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Cellular and Molecular Biology

Thermal stress involved in TRPV2 promotes tumorigenesis through the pathways of HSP70/27 and PI3K/Akt/mTOR in esophageal squamous cell carcinoma

British Journal of Cancer volume 127, pages 1424–1439 (2022)Cite this article

Subjects

Abstract

Background

The transient receptor potential vanilloid receptor 2 (TRPV2) has been found to participate in the pathogenesis of various types of cancers, however, its role(s) in the tumorigenesis of ESCC remain poorly understood.

Methods

Western blotting and immunohistochemistry were performed to determine the expression profiles of TRPV2 in the ESCC patient tissues. A series of in vitro and in vivo experiments were conducted to reveal the role of TRPV2 in the tumorigenesis of ESCC.

Results

Our study first uncovered that the activation of TRPV2 by recurrent acute thermal stress (54 °C) or O1821 (20 μM) promoted cancerous behaviours in ESCC cells. The pro-angiogenic capacity of the ESCC cells was found to be enhanced profoundly and both tumour formation and metastasis that originated from the cells were substantially promoted in nude mouse models upon the activation of TRPV2. These effects were inhibited significantly by tranilast (120 μM) and abolished by TRPV2 knockout. Conversely, overexpression of TRPV2 could switch the cells to tumorigenesis upon activation of TRPV2. Mechanistically, the driving role of TRPV2 in the progression of ESCC is mainly regulated by the HSP70/27 and PI3K/Akt/mTOR signalling pathways.

Conclusions

We revealed that TRPV2-PI3K/Akt/mTOR is a novel and promising target for the prevention and treatment of ESCC.

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Fig. 1: TRPV2 is upregulated in ESCC cells, and overactivation of TRPV2 promotes cellular proliferation.
Fig. 2: Overactivation of TRPV2 promotes the migration and invasion of ESCC and ectopically expressed TRPV2 NE2 cells.
Fig. 3: Overactivation of TRPV2 in ESCC cells promotes tumour-associated angiogenesis.
Fig. 4: Overactivation of TRPV2 promotes ESCC formation and invasion in nude mice.
Fig. 5: TRPV2 activation mediates HSP and PI3K signalling pathways.
Fig. 6: TRPV2 expression profile in ESCC patients.
Fig. 7: High expression level of TRPV2 was associated with worse survival in ESCC.

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Data availability

The data in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to Prof. GSW Tsao (Hong Kong University) for giving us the immortalised esophageal squamous cell line NE2 as a gift. We thank colleagues in GIBH, including Prof. Peng Li, Dr. Zhiwu Jiang for assistance in the establishment of GL-labelled cell lines, Dr. Kepin Wang, Dr. Jingke Xie for technical help with CRISPR–Cas9 editing and Prof. Liangxue Lai for giving us the Cas9-G418 plasmid. We thank prof. Huayu Qi for important comments on the manuscript.

Funding

This work was supported by Frontier Research Programs of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (Grant Nos. 2018GZR110105020 and 2018GZR110105019), the National Natural Science Foundation of China (31671211) and the Science and Technology Planning Project of Guangdong Province, China (2017B030314056).

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Authors and Affiliations

  1. CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Rongqi Huang, Shuai Li, Jean de Dieu Habimana, Zuoxian Lin, Yuchen Yang, Na Cheng & Zhiyuan Li

  2. University of Chinese Academy of Sciences, Beijing, China

    Rongqi Huang, Shuai Li, Jean de Dieu Habimana & Zhiyuan Li

  3. School of Life Sciences, University of Science and Technology of China, Hefei, China

    Chao Tian, Huifang Zhao, Ling Wang & Zhiyuan Li

  4. Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China

    Peng Zhou, Wei Xie, Jie Xiao & Zhiyuan Li

  5. Department of Pathology, the Second Xiangya Hospital of Central South University, Changsha, China

    Peng Zhou

  6. Department of Hepatobiliary Surgery, Provincial Cancer Hospital of Hunan, Changsha, China

    Wei Xie

  7. Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China

    Zuoxian Lin, Yuchen Yang, Na Cheng & Zhiyuan Li

  8. GZMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China

    Zhiyuan Li

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Contributions

Conception and design: Z Li and RH; development of methodology: RH, PZ, HZ and JX; acquisition of the data (provided animals, acquired and managed patients, provided facilities, etc.): PZ, WX, JX, Z Lin, and NC; analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): RH, SL, CT, LW and YY; writing, review, and/or revision of the manuscript: RH, JdDH and Z Li; study supervision: Z Li; all authors reviewed and approved the final version of the manuscript.

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Correspondence to Zhiyuan Li.

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All of the animal studies were conducted under protocols approved by the guidelines of the Ethics Committee of Animal Experiments at GIBH (No. 2016015). For the use of clinical materials for this study, prior patient consent and approval from the Institutional Research Ethics Committee of the Cancer Hospital of Hunan Province (No. CHH-YJ-0317005) and the Second Affiliated Hospital of Xiangya Medical School of Central South University (No. XY-2-18179) were obtained.

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Huang, R., Li, S., Tian, C. et al. Thermal stress involved in TRPV2 promotes tumorigenesis through the pathways of HSP70/27 and PI3K/Akt/mTOR in esophageal squamous cell carcinoma. Br J Cancer 127, 1424–1439 (2022). https://doi.org/10.1038/s41416-022-01896-2

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