Tumor suppressor OSR1 is modified by SUMO1 and regulates the Wnt/β-catenin signaling pathway in HCC
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Updated: Sep 13, 2025
SUMO-Binding Entities SUBEs as Tools for the Enrichment, Isolation, Identification, and Characterization of the SUMO Proteome in Liver Cancer
Published on: November 1, 2019
Xinju Lin1, Yuming Liu2, Zisen Lai2
1Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China; Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China.
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.
Insights
Small ubiquitin-related modifier (SUMO1) modifies OSR1, promoting hepatocellular carcinoma (HCC) by suppressing the Wnt/β-catenin pathway. OSR1 acts as a tumor suppressor, inhibiting HCC progression, with hypoxia exacerbating SUMO1
Area of Science:
- Molecular Oncology
- Cancer Biology
- Ubiquitination and Post-Translational Modifications
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally.
- Understanding the molecular mechanisms, including the roles of small ubiquitin-related modifier (SUMO) pathways, is crucial for developing effective therapies.
- The interaction between SUMOylation and specific target proteins in HCC pathogenesis remains an area of active investigation.
Purpose of the Study:
- To investigate the role of OSR1 in hepatocellular carcinoma (HCC) development.
- To elucidate the regulatory mechanism of OSR1 by small ubiquitin-related modifier 1 (SUMO1) in HCC.
- To explore the impact of the SUMO1-OSR1 interaction on the Wnt/β-catenin signaling pathway in HCC.
Main Methods:
- Immunohistochemistry on HCC tissue samples.
- Co-immunoprecipitation (co-IP) and immunofluorescence (IF) to confirm protein interactions.
- Quantitative PCR (qPCR) and Western blotting for gene and protein expression analysis.
- Cell proliferation (CCK-8, clone formation) and invasion (Transwell) assays in HepG2 cells.
- Nude mouse xenograft model for in vivo anti-tumor efficacy assessment.
- Analysis of downstream signaling pathways, including Wnt/β-catenin.
Main Results:
- Confirmed interaction between SUMO1 and OSR1 in HCC.
- OSR1 demonstrated tumor suppressor activity, inhibiting HepG2 cell proliferation and invasion in vitro and in vivo.
- SUMO1 modification of OSR1 promoted HCC development by suppressing the Wnt/β-catenin pathway, an effect potentially enhanced by hypoxia.
- SUMO1-OE antagonized OSR1-mediated β-catenin regulation in a context-dependent manner (nuclear vs. cytoplasmic localization).
Conclusions:
- OSR1 functions as a tumor suppressor in HCC by attenuating the Wnt/β-catenin pathway.
- SUMO1 modification of OSR1 plays a critical role in HCC progression by inhibiting the Wnt/β-catenin signaling pathway.
- The interplay between SUMO1 and OSR1 is oxygen-sensitive and influences HCC pathogenesis, suggesting potential therapeutic targets.
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