Combined HIF-1α and SHH Up-Regulation Is a Potential Biomarker to Predict Poor Prognosis in Postoperative Hepatocellular Carcinoma.

BACKGROUND

Hypoxia-inducible factor-1α (HIF-1α) or sonic hedgehog (SHH) is associated with hepatocellular carcinoma (HCC) progression. Hypoxia inhibits ferroptosis, which induces cancer cell death. However, the correlation between the combined HIF-1α and SHH up-regulation with prognosis, and the association between SHH and ferroptosis remain unclear. This study aimed to investigate them.

METHODS

We detected the expression of HIF-1α and SHH in HCC. Cox regression, clinical data, and Kaplan-Meier analyses were performed. In vitro cell experiments verified the relationship between HIF-1α and SHH, and observed the invasion of hypoxic HCC cells. The correlation between SHH and ferroptosis was also analyzed.

RESULTS

HIF-1α and SHH expression levels were significantly correlated with HCC ( < 0.0001). HIF-1α and SHH expression levels were found to be associated with TNM stage ( = 0.0121,  = 0.0078, respectively), vascular invasion ( < 0.0001,  < 0.0001, respectively), and recurrence ( = 0.0212,  = 0.0392, respectively). The combined upregulation of HIF-1α and SHH was an independent factor for predicting the overall survival (OS) of patients with HCC ( = 0.003), who had the shortest OS ( = 0.0009). SHH paralleled the increase in HIF-1α expression, which promotes cancer cell invasion. The upregulation of SHH was related to the inhibition of the expression of ferroptosis-related factors (FANCD2,  < 0.0001 and FTH1,  = 0.0009) in HCC.

CONCLUSION

Combined HIF-1α and SHH upregulation is a potentially poor prognosis indicator in patients with HCC because the upregulation of SHH inhibits ferroptosis in hypoxic cancer cells.