Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma.

Reona Okada,Tomohiko Ichikawa,Shogo Moriya,Naohiko Seki,Shunichi Asai,Mayuko Kato,Yusuke Goto,Yasutaka Yamada

doi:10.3390/biomedicines8120599

Abstract

We previously found that both the guide and passenger strands of the miR-139 duplex (miR-139-5p and miR-139-3p, respectively) were downregulated in cancer tissues. Analysis of TCGA datasets revealed that low expression of miR-139-5p (p < 0.0001) and miR-139-3p (p < 0.0001) was closely associated with 5-year survival rates of patients with renal cell carcinoma (RCC). Ectopic expression assays showed that miR-139-5p and miR-139-3p acted as tumor-suppressive miRNAs in RCC cells. Here, 19 and 22 genes were identified as putative targets of miR-139-5p and miR-139-3p in RCC cells, respectively. Among these genes, high expression of PLXDC1, TET3, PXN, ARHGEF19, ELK1, DCBLD1, IKBKB, and CSF1 significantly predicted shorter survival in RCC patients according to TCGA analyses (p < 0.05). Importantly, the expression levels of four of these genes, PXN, ARHGEF19, ELK1, and IKBKB, were independent prognostic factors for patient survival (p < 0.05). We focused on PXN (paxillin) and investigated its potential oncogenic role in RCC cells. PXN knockdown significantly inhibited cancer cell migration and invasion, possibly by regulating epithelial–mesenchymal transition. Involvement of the miR-139-3p passenger strand in RCC molecular pathogenesis is a new concept. Analyses of tumor-suppressive-miRNA-mediated molecular networks provide important insights into the molecular pathogenesis of RCC.

Highlights

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, with more than330,000 cases newly diagnosed in 2018 and more than 100,000 deaths annually [1]
The expression levels of miR-139-5p and miR-139-3p were evaluated in RNA sequencing data in RCC tissues compared with normal tissues (p < 0.0001 and p < 0.0001, respectively; Figure 1A)
From RCC tissue samples obtained from The Cancer Genome Atlas (TCGA). miR-139-5p and miR-139-3p were significantly datasets revealed low of miR-139-5p and downregulatedthe in RCC

Summary

Introduction

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, with more than. 330,000 cases newly diagnosed in 2018 and more than 100,000 deaths annually [1]. Clear cell RCC is the most common histological subtype of RCC, accounting for approximately 75% of all cases [2]. 20–30% of RCC patients have metastatic lesions at diagnosis, and the 5-year survival rate of these patients is less than 20% [2,3]. More than 20% of patients develop metastases during the postoperative follow-up period [4]. Elucidation of the molecular mechanisms involved in distant metastasis of RCC will contribute to the development of new diagnostic and therapeutic strategies.

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Results

Discussion

Conclusion