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ERO1L promotes NSCLC development by modulating cell cycle-related molecules.

ABSTRACT: Lung cancer is the leading cause of cancer-related death worldwide. Previous studies revealed that endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) played critical roles in the malignant behaviors of several cancer types, but its role in non-small cell lung cancer (NSCLC) remained unclear. In this study, we identified 26 upregulated and 102 downregulated genes in NSCLC using bioinformatics analyses, and these genes were enriched in the biological processes of the cell cycle. ERO1L was remarkably upregulated in NSCLC and overexpression of ERO1L was associated with poor prognosis of NSCLC. ERO1L deficiency markedly suppressed NSCLC cell proliferation, colony formation, migration, and invasion. ERO1L depletion caused a dramatically decreased expression of cell cycle-related factors in NSCLC cells. Collectively, our data validated that ERO1L could function as a tumor promoter in NSCLC, indicating the potential of targeting ERO1L for the treatment of NSCLC.

SUBMITTER: Shi X

PROVIDER: S-EPMC7692932 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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ERO1L promotes NSCLC development by modulating cell cycle-related molecules.

Shi Xiujuan X Wu Jiawen J Liu Yi Y Jiang Yuxiong Y Zhi Changjiang C Li Jue J

Cell biology international 20200915 12

Lung cancer is the leading cause of cancer-related death worldwide. Previous studies revealed that endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) played critical roles in the malignant behaviors of several cancer types, but its role in non-small cell lung cancer (NSCLC) remained unclear. In this study, we identified 26 upregulated and 102 downregulated genes in NSCLC using bioinformatics analyses, and these genes were enriched in the biological processes of the cell cycle. ERO1L was remark ...[more]

PMID: 32841447

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Project description:BACKGROUND:Ovarian cancer is characterized by the high mortality rate and poor prognosis. Nevertheless, the oncogenesis mechanisms of ovarian cancer remain unclear. In our study, we focused on the potential role of lncRNA LINC01127 in the pathogenesis of ovarian cancer and its underlying mechanism. METHODS:LINC01127, which may participate in the development of ovarian cancer, was screened out by bioinformatics analysis. GSEA was used to analyze the function of LINC01127. QRT-PCR was used to analyze the LINC01127 level in 72 cases of ovarian cancer tissues and 53 cases of normal ovarian tissues. LINC01127 level in ovarian cancer cell lines was also determined by qRT-PCR. Subsequently, the selected ovarian tumor cells were transfected with LINC01127 siRNA by Lipofectamine 2000, followed by cell cycle detection using flow cytometry. The regulatory effects of LINC01127 on tumor growth and cell cycle in nude mice were verified by tumor formation assay. The mechanism of LINC01127 involving in cell cycle regulation was further explored by Western Blot. RESULTS:LINC01127 expression in ovarian cancer tissues was significantly higher than that in normal ovary tissues. The expression level of LINC01127 was negatively correlated with the prognosis of patients with ovarian cancer. GSEA analysis showed that LINC01127 was mainly enriched in the regulation of cell cycle. After transfection with LINC01127 siRNA, the proliferative abilities of SKOV3 and HO8910 cells were inhibited and cell cycle was arrested at G1/G0 phase. Tumorigenicity assay in nude mice showed that low expression of LINC01127 inhibited the growth of ovarian tumors. Further study found that LINC01127 knockdown upregulated expression levels of Cyclin D, Cyclin E and CDK4, but dramatically upregulated expression levels of P16 and P21. Meanwhile, the AKT and ERK pathways were inhibited by LINC01127 knockdown. CONCLUSIONS:LINC01127 was up-regulated in ovarian cancer tissues. LINC01127 may be involved in the development of ovarian cancer by accelerating cell cycle progression through promoting the phosphorylation of ERK and AKT.

Project description:Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

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ERO1L promotes NSCLC development by modulating cell cycle-related molecules.

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ERO1L promotes NSCLC development by modulating cell cycle-related molecules.

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