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Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer

Oncogene volume 31, pages 3111–3123 (2012)Cite this article

Abstract

Chitinase 3-like 1 (CHI3L1), one of the mammalian members of the chitinase family, is expressed in several types of human cancer, and elevated serum level of CHI3L1 is suggested to be a biomarker of poor prognosis in advanced cancer patients. However, the overall biological function of CHI3L1 in human cancers still remains unknown. Studies were performed to characterize the role of CHI3L1 in cancer pathophysiology utilizing human colorectal cancer samples and human cell lines. Plasma protein and tissue mRNA expression levels of CHI3L1 in colorectal cancer were strongly upregulated. Immunohistochemical analysis showed that CHI3L1 was expressed in cancer cells, and CHI3L1 expression had a significant association with the number of infiltrated macrophages and microvessel density (MVD). By utilizing transwell migration and tube-formation assays, overexpression of CHI3L1 in SW480 cells (human colon cancer cells) enhanced the migration of THP-1 cells (human macrophage cells) and HUVECs (human endothelial cells), and the tube formation of HUVECs. The knockdown of CHI3L1 by RNA interference or the neutralization of CHI3L1 by anti-CHI3L1 antibody displayed strong suppression of CHI3L1-induced migration and tube formation. Cell proliferation assay showed that CHI3L1 overexpression significantly enhanced the proliferation of SW480 cells. Enzyme-linked immunosorbent assay (ELISA) analysis showed that CHI3L1 increased the secretion of inflammatory chemokines, IL-8 and monocyte chemoattractant protein-1 (MCP-1), from SW480 cells through mitogen-activated protein kinase (MAPK) signaling pathway. Both neutralization of IL-8 or MCP-1 and inhibition or knockdown of MAPK in SW480 cells significantly inhibited CHI3L1-induced migration and tube formation. In a xenograft mouse model, overexpression of CHI3L1 in HCT116 cells (human colon cancer cells) enhanced the tumor growth as well as macrophage infiltration and MVD. In conclusion, CHI3L1 expressed in colon cancer cells promotes cancer cell proliferation, macrophage recruitment and angiogenesis. Thus, the inhibition of CHI3L1 activity may be a novel therapeutic strategy for human colorectal cancer.

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Acknowledgements

This work was supported by Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (20790493, 21-40033, 23590937, 21229009), and Health and Labor Science Research Grants for Research on Intractable Diseases, and Research on Hepatitis from the Ministry of Health, Labor and Welfare, Japan, and Research Foundation of Translational Research Center, Kyoto University and by a research grant (R01DK80070) from the National Institutes of Health in USA.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    M Kawada, H Seno, K Kanda, Y Nakanishi, R Akitake, H Komekado & T Chiba

  2. Japan Society for the Promotion of Science (JSPS), Tokyo, Japan

    M Kawada

  3. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    K Kawada & Y Sakai

  4. Department of Medicine and Center for the Study of Inflammatory Bowel Disease, Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    E Mizoguchi

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  1. M Kawada
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Correspondence to M Kawada.

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Kawada, M., Seno, H., Kanda, K. et al. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene 31, 3111–3123 (2012). https://doi.org/10.1038/onc.2011.498

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