Abstract
Copious evidence demonstrates the crucial role of Rho GTPase-activating proteins in human malignancies. The downregulation of Rho GTPase-activating protein 15 (ARHGAP15), a Rac1-specific GAP, has been observed in glioma and pancreatic ductal adenocarcinoma. The present study explored the expression in colorectal cancer (CRC) by quantitative real-time PCR and immunohistochemistry analysis. The possible function of ARHGAP15 in CRC was investegated in vitro and in vivo. We found that ARHGAP15 expression was obviously lower in CRC specimens than in normal colonic mucosa. ARHGAP15 expression was significantly correlated with clinical stage, tumor size metastasis, vital status, and overall survival of CRC patients. ARHGAP15 overexpression inhibited cell growth, migration, and invasion of HT29 and RKO cells in vitro, whereas opposite results were observed in ARHGAP15-silenced LoVo cells. Mechanically, we found that PTEN (phosphatase and tensin homology deleted on chromosome 10) signaling pathway was closely correlated with ARHGAP15 expression by Gene set enrichment analysis with The Cancer Genome Atlas CRC data set. Increased PTEN and Forkhead box protein O1 (FOXO1, a downstream transcription factor of AKT), and decreased phosphorylation of AKT were observed in ARHGAP15-overexpressed HT29 and RKO cells. In addition, ARHGAP15 overexpression increased p21, which was responsible for the accelerated cell growth and S phase arrest, but decreased the protein levels of MMP-2 and MMP-9, which were stimuli for cell metastasis. Notably, upregulating PTEN expression, FOXO1 overexpression and interdicting the activation of AKT pathway with MK2206 suppressed the proliferation and the metastatic ability of ARHGAP15-silenced LoVo cells. In addition, FOXO1 overexpression markedly enhanced the expression and the promoter activity of ARHGAP15. Furthermore, ARHGAP15 overexpression significantly decelerated the pace of tumor growth and metastasis in the lung in vivo. In summary, these results suggest that ARHGAP15 might serve as a tumor suppressor during CRC progression and metastasis through PTEN/AKT/FOXO1-signaling pathway.
Highlights
Colorectal cancer (CRC) is the third frequently diagnosed malignancy in human and accounts for a staggering amount of cancer-related death next to lung cancer[1,2].Surgery, radiotherapy, and chemotherapy are conventional treatment options for CRC patients
We found that PTEN/AKT/Forkhead box protein O1 (FOXO1) axis was involved in the anti-proliferation and antiinvasion effects of ARHGAP15
To study ARHGAP15 expression in CRC tissues, two publicly available data sets, GSE934826 downloaded from Gene Expression Omnibus (GEO) database and the CRC data set from The Cancer Genome Atlas (TCGA), were reanalyzed
Summary
Colorectal cancer (CRC) is the third frequently diagnosed malignancy in human and accounts for a staggering amount of cancer-related death next to lung cancer[1,2]. Radiotherapy, and chemotherapy are conventional treatment options for CRC patients. The emergence of targeted drugs gives fresh impetus to the therapy of metastatic CRC3. The incidence and mortality rates have declined in the past decades among the individuals > 50 years old, there is a steady growth trend for CRC in the younger population[4,5]. It is still of great significance to dissect the pathogenesis of CRC. Rho family of GTPases is a subgroup of the Ras superfamily.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
