Bioinformatic Analysis of Expression Pattern and Prognostic Value of Oxidoreductase ERO1L in Pancreatic Cancer

Objective: As people continue to succumb to the progression of various forms of cancer, the extreme lethal nature of pancreatic cancer in particular suggests that new therapeutic targets and novel regulatory mechanisms need to be explored. Materials and Methods: We examined ERO1L expression in different cancer types using cBioPortal and Oncomine exploration tools. Next, we analyzed ERO1L levels in pancreatic cancer and healthy tissues via online public databases. The prognostic value of ERO1L and its correlation with clinopathological features were investigated using the UCSC, TNMplot and cBioPortal databases. The correlation analyses were then performed using data obtained from GEPIA, cBioPortal and the Gene Expression Omnibus. Results: The enzyme ERO1L was found to be highly expressed in pancreatic cancer and elevated in tumor compared to healthy tissue. Its levels correlated with the hypoxia level and ER stress activation status of the pancreatic cancer tissues. ERO1L and VEGFA levels were also found to be correlated exclusively in tumor tissue, thus underlying its pro-oncogenic nature. Conclusion: Oxidoreductase ERO1L is a potential prognostic marker and its oncogenic effects might be regulated via hypoxia/ER stress/ERO1L/ VEGFA axis in pancreatic cancer.

PDF

___

[1] Sung, H, Ferlay, J, Siegel, RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209-249.
[2] Siegel, RL, Miller, KD, Jemal, A Cancer statistics, 2020. CA Cancer J Clin. 2020; 70(1): 7-30.
[3] Strobel, O, Neoptolemos, J, Jager, D, et al. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol. 2019; 16(1): 11-26.
[4] Feige, MJ, Hendershot, LM Disulfide bonds in ER protein folding and homeostasis. Curr Opin Cell Biol. 2011; 23(2): 167-175.
[5] Benham, AM, van, LM, Sitia, R, et al. Ero1-PDI interactions, the response to redox flux and the implications for disulfide bond formation in the mammalian endoplasmic reticulum. Philos Trans R Soc Lond B Biol Sci. 2013; 368(1617): 20110403.
[6] Gess, B, Hofbauer, KH, Wenger, RH, et al. The cellular oxygen tension regulates expression of the endoplasmic oxidoreductase ERO1-Lalpha. Eur J Biochem. 2003; 270(10): 2228-2235.
[7] Pagani, M, Fabbri, M, Benedetti, C, et al. Endoplasmic reticulum oxidoreductin 1-lbeta (ERO1-Lbeta), a human gene induced in the course of the unfolded protein response. J Biol Chem. 2000; 275(31): 23685-23692.
[8] Zhang, J, Yang, J, Lin, C, et al. Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer. Theranostics. 2020; 10(18): 8400-8414.
[9] Kutomi, G, Tamura, Y, Tanaka, T, et al. Human endoplasmic reticulum oxidoreductin 1-alpha is a novel predictor for poor prognosis of breast cancer. Cancer Sci. 2013; 104(8): 1091-1096.
[10] Seol, SY, Kim, C, Lim, JY, et al. Overexpression of Endoplasmic Reticulum Oxidoreductin 1-alpha (ERO1L) Is Associated with Poor Prognosis of Gastric Cancer. Cancer Res Treat. 2016; 48(4): 1196-1209.
[11] Yang, S, Yang, C, Yu, F, et al. Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/ VEGF-A pathway. Cell Death Dis. 2018; 9(11): 1105
[12] Tanaka, T, Kutomi, G, Kajiwara, T, et al. Cancer-associated oxidoreductase ERO1-alpha drives the production of VEGF via oxidative protein folding and regulating the mRNA level. Br J Cancer. 2016; 114(11): 1227-1234.
[13] Varone, E, Decio, A, Chernorudskiy, A, et al. The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions. Oncogene. 2021; 40(9): 1721-1736.
[14] Hidalgo, M Pancreatic cancer. N Engl J Med. 2010; 362(17): 1605-1617.
[15] Costache, MI, Ioana, M, Iordache, S, et al. VEGF Expression in Pancreatic Cancer and Other Malignancies: A Review of the Literature. Rom J Intern Med. 2015; 53(3): 199-208.
[16] Cerami, E, Gao, J, Dogrusoz, U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2(5): 401-404.
[17] Gao, J, Aksoy, BA, Dogrusoz, U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6(269): l1.
[18] Rhodes, DR, Kalyana-Sundaram, S, Mahavisno, V, et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007; 9(2): 166-180.
[19] Gou, R, Zhu, L, Zheng, M, et al. Annexin A8 can serve as potential prognostic biomarker and therapeutic target for ovarian cancer: based on the comprehensive analysis of Annexins. J Transl Med. 2019; 17(1): 275.
[20] Bartha, A, Gyorffy, B TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues. Int J Mol Sci. 2021; 22(5).
[21] Tang, Z, Li, C, Kang, B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1): W98-W102.
[22] Zhang, G, Schetter, A, He, P, et al. DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma. PLoS One. 2012; 7(2): e31507.
[23] Goldman, MJ, Craft, B, Hastie, M, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020; 38(6): 675-678.
[24] Rapin, N, Bagger, FO, Jendholm, J, et al. Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients. Blood. 2014; 123(6): 894-904.
[25] di Magliano, MP, Logsdon, CD Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013; 144(6): 1220-1229.
[26] Windon, AL, Loaiza-Bonilla, A, Jensen, CE, et al. A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma. J Gastrointest Oncol. 2018; 9(1): 1-10.
[27] Brahimi-Horn, MC, Chiche, J, Pouyssegur, J Hypoxia and cancer. J Mol Med (Berl). 2007; 85(12): 1301-1307.
[28] May, D, Itin, A, Gal, O, et al. Ero1-L alpha plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer. Oncogene. 2005; 24(6): 1011-1020.
[29] Liu, L, Wang, C, Li, S, et al. ERO1L Is a Novel and Potential Biomarker in Lung Adenocarcinoma and Shapes the Immune-Suppressive Tumor Microenvironment. Front Immunol. 2021; 12: 677169.
[30] Shah, VM, Sheppard, BC, Sears, RC, et al. Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer. Cancer Lett. 2020; 492: 63-70.
[31] Chen, X, Cubillos-Ruiz, JR Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021; 21(2): 71-88.
[32] Han, CC, Wan, FS New Insights into the Role of Endoplasmic Reticulum Stress in Breast Cancer Metastasis. J Breast Cancer. 2018; 21(4): 354-362.
[33] Matsusaki, M, Okuda, A, Matsuo, K, et al. Regulation of plant ER oxidoreductin 1 (ERO1) activity for efficient oxidative protein folding. J Biol Chem. 2019; 294(49): 18820-18835.
[34] Bostrom, PJ, Thoms, J, Sykes, J, et al. Hypoxia Marker GLUT- 1 (Glucose Transporter 1) is an Independent Prognostic Factor for Survival in Bladder Cancer Patients Treated with Radical Cystectomy. Bladder Cancer. 2016; 2(1): 101-109.
[35] Jia, SZ, Xu, XW, Zhang, ZH, et al. Selenoprotein K deficiencyinduced apoptosis: A role for calpain and the ERS pathway. Redox Biol. 2021; 47: 102154.
[36] Chen, X, Liu, F, Xue, Q, et al. Metastatic pancreatic cancer: Mechanisms and detection (Review). Oncol Rep. 2021; 46(5).
[37] Kim, M, Jang, K, Miller, P, et al. VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug. Oncogene. 2017; 36(36): 5199-5211.
[38] Lei, Y, Zang, R, Lu, Z, et al. ERO1L promotes IL6/sIL6R signaling and regulates MUC16 expression to promote CA125 secretion and the metastasis of lung cancer cells. Cell Death Dis. 2020; 11(10): 853.
[39] Tao, LY, Zhang, LF, Xiu, DR, et al. Prognostic significance of K-ras mutations in pancreatic cancer: a meta-analysis. World J Surg Oncol. 2016; 14: 146.
[40] Van, CE, Paccard, C, Chiron, M, et al. Impact of Prior Bevacizumab Treatment on VEGF-A and PlGF Levels and Outcome Following Second-Line Aflibercept Treatment: Biomarker Post Hoc Analysis of the VELOUR Trial. Clin Cancer Res. 2020; 26(3): 717-725.