Mechanisms of C5ORF13 in promoting epithelial-mesenchymal transition in hepatocellular carcinoma via eIF6 and the intervention of valproic acid.

OBJECTIVE

To investigate the mechanism by which C5ORF13 promotes epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) through interaction with eukaryotic translation initiation factor 6 (eIF6) and its clinical significance, and to identify the potential use of valproic acid (VPA) as an eIF6 inhibitor in HCC.

METHODS

The expression of C5ORF13 in HCC and its prognostic impact were analyzed using GEPIA, UALCAN, and The HUMAN PROTEIN ATLAS databases. Lentiviral transfection technology was used to knock down or overexpress C5ORF13 and eIF6. The effects on the biological behavior of HCC cells were assessed using CCK-8, scratch, Transwell assays, and animal models. The interaction between C5ORF13 and eIF6 was verified using co-immunoprecipitation and immunofluorescence co-localization techniques. Molecular docking, CETSA experiments, and Western Blot were utilized to investigate the mechanism of action of VPA (an eIF6 inhibitor) on eIF6.

RESULTS

C5ORF13 was highly expressed in HCC and significantly correlated with cancer staging, tumor grading, lymph node metastasis, and poor patient prognosis. Knockdown of C5ORF13 significantly inhibited the proliferation, migration, invasion, and EMT process of HCC cells. C5ORF13 interacted with eIF6 in HCC cells, and C5ORF13 promoted EMT and HCC metastasis by regulating eIF6 protein expression. In vivo experiments further confirmed that knockdown of C5ORF13 or eIF6 significantly inhibited lung metastasis of HCC cells. Clinical sample analysis showed that the expression of C5ORF13 and eIF6 in HCC tissues was significantly higher than that in normal tissues, and the expression of both was positively correlated. Additionally, VPA reduced the protein stability of eIF6 by binding to it, inhibiting its expression, and subsequently suppressing the migration, invasion, and EMT process of HCC cells.

CONCLUSION

C5ORF13 drives the malignant progression of HCC by increasing eIF6 levels, including proliferation, invasion, migration, and the EMT process. VPA, as an eIF6 inhibitor, shows potential application value in the treatment of HCC.