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Hyaluronan synthase 2 (HAS2) regulates cell phenotype and invadopodia formation in luminal-like breast cancer cells

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Abstract

Although luminal breast cancer cells are typically highly cohesive epithelial cells and have low invasive ability, many eventually develop metastasis. Until now, the underlying mechanisms remain obscure. In this work, we showed that the level of hyaluronic acid synthase 2 (HAS2) was positively correlated with the malignant phenotype of breast cancer cells. Notably, the increased expression of HAS2 promoted the invasive and migratory abilities of luminal breast cancer cells in vitro, followed by a reduced expression of E-cadherin, β-catenin, and ZO-1, and an elevated expression of N-cadherin and vimentin. Furthermore, overexpression of HAS2 promoted while knockdown of HAS2 impeded invadopodia formation, which subsequently increased or decreased the activation of cortactin, Tks5, and metalloproteinases (MMPs). Activation of these invadopodia-related proteins was prevented by inhibition of HAS2 or disruption of HA, which in turn attenuated the increased motility and invasiveness. Further, in vivo study showed that, HAS2 increased tumor growth and the rate of lung metastasis via driving transition to an invasive cell phenotype in SCID mice that were orthotopically transplanted with luminal breast cancer cells. Collectively, our results showed that HAS2 promoted cell invasion by inducing transition to an invasive phenotype and by enhancing invadopodia formation in luminal breast cancer cells, which may provide new mechanistic insights into its role in tumor metastasis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81572821, 81502490, 81502491, 81672843, 81702852, 81974445, 81974446, 82073199), the Natural Science Foundation of Shanghai Municipality (14YF1412200), the Program of Shanghai Leading Talents (2013–038), the Shanghai Shen-Kang Hospital Development Center (SHDC22014004), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20171924).

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  1. Yumeng Sheng and Manlin Cao are co-first authors.

Authors and Affiliations

  1. Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Yumeng Sheng, Yiwen Liu, Yiqing He, Guoliang Zhang, Yan Du, Feng Gao & Cuixia Yang

  2. Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Feng Gao & Cuixia Yang

  3. Department of Rehabilitation Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Manlin Cao

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Sheng, Y., Cao, M., Liu, Y. et al. Hyaluronan synthase 2 (HAS2) regulates cell phenotype and invadopodia formation in luminal-like breast cancer cells. Mol Cell Biochem 476, 3383–3391 (2021). https://doi.org/10.1007/s11010-021-04165-7

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