Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
J Invest Surg. 2022 Aug;35(8):1660-1667. doi: 10.1080/08941939.2022.2090034. Epub 2022 Jun 29.
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.
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.
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.
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.
缺氧诱导因子-1α（HIF-1α）或 sonic 刺猬（SHH）与肝细胞癌（HCC）的进展有关。缺氧抑制铁死亡，导致癌细胞死亡。然而，HIF-1α 和 SHH 上调与预后的相关性，以及 SHH 与铁死亡的关系尚不清楚。本研究旨在对此进行探讨。
我们检测了 HCC 中 HIF-1α 和 SHH 的表达。进行 Cox 回归、临床数据分析和 Kaplan-Meier 分析。体外细胞实验验证了 HIF-1α 和 SHH 之间的关系，并观察了缺氧 HCC 细胞的侵袭。还分析了 SHH 与铁死亡的相关性。
HIF-1α 和 SHH 的表达水平与 HCC 显著相关（<0.0001）。HIF-1α 和 SHH 的表达水平与 TNM 分期（=0.0121，=0.0078）、血管侵犯（<0.0001，<0.0001）和复发（=0.0212，=0.0392）相关。HIF-1α 和 SHH 的联合上调是预测 HCC 患者总生存（OS）的独立因素（=0.003），这些患者的 OS 最短（=0.0009）。SHH 与 HIF-1α 表达的增加平行，促进了癌细胞的侵袭。SHH 的上调与铁死亡相关因子（FANCD2，<0.0001 和 FTH1，=0.0009）在 HCC 中的表达抑制有关。
HIF-1α 和 SHH 的联合上调是 HCC 患者潜在的不良预后指标，因为 SHH 的上调抑制了缺氧癌细胞中的铁死亡。
