Abstract 1039: c-Met activation promotes epithelial-to-mesenchymal transition (EMT) in renal cancer cells through the upregulation of the chemokine receptor CXCR7

Abstract

Abstract Purpose: The purpose of this study is to explore how the receptor tyrosine kinase (RTK) c-Met modulates the expression of the pro-tumorigenic molecule CXCR7, a chemokine receptor, in renal cancer cells; and to investigate the role of c-Met and CXCR7 in promoting the epithelial-mesenchymal transition (EMT) of renal cancer cells. Background: c-Met, a pro-oncogenic RTK, can play a major role in the survival and progression of cancer cells; and it is often overexpressed in both clear cell and papillary renal cell carcinoma (RCC). c-Met, upon activation by its specific ligand hepatocyte growth factor (HGF), can induce a broad spectrum of biological pathways involved in the growth of cancer cells. CXCR family of chemokine receptors and their chemokine ligands were shown to exhibit decisive roles in tumor initiation, promotion, progression, and metastasis. CXCR7 is upregulated in several types of cancers, including renal cancer, and found to be involved in tumor cell development, survival, and metastasis. A global process integral to the cancer metastasis is EMT, which results in the disruption of cell-to-cell junctions and endows epithelial cells with the ability to migrate and invade surrounding tissue. EMT process is associated with an increase of mesenchymal markers like vimentin and a decrease of epithelial markers like E-cadherin in cancer cells. Sustained activation of c-Met induces EMT in renal cancer cells, however, the cross-talk between CXCR7 and c-Met signaling in the promotion of renal cancer EMT remains unclear. Results: We assessed the expression levels of CXCR7 by Western blot analysis and found that CXCR7 is overexpressed in human renal cancer cells (both 786-O and ACHN) when compared to normal renal epithelial cells (RPTEC). Also, in both 786-O and ACHN cells, HGF-induced activation of c-Met further increased the expression of CXCR7 at both RNA and protein levels. In renal cancer cells (both 786-O and ACHN), siRNA-mediated knockdown of c-Met or treatment with XL-184 (a small molecule inhibitor of c-Met) inhibited c-Met-induced upregulation of CXCR7. c-Met activation increased the expression of pro-EMT markers such as vimentin, N-cadherin, and MMP-9 and suppressed the expression of anti-EMT molecule E-cadherin, as measured by Western blot and flow cytometry. On the other hand, siRNA-mediated silencing of CXCR7 attenuated the induction of EMT, suggesting that CXCR7 plays a major role in c-Met-induced EMT in renal cancer cells. Conclusion: Together, our findings demonstrate that the c-Met-CXCR7 axis can trigger the EMT, which can play an important role(s) in renal cancer proliferation and migration. Citation Format: Samik Chakraborty, Murugabaskar Balan, Soumitro Pal. c-Met activation promotes epithelial-to-mesenchymal transition (EMT) in renal cancer cells through the upregulation of the chemokine receptor CXCR7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1039.