Replisome genes regulation by antitumor miR‐101‐5p in clear cell renal cell carcinoma

Abstract

| INTRODUC TI ONRenal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and is the 12th most prevalent malignancy worldwide, with 338 000 newly diagnosed patients in 2012 and approximately 100 000 deaths annually. 1 Clear cell RCC (ccRCC) is pathologically the most common type and accounts for approximately 75% of all cases. 2 Although the prognosis is favorable with surgical resection for nonmetastatic RCC, approximately 20%-30% of RCC patients have metastatic sites at the diagnosis and the 5-year survival rate is less than 20%. 2,3 In addition, more than 20% of patients develop metastases during postoperative follow-up periods. 4 These clinical issues are caused by a lack of useful biomarkers for early detection of RCC and the inefficiency of therapy for patients with metastatic or treatment-resistant RCC. Abstract Analysis of microRNA (miRNA) regulatory networks is useful for exploring novel biomarkers and therapeutic targets in cancer cells. The Cancer Genome Atlas dataset shows that low expression of both strands of pre-miR-101 (miR-101-5p and miR-101-3p) significantly predicted poor prognosis in clear cell renal cell carcinoma (ccRCC). The functional significance of miR-101-5p in cancer cells is poorly understood. Here, we focused on miR-101-5p to investigate the antitumor function and its regulatory networks in ccRCC cells. Ectopic expression of mature miRNAs or siRNAs was investigated in cancer cell lines to characterize cell function, ie, proliferation, apoptosis, migration, and invasion. Genome-wide gene expression and in silico database analyses were undertaken to predict miRNA regulatory networks. Expression of miR-101-5p caused cell cycle arrest and apoptosis in ccRCC cells. Downstream neighbor of son (DONSON) was directly regulated by miR-101-5p, and its aberrant expression was significantly associated with shorter survival in propensity score-matched analysis (P = .0001). Knockdown of DONSON attenuated ccRCC cell aggressiveness. Several replisome genes controlled by DONSON and their expression were closely associated with ccRCC pathogenesis.The antitumor miR-101-5p/DONSON axis and its modulated replisome genes might be a novel diagnostic and therapeutic target for ccRCC.

Downstream neighbor of SON (DONSON) is associated with unfavorable survival across diverse cancers with oncogenic properties in clear cell renal cell carcinoma

“…Our functional investigations already underline this hypothesis as DONSON-depletion caused growth restriction in a time-dependent manner in our RCC cell culture model. This is in line with previous literature, where DONSON-depletion also induced apoptosis [ 16 ]. Nevertheless, it should be mentioned that DONSON's potential as a therapeutic target requires further investigation.…”

“…Recently, the tumor-suppressive miR-101-5p was shown to negatively regulate DONSON and several replisome genes in KIRC. Expression of miR-101-5p, as well as siRNA-mediated DONSON knockdown, caused cell cycle arrest, apoptosis, and impaired motility in the RCC cell lines 786O and A498 [ 16 ]. Our results are, therefore, in line with this previously published study.…”

“…A MicroRNA (miRNA) passenger strand, miR101-5p , acting tumor suppressive in RCC, was found to directly regulate the DONSON expression. Ectopic expression of miR101-5p , as well as a siRNA-mediated DONSON-knockdown, attenuated the malignant features of RCC cells [ 16 ].…”

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

“…The A498 and 786-O human RCC cell lines were used in this study and were obtained from the Japanese Collection of Research Bioresources Cell Bank. Cell maintenance was performed as we described previously [ 15 ].…”

“…Our RNA-sequencing-based signatures refute this concept, and our recent studies showed downregulation of both the guide and passenger strands of miRNA duplexes (e.g., miR-30c , miR-99a , miR-101 , miR-143 , miR-145 , and miR-150 ) in cancer tissues [ 10 , 11 , 12 ]. Furthermore, ectopic expression assays revealed that the passenger strand of some miRNAs, similar to the guide strand, functions as tumor-suppressive miRNAs, regulating many oncogenes intracellularly [ 13 , 14 , 15 , 16 ]. Involvement of miRNA passenger strands in the molecular pathogenesis of human cancers is a new concept, and additional research on passenger strands is needed.…”