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Cellular and Molecular Biology

Endolysosomal ion channel MCOLN2 (Mucolipin-2) promotes prostate cancer progression via IL-1β/NF-κB pathway

British Journal of Cancer volume 125, pages 1420–1431 (2021)Cite this article

Subjects

Abstract

Background

Prostate cancer (Pca) is the most common cancer type among males worldwide. Dysregulation of Ca2+ signaling plays important roles during Pca progression. However, there is lack of information about the role of endolysosomal Ca2+ -permeable channels in Pca progression.

Methods

The expression pattern of MCOLN2 was studied by immunohistochemistry and western blot. Cell viability assay, transwell assay and in vivo tumorigenesis were performed to evaluate the functional role of MCOLN2. Downstream targets of MCOLN2 were investigated by cytokine array, enzyme-linked immunosorbent assay, Ca2+ release experiments and luciferase reporter assays.

Results

We report that MCOLN2 expression is significantly elevated in Pca tissues, and associated with poor prognosis. Overexpression of MCOLN2 promoted Pca cells proliferation, migration and invasion. Importantly, knockdown of MCOLN2 inhibited Pca xenograft tumor growth and bone lesion development in vivo. In addition, MCOLN2 promoted the production and release of IL-1β. Moreover, luciferase reporter assay and western blot revealed that MCOLN2 promoted Pca development by regulating the IL-1β/NF-κB pathway.

Conclusion

In summary, MCOLN2 is crucially involved in Pca progression. Mechanistically, MCOLN2 regulates Pca progression via IL-1β/NF-κB pathway. Our study highlights an intriguing possibility of targeting MCOLN2 as potential therapeutic strategy in Pca treatment.

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Fig. 1: MCOLN2 expression was increased during malignant transformation and predicted a poor prognosis in Pca.
Fig. 2: MCOLN2 promoted proliferation of Pca cells in vitro and in vivo.
Fig. 3: MCOLN2 promoted Pca cells migration, invasion and bone lesion developmengt through epithelial-mesenchymal transition (EMT).
Fig. 4: Identification of IL-1β as the downstream target of MCOLN2.
Fig. 5: MCOLN2 mediated endolysosomal Ca2+ release to regulate IL-1β production and release.
Fig. 6: MCOLN2 regulated IL-1β/NF-κB pathway.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Not applicable.

Funding

This work was supported by the grants from Hong Kong Research Grant Committee [AoE/M-05/12, 14100619, RIF/R4005-18F]; Hong Kong Health and Medical Research Fund 06170176; The National Natural Science Foundation of China (81702533); the Fundamental Research Funds for the Central Universities (19ykpy07) and the Natural Science Foundation of Guangdong Province (2019A1515010099;2021A1515012081).

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Authors and Affiliations

  1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Hongyan Yu, Mingxu Xie, Zhaoyue Meng, Chun-Yin Lo, Franky Leung Chan & Xiaoqiang Yao

  2. Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China

    Hongyan Yu, Mingxu Xie, Zhaoyue Meng, Chun-Yin Lo & Xiaoqiang Yao

  3. Centre for Cell and Developmental Biology, State Key Laboratory of Agrobiotechnology, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Liwen Jiang & Xiaoqiang Yao

  4. Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Xiangqi Meng

  5. Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xiangqi Meng

  6. Department of Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China

    Hongyan Yu

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Contributions

HY, MX, ZM, CL and XM performed the experiments. HY, XM and XY conceived and designed the study, analyzed and interpreted the data. FC and LJ provided assistance in the study. HY, XM and XY wrote the paper with feedback from all authors. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiangqi Meng or Xiaoqiang Yao.

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All animal experiments were approved by the Animal Experimentation Ethics Committee of The Chinese University of Hong Kong, performed in compliance with the guide for the care and used of laboratory animals.

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Yu, H., Xie, M., Meng, Z. et al. Endolysosomal ion channel MCOLN2 (Mucolipin-2) promotes prostate cancer progression via IL-1β/NF-κB pathway. Br J Cancer 125, 1420–1431 (2021). https://doi.org/10.1038/s41416-021-01537-0

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