2. We analyzed protein sequences using NetMHC and NETMHCII to predict high-affinity peptides for common class-I and class-II HLA alleles. To correlate MHC allelic preference with candidate expression in our cohort, we performed HLA-typing for 29 samples using Optitype. To support our scRNAseq-driven findings, we cross-referenced gene expression data with 907 bulk RNA-sequencing samples, including 15 from internal studies and 892 from the Multiple Myeloma Research Foundation (MMRF), as well as bulk global proteomics data from 4 MM cell lines (TIB.U266, RPMI8226, OPM2, MM1ST) and 4 patients. We see consistent trends across both cohorts, with high positive correlation (Pearson R ranging between 0.60 and 0.99) for a majority of genes when comparing scRNA and bulk RNA expression in the same samples. Our experimental design and analysis strategies enabled the efficient discovery of myeloma-associated therapeutic target candidates. In conclusion, this study identified a set of promising myeloma CAR-T targets, providing novel treatment options for myeloma patients. Disclosures Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.
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Cassano, Tommaso, Flavia Giamogante, Silvio Calcagnini, Adele Romano, Angelo Michele Lavecchia, Francesca Inglese, Giuliano Paglia, et al. "PDIA3 Expression Is Altered in the Limbic Brain Regions of Triple-Transgenic Mouse Model of Alzheimer’s Disease." International Journal of Molecular Sciences 24, no. 3 (February 3, 2023): 3005. http://dx.doi.org/10.3390/ijms24033005.
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In the present study, we used a mouse model of Alzheimer’s disease (AD) (3×Tg-AD mice) to longitudinally analyse the expression level of PDIA3, a protein disulfide isomerase and endoplasmic reticulum (ER) chaperone, in selected brain limbic areas strongly affected by AD-pathology (amygdala, entorhinal cortex, dorsal and ventral hippocampus). Our results suggest that, while in Non-Tg mice PDIA3 levels gradually reduce with aging in all brain regions analyzed, 3×Tg-AD mice showed an age-dependent increase in PDIA3 levels in the amygdala, entorhinal cortex, and ventral hippocampus. A significant reduction of PDIA3 was observed in 3×Tg-AD mice already at 6 months of age, as compared to age-matched Non-Tg mice. A comparative immunohistochemistry analysis performed on 3×Tg-AD mice at 6 (mild AD-like pathology) and 18 (severe AD-like pathology) months of age showed a direct correlation between the cellular level of Aβ and PDIA3 proteins in all the brain regions analysed, even if with different magnitudes. Additionally, an immunohistochemistry analysis showed the presence of PDIA3 in all post-mitotic neurons and astrocytes. Overall, altered PDIA3 levels appear to be age- and/or pathology-dependent, corroborating the ER chaperone’s involvement in AD pathology, and supporting the PDIA3 protein as a potential novel therapeutic target for the treatment of AD.