Uncontrolled proliferation of intestinal epithelial cells caused by mutations in genes of the WNT/β-catenin pathway is associated with development of intestinal cancers. We previously reported that intestinal stromal cell-derived angiopoietin-like protein 2 (ANGPTL2) controls epithelial regeneration and intestinal immune responses. However, the role of tumor cell-derived ANGPTL2 in intestinal tumorigenesis remained unclear. Here, we show that tumor cell-derived ANGPTL2 promotes β-catenin-driven intestinal tumorigenesis. ANGPTL2 deficiency suppressed intestinal tumor development in an experimental mouse model of sporadic colon cancer. We also found that increased ANGPTL2 expression in colorectal cancer (CRC) cells augments β-catenin pathway signaling and promotes tumor cell proliferation. Relevant to mechanism, our findings suggest that tumor cell-derived ANGPTL2 upregulates expression of OB-cadherin, which then interacts with β-catenin, blocking destruction complex-independent proteasomal degradation of β-catenin proteins. Moreover, our observations support a model whereby ANGPTL2-induced OB-cadherin expression in CRC cells is accompanied by decreased cell surface integrin α5β1 expression. These findings overall provide novel insight into mechanisms of β-catenin-driven intestinal tumorigenesis.
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We thank Kiyoka Tabu, Noriko Shirai, and Sayomi Iwaki for technical assistance. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (grant 21K07101 to TK and grant 21K15508 to HH), the Takeda Science Foundation (HH, TK), and Tasaki Memorial Research Grant for 2021 (HH).
The authors declare no competing interests.
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Horiguchi, H., Kadomatsu, T., Yumoto, S. et al. Tumor cell-derived ANGPTL2 promotes β-catenin-driven intestinal tumorigenesis. Oncogene 41, 4028–4041 (2022). https://doi.org/10.1038/s41388-022-02405-8