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Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation

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Abstract

Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells significantly decreased primary tumor xenograft growth, while increasing tumor apoptosis. Furthermore, TSPAN12 removal markedly enhanced tumor-endothelial interactions and increased metastasis to mouse lungs. TSPAN12 removal from human MDA-MB-231 cells also caused diminished association between FZD4 (a key canonical Wnt pathway receptor) and its co-receptor LRP5. The result likely explains substantially enhanced proteosomal degradation of β-catenin, a key effecter of canonical Wnt signaling. Consistent with disrupted canonical Wnt signaling, TSPAN12 ablation altered expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1, and GSKβ3 proteins. TSPAN12 ablation also altered expression of several genes regulated by β-catenin (e.g. CCNA1, CCNE2, WISP1, ID4, SFN, ME1) that may help to explain altered tumor growth and metastasis. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4–LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced β-catenin expression and function.

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Acknowledgments

This work was supported by National Institutes of Health Grant CA42368 (to M.E.H.).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Konstantin Knoblich, Hong-Xing Wang, Chandan Sharma, Anne L. Fletcher, Shannon J. Turley & Martin E. Hemler

  2. Monash University, Immunology and Stem Cell Laboratories, Clayton, Australia

    Anne L. Fletcher

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  1. Konstantin Knoblich
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  2. Hong-Xing Wang
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  3. Chandan Sharma
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  4. Anne L. Fletcher
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Correspondence to Martin E. Hemler.

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Knoblich, K., Wang, HX., Sharma, C. et al. Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation. Cell. Mol. Life Sci. 71, 1305–1314 (2014). https://doi.org/10.1007/s00018-013-1444-8

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  • DOI: https://doi.org/10.1007/s00018-013-1444-8

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