Journal
THERANOSTICS
Volume 10, Issue 13, Pages 5998-6010Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.43427
Keywords
colorectal cancer; tumor metastasis; ARHGAP5; CREB1; miR-137
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Funding
- National Natural Science Foundation of China [81972569, 81672665, 81872267, 81772925, 81702761, 81972623]
- Pearl River S&T Nova Program of Guangzhou [201806010002]
- Guangdong Esophageal Cancer Institute Science and Technology Program [M201802, Q201702]
- Natural Science Foundation of Guangdong Grant [2017A030313615, 2018A0303130282]
- Sci-Tech Project Foundation of Guangzhou City [201607020038]
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Background: Metastatic colorectal cancer (CRC) is a lethal disease; however, the underlying molecular mechanisms remain unclear and require further study. Methods: RNA-Seq, PCR, Western blotting, immunohistochemistry, ChIP and RNAi assays were performed to investigate Rho GTPase-activating protein 5 (ARHGAP5, aslo known as p190RhoGAP-B, p190-B) expression and the clinical relevance, functional roles and regulatory mechanisms of this protein using human CRC cells and tissues. In vivo, two cell-based xenograft models were used to evaluate the roles of ARHGAP5 in CRC metastasis. Results: Here, we report that ARHGAP5 expression is significantly increased in metastatic CRC tissues and is inversely associated with patient overall survival. The suppression of ARHGAP5 reduces CRC cell metastasis in vitro and in cell-based xenograft models. Furthermore, we show that ARHGAP5 promotes CRC cell epithelial-mesenchymal transition by negatively regulating RhoA activity. Mechanistically, cAMP response element-binding protein (CREB1) transcriptionally upregulates ARHGAP5 expression, and decreased miR-137 further contributes to ARHGAP5 mRNA stability in CRC. Conclusions: Overall, our study highlights the crucial function of ARHGAP5 in CRC metastasis, thus suggesting novel prognostic biomarkers and hypothetical therapeutic targets.
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