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.
Disclosure statement
The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.
Additional information
Funding
Notes on contributors
Jiali Zhao
Jiali Zhao and Guifang Zeng contributed to data collection, wrote the article, created tables and fgures. En Lin, Chaonong Cai and Peiping Li contributed to data collection and statistical analysis. Jian Li and Baojia Zou contributed to critical revision of statistics, conception of study, reviewed the manuscript, and supervised the project. The manuscript was approved by all authors.
Guifang Zeng
Jiali Zhao and Guifang Zeng contributed to data collection, wrote the article, created tables and fgures. En Lin, Chaonong Cai and Peiping Li contributed to data collection and statistical analysis. Jian Li and Baojia Zou contributed to critical revision of statistics, conception of study, reviewed the manuscript, and supervised the project. The manuscript was approved by all authors.
En Lin
Jiali Zhao and Guifang Zeng contributed to data collection, wrote the article, created tables and fgures. En Lin, Chaonong Cai and Peiping Li contributed to data collection and statistical analysis. Jian Li and Baojia Zou contributed to critical revision of statistics, conception of study, reviewed the manuscript, and supervised the project. The manuscript was approved by all authors.
Chaonong Cai
Jiali Zhao and Guifang Zeng contributed to data collection, wrote the article, created tables and fgures. En Lin, Chaonong Cai and Peiping Li contributed to data collection and statistical analysis. Jian Li and Baojia Zou contributed to critical revision of statistics, conception of study, reviewed the manuscript, and supervised the project. The manuscript was approved by all authors.
Peiping Li
Jiali Zhao and Guifang Zeng contributed to data collection, wrote the article, created tables and fgures. En Lin, Chaonong Cai and Peiping Li contributed to data collection and statistical analysis. Jian Li and Baojia Zou contributed to critical revision of statistics, conception of study, reviewed the manuscript, and supervised the project. The manuscript was approved by all authors.
Baojia Zou
Jiali Zhao and Guifang Zeng contributed to data collection, wrote the article, created tables and fgures. En Lin, Chaonong Cai and Peiping Li contributed to data collection and statistical analysis. Jian Li and Baojia Zou contributed to critical revision of statistics, conception of study, reviewed the manuscript, and supervised the project. The manuscript was approved by all authors.
Jian Li
Jiali Zhao and Guifang Zeng contributed to data collection, wrote the article, created tables and fgures. En Lin, Chaonong Cai and Peiping Li contributed to data collection and statistical analysis. Jian Li and Baojia Zou contributed to critical revision of statistics, conception of study, reviewed the manuscript, and supervised the project. The manuscript was approved by all authors.