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Cellular and Molecular Biology

HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/β-catenin signalling pathway

British Journal of Cancer volume 127, pages 474–487 (2022)Cite this article

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Abstract

Background

This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/β-catenin pathway in oesophageal squamous cell carcinoma (ESCC).

Methods

The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry.

Results

The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, migration/invasion and epithelial–mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1α and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients.

Conclusions

HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway.

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Fig. 1: 1% O2 or CoCl2 induced hypoxia and HIF-1α shRNA regulating HIF-1α expression in ESCC cell lines.
Fig. 2: The role of HIF-1α in ESCC cell proliferation, migration, invasion, apoptosis and cell cycle in vitro.
Fig. 3: HIF-1α was involved in hypoxia-induced EMT activation in T.Tn and TE1 cell lines.
Fig. 4: HIF-1α mediated the resistance of ESCC cell lines to 5-FU in vitro and in vivo.
Fig. 5: Crosstalk between HIF-1α and Wnt/β-catenin signalling pathway in ESCC cell lines.
Fig. 6: HIF-1α expression was associated with TCF4/TCF7L2 expression in ESCC tissues, which was correlated with poor prognosis.

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Data availability

All data required to evaluate the findings in the paper is available in the paper and supplementary materials.

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Acknowledgements

We sincerely thank the first author’s wife, Dr. Xiayun Wan, for her psychological counselling during the author’s writing period.

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Authors and Affiliations

  1. Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan

    Kang Tang, Takeshi Toyozumi, Kentaro Murakami, Haruhito Sakata, Masayuki Kano, Satoshi Endo, Yasunori Matsumoto, Hiroshi Suito, Masahiko Takahashi, Nobufumi Sekino, Ryota Otsuka, Kazuya Kinoshita, Soichiro Hirasawa, Jie Hu, Masaya Uesato, Koichi Hayano & Hisahiro Matsubara

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Contributions

KT, TT, KM, HS, MK, SE, YM, MU, KH and HM conceived this study. KT performed all the experiments. HS, MT, NS, RO, KK, SH and JH monitored the progress of the experiment, provided comments and helped write the manuscript. KT performed the statistics and wrote the manuscript. TT revised the manuscript. HM approved the final version. All authors have reviewed the manuscript and all have approved the submission.

Corresponding author

Correspondence to Takeshi Toyozumi.

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The authors declare no competing interests.

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This research was performed in accordance with the Declaration of Helsinki. Our animal research was approved by the Animal Care and Use Committee of Chiba University (No. A3-22) and follows the policies for institutional animal care. The clinical analyses in this study were authorised by the Institutional Review Board of Chiba University (No. 1120-942) and written informed consent was obtained from all participants.

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Tang, K., Toyozumi, T., Murakami, K. et al. HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/β-catenin signalling pathway. Br J Cancer 127, 474–487 (2022). https://doi.org/10.1038/s41416-022-01825-3

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