USP14 exhibits high expression levels in hepatocellular carcinoma and plays a crucial role in promoting the growth of liver cancer cells through the HK2/AKT/P62 axis

Abstract

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor with strong invasiveness and poor prognosis. Previous studies have demonstrated the significant role of USP14 in various solid tumors. However, the role of USP14 in the regulation of HCC development and progression remains unclear.

Methods: We discovered through GEO and TCGA databases that USP14 may play an important role in liver cancer. Using bioinformatics analysis based on the Cancer Genome Atlas (TCGA) database, we screened and identified USP14 as highly expressed in liver cancer. We detected the growth and metastasis of HCC cells promoted by USP14 through clone formation, cell counting kit 8 assay, Transwell assay, and flow cytometry. In addition, we detected the impact of USP14 on the downstream protein kinase B (AKT) and epithelial-mesenchymal transition (EMT) pathways using western blotting. The interaction mechanism between USP14 and HK2 was determined using immunofluorescence and coimmunoprecipitation (CO-IP) experiments.

Results: We found that sh-USP14 significantly inhibits the proliferation, invasion, and invasion of liver cancer cells, promoting apoptosis. Further exploration revealed that sh-USP14 significantly inhibited the expression of HK2. Sh-USP14 can significantly inhibit the expression of AKT and EMT signals. Further verification through immunofluorescence and CO-IP experiments revealed that USP14 co-expressed with HK2. Further research has found that USP14 regulates the glycolytic function of liver cancer cells by the deubiquitination of HK2. USP14 regulates the autophagy function of liver cancer cells by regulating the interaction between SQSTM1/P62 and HK2.

Conclusions: Our results indicate that USP14 plays a crucial role in the carcinogenesis of liver cancer. We also revealed the protein connections between USP14, HK2, and P62 and elucidated the potential mechanisms driving cancer development. The USP14/HK2/P62 axis may be a new therapeutic biomarker for the diagnosis and treatment of HCC.

Keywords: Double quinone enzymes; Hepatocellular carcinoma; USP14.