Combined HIF-1α and SHH Up-Regulation Is a Potential Biomarker to Predict Poor Prognosis in Postoperative Hepatocellular Carcinoma
Combined HIF-1α and SHH Up-Regulation Is a Potential Biomarker to Predict Poor Prognosis in Postoperative Hepatocellular Carcinoma
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DOI：
10.1080/08941939.2022.2090034
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发表时间：
2022-06
影响因子：
1.9
通讯作者：
Jiali Zhao;Guifang Zeng;En Lin;C. Cai;Pei-ping Li;Baojia Zou;Jian Li
中科院分区：
文献类型：
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作者：
Jiali Zhao;Guifang Zeng;En Lin;C. Cai;Pei-ping Li;Baojia Zou;Jian Li
摘要背景缺氧诱导因子-1 α（HIF-1α）或音刺猬因子（SHH）与肝细胞癌（HCC）的进展有关。缺氧抑制铁凋亡，从而诱导癌细胞死亡。然而，HIF-1α和SHH联合上调与预后的关系以及SHH与铁凋亡的关系尚不清楚。本研究旨在调查他们。方法检测HCC组织中HIF-1α和SHH的表达。进行了考克斯回归、临床数据和Kaplan-Meier分析。体外细胞实验验证了HIF-1α与SHH的关系，并观察了缺氧肝癌细胞的侵袭能力。并分析SHH与铁凋亡的相关性。结果HIF-1α和SHH的表达与HCC的发生密切相关（p < 0.0001）。HIF-1α和SHH表达水平与TNM分期（分别为p = 0.0121，p = 0.0078）、血管浸润（分别为p < 0.0001，p < 0.0001）和复发（分别为p = 0.0212，p = 0.0392）相关。HIF-1α和SHH的联合上调是预测HCC患者总生存期（OS）的独立因素（p = 0.003），HCC患者的OS最短（p = 0.0009）。SHH抑制了HIF-1α表达的增加，从而促进癌细胞的侵袭。SHH的上调与HCC中铁凋亡相关因子（FANCD 2，p < 0.0001和FTH 1，p = 0.0009）表达的抑制有关。结论HIF-1α和SHH联合表达可能是HCC患者预后不良的一个潜在指标，因为SHH表达上调可抑制缺氧癌细胞的铁凋亡。
Abstract 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 (p < 0.0001). HIF-1α and SHH expression levels were found to be associated with TNM stage (p = 0.0121, p = 0.0078, respectively), vascular invasion (p < 0.0001, p < 0.0001, respectively), and recurrence (p = 0.0212, p = 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 (p = 0.003), who had the shortest OS (p = 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, p < 0.0001 and FTH1, p = 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.