COA6 deficiency inhibits hepatocellular carcinoma progression by regulating cuproptosis through the JAK/STAT signaling pathway

Background

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignant tumors with limited therapeutic strategies. COA6 is a mitochondria-associated protein that plays an important role in regulating tumor cuproptosis, but its role in HCC is currently unknown. In this study, we aimed to investigate the expression and potential mechanism of action of COA6 in HCC.

Methods

TCGA-LIHC database was analyzed for differentially expressed cuproptosis-related genes (CRGs) in HCC and prognostic value, which was validated by immunohistochemistry and Western blot. CCK8, flow cytometry, wound healing, transwell and subcutaneous graft tumor assays were performed to explore the function of COA6 in HCC. Impact of COA6 on cuproptosis was assessed by assay kit and Western blot. RNA-sequencing were used to determine molecular mechanism. Immunoprecipitation (Co-IP) and immunofluorescence were used to assess the relationship between COA6 and NDUFA4L2. western blotting was used to detect the effect of COA6 on the JAK-STAT pathway.

Results

COA6 was significantly overexpressed in HCC tissues and HCC cell lines and was closely associated with poor prognosis. Silencing COA6 significantly inhibited the malignant phenotype of HUH7 and HepG2 cells in vitro and tumor growth in vivo. Moreover, silencing COA6 promoted ROS accumulation and activated cuproptosis in HCC cells. Interestingly, we found that COA6 interacted with NDUFA4L2 and COA6 deficiency significantly inhibited the JAK-STAT signaling pathway.

Conclusions

In conclusion, our data show that COA6 was highly expressed in HCC, and silencing COA6 blocked the JAK-STAT signaling pathway and activated cuproptosis, and inhibits the malignant phenotype and tumor growth of HCC cells. Therefore, targeting COA6 may be a potential therapeutic approach to inhibit HCC progression.