Tumor suppressor OSR1 is modified by SUMO1 and regulates the Wnt/β-catenin signaling pathway in HCC.

Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world. Exploring the underlying molecular mechanisms of HCC, such as those involving small ubiquitin-related modifier (SUMO) and its targets, is worthwhile. A total of 12 HCC tissue samples were collected for immunohistochemistry. The interaction between SUMO1 and OSR1 was confirmed by co-IP and immunofluorescence (IF). The expression (qPCR and Western blot), cytological function (CCK-8, clone formation and transwell assays) of OSR1 was further investigated in HepG2 cells. The anti-tumor function of OSR1 was also verified in the nude mouse xenograft model. Western blot analysis revealed the underlying downstream signaling pathway of SUMO1-modified OSR1 in HCC. Up-regulated co-expression of SUMO1-OSR1 was observed in the HepG2 cells. Through the cytological experiments and a nude mouse xenograft model, we found that OSR1 is a tumor suppressor gene that inhibits the proliferation and invasion of the HepG2 cells in vitro. Intriguingly, SUMO1-OE antagonized OSR1-mediated β-catenin regulation: in nuclei, SUMO1-OE enhanced β-catenin expression, counteracting OSR1-OE-induced suppression, whereas in the cytoplasm, SUMO1-OE inhibited β-catenin accumulation and attenuated OSR1-OE-driven promotion. Hypoxia reversed these effects, suggesting an oxygen-sensitive interplay between SUMO1 and OSR1. In conclusion, OSR1 is a tumor suppressor in HCC via attenuation of the Wnt/β-catenin pathway. SUMO1 modifies OSR1, suppressing the Wnt/β-catenin signaling pathway and promoting the occurrence and development of HCC; this effect of which could be enhanced by hypoxia.