Role of Rac1 pathway in epithelial-to-mesenchymal transition and cancer stem-like cell phenotypes in gastric adenocarcinoma Journal Article
| Authors: | Yoon, C.; Cho, S. J.; Chang, K. K.; Park, D. J.; Ryeom, S. W.; Yoon, S. S. |
| Article Title: | Role of Rac1 pathway in epithelial-to-mesenchymal transition and cancer stem-like cell phenotypes in gastric adenocarcinoma |
| Abstract: | Rac1, a Rho GTPase family member, is dysregulated in a variety of tumor types including gastric adenocarcinoma, but little is known about its role in cancer stem-like cells (CSCs). Therefore, Rac1 activity and inhibition were examined in gastric adenocarcinoma cells and mouse xenograft models for epithelial-to-mesenchymal transition (EMT) and CSC phenotypes. Rac1 activity was significantly higher in spheroid-forming or CD44+ gastric adenocarcinoma CSCs compared with unselected cells. Rac1 inhibition using Rac1 shRNA or a Rac1 inhibitor (NSC23766) decreased expression of the self-renewal transcription factor, Sox-2, decreased spheroid formation by 78%-81%, and prevented tumor initiation in immunodeficient mice. Gastric adenocarcinoma CSCs had increased expression of the EMT transcription factor Slug, 4.4- to 8.3-fold greater migration, and 4.2- to 12.6-fold greater invasion than unselected cells, and these increases could be blocked completely with Rac1 inhibition. Gastric adenocarcinoma spheroid cells were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed with Rac1 shRNA or NSC23766. The PI3K/Akt pathway may be upstream of Rac1, and JNK may be downstream of Rac1. In the MKN-45 xenograft model, cisplatin inhibited tumor growth by 50%, Rac1 inhibition by 35%, and the combination by 77%. Higher Rac1 activity, in clinical specimens from gastric adenocarcinoma patients who underwent potentially curative surgery, correlated with significantly worse survival (P = 0.017). In conclusion, Rac1 promotes the EMT program in gastric adenocarcinoma and the acquisition of a CSC state. Rac1 inhibition in gastric adenocarcinoma cells blocks EMT and CSC phenotypes, and thus may prevent metastasis and augment chemotherapy. ©2017 AACR. |
| Journal Title: | Molecular Cancer Research |
| Volume: | 15 |
| Issue: | 8 |
| ISSN: | 1541-7786 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-08-01 |
| Start Page: | 1106 |
| End Page: | 1116 |
| Language: | English |
| DOI: | 10.1158/1541-7786.mcr-17-0053 |
| PROVIDER: | scopus |
| PMCID: | PMC5540756 |
| PUBMED: | 28461325 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 5 September 2017 -- Source: Scopus |
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