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

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.