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Tumor cell-derived ANGPTL2 promotes β-catenin-driven intestinal tumorigenesis

Oncogene volume 41, pages 4028–4041 (2022)Cite this article

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Abstract

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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Fig. 1: Colonic tumor cells express ANGPTL2 in vivo.
Fig. 2: ANGPTL2 deficiency suppresses colorectal tumorigenesis.
Fig. 3: ANGPTL2 deficiency decreases β-catenin signaling in CRC cells.
Fig. 4: Tumor cell-derived ANGPTL2 enhances β-catenin signaling.
Fig. 5: ANGPTL2 expression suppresses proteasomal degradation of β-catenin.
Fig. 6: Regulation of β-catenin signaling by ANGPTL2 requires OB-cadherin.
Fig. 7: ANGPTL2 induction of CDH11 is accompanied by decreased levels of cell surface integrin α5β1.

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan

    Haruki Horiguchi, Tsuyoshi Kadomatsu, Shinsei Yumoto, Keishi Miyata, Shuji Yamamura, Michio Sato, Jun Morinaga & Yuichi Oike

  2. Department of Aging and Geriatric Medicine, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan

    Haruki Horiguchi & Yuichi Oike

  3. Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Tsuyoshi Kadomatsu, Keishi Miyata, Toshiro Moroishi & Yuichi Oike

  4. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Shinsei Yumoto & Hideo Baba

  5. Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Takeshi Masuda & Sumio Ohtsuki

  6. Department of Cell Signaling and Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Toshiro Moroishi

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Contributions

HH designed the study, performed and analyzed most of experiments, and wrote the paper. TK designed the study and wrote the paper. SYumoto and HB collected human data. TMasuda and SO performed proteomics. KM provided Angptl2 mutant mice. SYamamura, MS, and JM discussed the data. TMoroishi designed and supervised the study. YO coordinated, designed, and supervised the study, and wrote the paper. All authors discussed the data and commented on the paper.

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Correspondence to Tsuyoshi Kadomatsu or Yuichi Oike.

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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

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