72P - SNCG promotes the malignant progression of hepatocellular carcinoma by activation EGFR signaling and recycling

Background

Hepatocellular carcinoma is the most common primary liver cancer, with poor prognosis. The expression of Gamma-synuclein (SNCG) is correlated with recurrence and radiotherapy resistance in several tumor types. However, the role and mechanism of SNCG in hepatocellular carcinoma (HCC) progression remain largely unclear.

Methods

SNCG was identified as a prognosis-related biomarker for HCC based on analysis of clinical characteristics and RNA-seq data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and the JP Project of the International Cancer Genome Consortium (ICGC-LIRI-JP). SNCG expression was analyzed in cancer tissues and adjacent noncancerous tissues via immunohistochemistry and Western blotting. Multiple in vivo and in vitro experimental techniques (such as CCK-8, colony formation, EdU, and Transwell assays; flow cytometry; Western blotting; quantitative RT-PCR; Coimmunoprecipitation assay were used to assess the functions of SNCG in the pathogenesis of HCC.

Results

We found that the expression of SNCG was upregulated and associated with a poor prognosis in HCC patients. SNCG promoted HCC cell proliferation, migration, invasion and metastasis. Knockdown of SNCG significantly inhibited HCC cell proliferation. Mechanistically, we demonstrated that SNCG promoted HCC cell proliferation and metastasis via direct interaction with the E3 ubiquitin ligase c-Cbl, suppresses EGFR ubiquitination, influenced EGFR endosomal trafficking and degradation and subsequently activated ERK1/2 and Akt signaling. In addition, we showed that SNCG knockdown sensitized HCC cells to the tyrosine kinase inhibitor erlotinib in vitro and in vivo.

Conclusions

Collectively, our results indicate that SNCG drives HCC progression and erlotinib resistance by suppressing c-Cbl mediated EGFR ubiquitination and therefore can be a potential therapeutic target for HCC.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.