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HSP47 promotes metastasis of breast cancer by interacting with myosin IIA via the unfolded protein response transducer IRE1α

Oncogene volume 39, pages 4519–4537 (2020)Cite this article

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Abstract

Breast cancer (BC) is an aggressive cancer that is a leading cause of cancer-associated death in women worldwide. Although increased expression of heat shock protein 47 (HSP47), a collagen-specific chaperone, is associated with the high malignancy of BC, its role in BC remains largely unclear. Here we show that a small population of high-invasive BC cells expresses HSP47 and that HSP47-positive high-invasive BC cells have a high metastatic potential that is completely abolished by disruption of HSP47. HSP47 interacts with non-muscle myosin IIA (NMIIA) via the unfolded protein response transducer IRE1α, resulting in enhancement of the metastatic potential of high-invasive BC cells by augmenting the contractile force of actin filaments. Ablation of NMIIA abrogates the metastatic potential of HSP47-positive high-invasive BC cells. We further show that forced expression of NMIIA confers a high metastatic potential on low-invasive BC cells in which HSP47 but not NMIIA is expressed. Overall, our study indicates that HSP47 acts as a stimulator for metastasis of BC cells and suggest that HSP47 may be a candidate for a therapeutic target against BC.

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Fig. 1: HSP47 is expressed in a small population of high-invasive BC cells.
Fig. 2: Overexpression of HSP47 promotes the metastatic potential of high-invasive BC cells.
Fig. 3: In vivo-derived HSP47+high-invasive BC cells have a high potential for metastasis.
Fig. 4: Disruption of HSP47 abolishes the metastatic potential of high-invasive BC cells.
Fig. 5: HSP47 interacts with NMIIA in high-invasive BC cells.
Fig. 6: Disruption of NMIIA abolishes the metastatic potential of HSP47+high-invasive BC cells.
Fig. 7: Expression of NMIIA promotes the metastatic potential of low-invasive BC cells.

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Acknowledgements

The authors thank Dr Takayuki Sakurai (Shinshu University, Matsumoto, Japan) and Dr Norio Takei (Hokkaido University, Sapporo, Japan) for providing pCG-Sap I vector. The authors also thank Kaori Sakai-Sawada (Hokkaido University, Sapporo, Japan) for technical assistance of data acquisition in this study.

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Authors and Affiliations

  1. Department of Molecular Therapeutics, Center for Food & Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, Sapporo, 001-0021, Japan

    Akihiro Yoneda, Kenjiro Minomi & Yasuaki Tamura

  2. Research & Development Department, Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Sapporo, 001-0021, Japan

    Kenjiro Minomi

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Contributions

Study design and concept: AY, KM, YT. Data acquisition: AY. Data analysis and interpretations: AY. Manuscript preparation: AY, YT. Manuscript review: AY, KM, YT. All authors read and approved the final manuscript. This work was supported by Nitto Denko Corporation (Osaka, Japan). This work was also supported in part by the Grant-in-Aid for Scientific Research C from MEXT Japan Society for the Promotion of Science (KAKENHI18K07287 to AY).

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Correspondence to Akihiro Yoneda.

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All procedures of mouse experiments were reviewed and approved by Experimental Animal Ethics Committee of Hokkaido University.

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Yoneda, A., Minomi, K. & Tamura, Y. HSP47 promotes metastasis of breast cancer by interacting with myosin IIA via the unfolded protein response transducer IRE1α. Oncogene 39, 4519–4537 (2020). https://doi.org/10.1038/s41388-020-1311-7

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