Abstract
MicroRNA-148a (miR-148a) has been reported to be deregulated in different tumor types, whereas the biological function of miR-148a in renal cell carcinoma (RCC) largely remains unexplored. In the present study we investigated the clinical significance, biological effects, and the underlying molecular mechanisms of miR-148 in RCC. Here, we showed that miR-148a was significantly downregulated in RCC tissues and cell lines. Low expression of miR-148a in RCC tissues was associated with large tumor size, advanced TNM stage, and lymph node metastasis. Functional assays revealed that overexpression of miR-148a significantly inhibited RCC cell proliferation, colony formation, migration and invasion invitro and suppressed RCC xenograft tumor growth invivo. In addition, using quantitative RT-PCR (qRT-PCR), western blot analysis and luciferase reporter assays, AKT2 was confirmed to be a direct target of miR-148a. AKT2 expression was upregulated, and was negatively correlated with miR-148a expression in RCC tissues (r=-0.641, P<0.001). Silencing of AKT2 phenotypically copied miR-148a-induced phenotypes, whereas re-expression of AKT2 reversed the suppressive effects of miR-148a in RCC cells. Further mechanistic investigations showed that miR-148a exerted its antitumor activity via inhibition of the AKT pathway invitro and invivo. Taken together, these findings suggest that miR-148a functions as tumor suppressor in RCC by targeting AKT2.
Highlights
Renal cell carcinoma (RCC) is the most common malignant cancer in the adult kidney, and accounts for approximately 85% of all primary malignant kidney tumors and 3% of all MicroRNAs are small endogenous non-coding RNAs composed of ~19-25 nucleotides that negatively regulate gene expression by degrading target mRNAs or repressing protein translation by binding to the 3' untranslated region (3'UTR) of their target mRNAs [6]
Deregulation of miR-148a has been reported in several types of cancer, including breast cancer [12], hepatocellular carcinoma [13], osteosarcoma [14], gastric cancer [15], colorectal cancer [16], medulloblastoma [17], bladder cancer [18] and non-small cell lung cancer [19]. miR-148a has been previously characterized as a tumor suppressor or oncogene with functions in regulating cell proliferation, apoptosis, and migration and invasion in several types of cancer [12,13,14,15,16,17,18,19,20]
Results of quantitative RT-PCR (qRT-PCR) showed that expression of miR-148a was decreased in all of the renal cell carcinoma (RCC) cell lines compared with the HK-2 cells (Fig. 1A)
Summary
Renal cell carcinoma (RCC) is the most common malignant cancer in the adult kidney, and accounts for approximately 85% of all primary malignant kidney tumors and 3% of all MicroRNAs (miRNAs) are small endogenous non-coding RNAs composed of ~19-25 nucleotides that negatively regulate gene expression by degrading target mRNAs or repressing protein translation by binding to the 3' untranslated region (3'UTR) of their target mRNAs [6]. MiRNAs have been shown to function as either oncogenes or tumor suppressors in different types of cancer, which manifest as the regulation of cellular proliferation, cell death and angiogenesis in tumor progression [8,9]. Numerous related studies have been carried out in RCC and have shown that dysregulation in miRNAs are involved in the occurrence and progression of RCC by regulating the expression of their target oncogenes and tumor suppressors [10,11], suggesting that miRNAs could serve as diagnostic markers or therapeutic agents for RCC. The detailed biological function and underlying molecular mechanisms of miR-148a in human RCC remain unclear. The aims of this study were to investigate the clinical significance, biological function and underlying molecular mechanisms of miR-148a in RCC
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