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  • Title: ARHGAP25: A negative regulator of colorectal cancer (CRC) metastasis via the Wnt/β-catenin pathway.
    Author: Tao L, Zhu Y, Gu Y, Zheng J, Yang J.
    Journal: Eur J Pharmacol; 2019 Sep 05; 858():172476. PubMed ID: 31228451.
    Abstract:
    Herein, we found ARHGAP25 was down-regulated in colon biopsies of patients with colorectal cancer (CRC). Gene set enrichment analysis (GSEA) also showed that ARHGAP25 was negatively correlated with Wnt/β-catenin activation. To study the role of ARHGAP25 in CRC and its possible mechanism, we established lentiviral-mediated ARHGAP25 overexpression in HCT116 and RKO cells along with siRNA-mediated ARHGAP25 knockdown in SW620 cells. The metastatic capacity of the CRC cell lines in vitro was assessed by measuring cell proliferation, migration and invasion. Additionally, expression of matrix metalloproteinases (MMP2, MMP7 and MMP9), EMT-associated factors (E-cadherin, ZEB1, Snail and Twist1) and β-catenin (a core part of Wnt/β-catenin signaling) was determined. XAV939, a Wnt/β-catenin inhibitor, was used for treatment. Our data suggests that ARHGAP25 overexpression significantly inhibits CRC cell growth, suppresses cell migration and invasion, and reduces expression of MMPs, EMT-associated factors and β-catenin. Our results suggest not only that ARHGAP25 has an anti-metastatic role in CRC cells, but also that the inactivation of the Wnt/β-catenin pathway is important in this process. Accordingly, siRNA-ARHGAP25 resulted in the opposite effect, favoring CRC metastasis in vitro, and activating the Wnt/β-catenin pathway in CRC cells. In addition, the siRNA-ARHGAP25 induced changes on cell proliferation, migration, and invasion were significantly reversed with XAV939 treatment. Importantly, the anti-metastatic effects of ARHGAP25 were further substantiated in a CRC lung metastasis xenograft model. We conclude that ARHGAP25 negatively regulates the metastatic potential of CRC cells via the Wnt/β-catenin pathway. Thus, our findings implicate ARHGAP25 as a potential therapeutic target in CRC metastasis.
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