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

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.

Keywords:

• HCC
• HIF-1α
• SHH
• prognosis
• ferroptosis
• postoperative

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

This work was supported by National Natural Science Foundation of China (grant number: 81971773), Natural Science Foundation of Guangdong Province (grant number: 2018A0303130292,2019A1515011356, 2020A1515010203, 2022A1515011244).

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.