MicroRNA-205 Inhibits Src-Mediated Oncogenic Pathways in Renal Cancer

Abstract

The Src family of protein kinases (SFKs) plays key roles in regulating fundamental cellular processes, including cell growth, differentiation, cell shape, migration and survival, and specialized cell signals in various malignancies. The pleotropic functions of SFKs in cancer make them promising targets for intervention. Here we sought to investigate the role of miR-205 in inhibition of Src-mediated oncogenic pathways in renal cancer. We report that expression of miR-205 was significantly suppressed in renal cancer cell lines and tumors when compared with normal tissues and a non-malignant cell line, and is correlated inversely with the expression of SFKs. miR-205 significantly suppressed the luciferase activity of reporter plasmids containing the 3’UTR sequences complementary to either Src, Lyn or Yes, which was abolished by mutations in these 3’UTR regions. Over-expression of miR-205 in A498 cells reduced Src, Lyn and Yes expression both at mRNA and protein levels. Proliferation of renal cancer cells was suppressed by miR-205, mediated by the phosphoSrc-regulated ERK1/2 pathway. Cell motility factor- FAK and STAT3 activation was also inhibited by miR-205. Transient as well as stable over-expression of miR-205 in A498 cells resulted in induction of G0/G1 cell cycle arrest and apoptosis as indicated by decreased levels of cyclin D1 and cMyc, suppressed cell proliferation, colony formation, migration, and invasion in renal cancer cells. miR-205 also inhibited tumor cell growth in vivo. This is the first study demonstrating that miRNA-205 inhibits protooncogenic Src family of kinases indicating a therapeutic potential of miR-205 in the treatment of renal cancer.

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

“…miRNAs are known to contribute to multiple tumorigenic steps in human cancers, including RCC. Recent studies have identified regulatory activities of miRNAs in ccRCC cell growth (4)(5)(6)(7)(8), apoptosis (5,6,8,9), migration, and invasion (5)(6)(7)(8). A predominant and systemic alteration in miRNA expression during renal carcinogenesis has been indicated by present studies of miRNA expression profiling (10)(11)(12)(13)(14)(15)(16)(17).…”

MicroRNA expression profiling identifies decreased expression of miR-205 in inflammatory breast cancer

“…Additional targets of miR-205 identified in other tissue types have not been validated in breast cancer. [83][84][85][86] Likely, miR-205 plays a role in specific pathways in tumorigenesis and tumor progression in a cell type-specific manner.…”

Loss of microRNA-205 expression is associated with melanoma progression

“…miR-205 is upregulated compared with normal tissues in transitional cell carcinoma of the bladder; 42,43 squamous cell carcinoma of the uterine cervix; 44 endometrial adenocarcinomas, including the endometrioid 45 and serous 46 types; ovarian endometrioid adenocarcinoma; 47 and nonsmall cell carcinomas (adenocarcinoma and squamous cell carcinoma) of the lung. 48 In contrast, miR-205 is downregulated in breast carcinomas; 49,50 adenocarcinoma of the prostate; 51,52 renal cell carcinoma; 53 and spindle cell carcinomas of the head and neck. 54 This apparent disparity of function likely reflects the molecular plasticity of miR-205 as a regulator of multiple different gene targets, which would exert potentially pleiotropic effects.…”