Upregulation of ERp57 promotes clear cell renal cell carcinoma progression by initiating a STAT3/ILF3 feedback loop.

ERp57 dysfunction has been shown to contribute to tumorigenesis in multiple malignances. However, the role of ERp57 in clear cell renal carcinoma (ccRCC) remains unclear.

Cell proliferation ability was measured by MTT and colony forming assays. Western blotting and quantitative real-time PCR (qRT-PCR) were performed to measure protein and mRNA expression. Co-immunoprecipitation (CoIP) and proximity ligation assay (PLA) were performed to detect protein-protein interaction. Chromatin immunoprecipitation (ChIP), ribonucleoprotein immunoprecipitation (RIP), and oligo pull-down were used to confirm DNA-protein and RNA-protein interactions. Promoter luciferase analysis was used to detect transcription factor activity.

Here we found ERp57 was overexpressed in ccRCC tissues, and the higher levels of ERp57 were correlated with poor survival in patients with ccRCC. In vivo and in vitro experiments showed that ccRCC cell proliferation was enhanced by ERp57 overexpression and inhibited by ERp57 deletion. Importantly, we found ERp57 positively regulated ILF3 expression in ccRCC cells. Mechanically, ERp57 was shown to bind to STAT3 protein and enhance the STAT3-mediated transcriptional activity of ILF3. Furthermore, ILF3 levels were increased in ccRCC tissues and associated with poor prognosis. Interestingly, we revealed that ILF3 could bind to ERp57 and positively regulate its expression by enhancing its mRNA stability. Furthermore, ccRCC cell proliferation was moderated via the ERp57/STAT3/ILF3 feedback loop.

In summary, our results indicate that the ERp57/STAT3/ILF3 feedback loop plays a key role in the oncogenesis of ccRCC and provides a potential therapeutic target for ccRCC treatment.

Journal of experimental & clinical cancer research : CR. 2019 Oct 30*** epublish ***

Yan Liu, Jian-Xing Wang, Zi-Yuan Nie, Yue Wen, Xin-Ju Jia, Li-Na Zhang, Hui-Jun Duan, Yong-Hong Shi

Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China., Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping West Road Shijiazhuang, 050000, Shijiazhuang, People's Republic of China., Department of Endocrinology, The First Hospital of Hebei Medical University, 89 Donggang Road Shijiazhuang, 050000, Shijiazhuang, People's Republic of China., Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China. ., Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China. .