miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma

Abstract

MicroRNAs (miRNAs) play a crucial role in tumor progression and metastasis. We, and others, recently identified a number of miRNAs that are dysregulated in metastatic renal cell carcinoma compared with primary renal cell carcinoma. Here, we investigated three miRNAs that are significantly downregulated in metastatic tumors: miR-192, miR-194 and miR-215. Gain-of-function analyses showed that restoration of their expression decreases cell migration and invasion in renal cell carcinoma cell line models, whereas knockdown of these miRNAs resulted in enhancing cellular migration and invasion abilities. We identified three targets of these miRNAs with potential role in tumor aggressiveness: murine double minute 2, thymidylate synthase, and Smad Interacting protein 1/zinc finger E-box binding homeobox 2. We observed a convergent effect (the same molecule can be targeted by all three miRNAs) and a divergent effect (the same miRNA can control multiple targets) for these miRNAs. We experimentally validated these miRNA-target interactions using three independent approaches. First, we observed that miRNA overexpression significantly reduces the mRNA and protein levels of their targets. In the second, we observed significant reduction of the luciferase signal of a vector containing the 3'UTR of the target upon miRNA overexpression. Finally, we show the presence of inverse correlation between miRNA changes and the expression levels of their targets in patient specimens. We also examined the prognostic significance of miR-215 in renal cell carcinoma. Lower expression of miR-215 is associated with significantly reduced disease-free survival time. These findings were validated on an independent data set from The Cancer Genome Atlas. These results can pave the way to the clinical use of miRNAs as prognostic markers and therapeutic targets.

Promotional effect of microRNA-194 on breast cancer cells via targeting F-box/WD repeat-containing protein 7

“…In addition, in cancer of the gut (37,38) and kidney (39), miR-194 served a similar inhibitory role. By contrast, it was suggested that miR-194 served a role in the promotion and progression of breast cancer (9) and pancreatic ductal adenocarcinoma (40). These studies indicated that miR-194 had various target genes (31)(32)(33)(34)(35)(36)(37)(38)(39)(40).…”

“…By contrast, it was suggested that miR-194 served a role in the promotion and progression of breast cancer (9) and pancreatic ductal adenocarcinoma (40). These studies indicated that miR-194 had various target genes (31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Previous studies have demonstrated that miR-194 inhibited cell migration and invasion, which may have contributed to the anti-tumor activity of trastuzumab on HER2-overexpressing breast cancer cells (41,42).…”

Identification of miR-125a-5p as a tumor suppressor of renal cell carcinoma, regulating cellular proliferation, migration and apoptosis

“…Numerous miRNAs have been confirmed to be upregulated in RCC, including miR-21, miR-210 and miR-155 (18,19), while miR-127-3p, miR-145 and miR-126 have been shown to be significantly downregulated and correlated with relapse-free survival in patients with nonmetastatic RCC (20). Furthermore, serum miRNA levels have been associated with RCC and may be used as potential biomarkers; including miR-210 for early detection (19), miR-378 and miR-451 for diagnosis (21), and miR-122, miR-514, miR-192 and miR-215 for prognosis prediction and as therapeutic targets (18,22). MiR-125a-5p has been described as a tumor suppressor in numerous human cancers (10)(11)(12)(13).…”

MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway

“…8,9 Recent data have shown that miR-194 plays an important part in tumorigenesis. For example, miR-194 was found to act as a tumor suppressor in gastric cancer, 10 endometrial cancer, 11 renal cell carcinoma, 12 lung cancer, 13 and breast cancer, 14 while upregulated as an oncogene in pancreatic cancer. 15 In CRC, miR-194 has been reported to be downregulated in colon tissues 16 and can predict adenoma recurrence.…”