Background: Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1) plays key regulatory roles in cancer development and progression. However, its specific functions and potential mechanisms of action remain to be described in hepatocellular carcinoma (HCC).
Materials and Methods: WHSC1 expression in HCC was evaluated using The Cancer Genome Atlas and verified in HCC tissues and cell lines using qRT-PCR, Western blotting, and immunohistochemistry. Functional assays were performed to explore the role of WHSC1 in HCC progression. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, immunofluorescence, and immunohistochemistry were conducted to evaluate the interaction between WHSC1 and prolyl 4-hydroxylase subunit beta (P4HB). Pathway enrichment was performed using gene set enrichment analysis.
Results: WHSC1 was markedly overexpressed in HCC tissues and cell lines. The level of expression was strongly associated with adverse clinicopathological characteristics. Survival analyses revealed that WHSC1 upregulation predicted poor overall survival and higher recurrence rates in patients with HCC. Functional studies revealed that WHSC1 significantly stimulated HCC proliferation, migration, and invasion in vitro and in vivo. WHSC1 was shown to interact with P4HB to stimulate P4HB expression and subsequently activate mTOR1 signaling.
Conclusion: We determined the oncogenic role of WHSC1 in HCC, via P4HB interaction, which activates mTOR1 signaling, and identified WHSC1 as a promising therapeutic target for HCC.
Keywords: apoptosis, metastasis, P4HB, poor prognosis, hepatocarcinogenesis