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CTGF regulates cell proliferation, migration, and glucose metabolism through activation of FAK signaling in triple-negative breast cancer

Abstract

Connective tissue growth factor (CTGF), also known as CCN2, is a member of the CCN protein family of secreted proteins with roles in diverse biological processes. CTGF regulates biological functions such as cell proliferation, migration, adhesion, wound healing, and angiogenesis. In this study, we demonstrate a mechanistic link between CTGF and enhanced aerobic glycolysis in triple-negative breast cancer (TNBC). We found that CTGF is overexpressed in TNBC and high CTGF expression is correlated with a poor prognosis. Also, CTGF was required for in vivo tumorigenesis and in vitro proliferation, migration, invasion, and adhesion of TNBC cells. Our results indicate that extracellular CTGF binds directly to integrin αvβ3, activating the FAK/Src/NF-κB p65 signaling axis, which results in transcriptional upregulation of Glut3. Neutralization of CTGF decreased cell proliferation, migration, and invasion through downregulation of Glut3-mediated glycolytic phenotypes. Overall, our work suggests a novel function for CTGF as a modulator of cancer metabolism, indicating that CTGF is a potential therapeutic target in TNBC.

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Fig. 1: CTGF is overexpressed in triple-negative breast cancer.
Fig. 2: CTGF regulates cell proliferation, migration, and adhesion.
Fig. 3: CTGF promotes aerobic glycolysis.
Fig. 4: CTGF knockdown results in decreased Glut3 expression.
Fig. 5: CTGF induces Glut3 expression through integrin αvβ3 signaling.
Fig. 6: CTGF/NF-κB p65/Glut3 signaling is required for enhanced proliferation of TNBC cells.
Fig. 7: CTGF/NF-κB p65/Glut3 signaling confers cell migration and invasion.

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Acknowledgements

This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korea government (MIST) (2019R1H1A2079999, 2020R1F1A1048616, 2020R1A6A3A13074546).

Financial Support

Grant source, National Research Foundation of Korea (NRF); Grant numbers (grant recipient), 2019R1H1A2079999 (Incheol Shin), 2020R1F1A1048616 (Incheol Shin), 2020R1A6A3A13074546 (Hyungjoo Kim).

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Kim, H., Son, S., Ko, Y. et al. CTGF regulates cell proliferation, migration, and glucose metabolism through activation of FAK signaling in triple-negative breast cancer. Oncogene 40, 2667–2681 (2021). https://doi.org/10.1038/s41388-021-01731-7

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