The hsa-miR-3613-5p, a potential oncogene correlated with diagnostic and prognostic merits in kidney renal clear cell carcinoma.

MicroRNA-3613 (hsa-miR-3613-5p), a biomarker with a dual role as an oncogenic or tumor suppressor, is associated with different types of cancer. This study aimed to determine the correlation between the hsa-miR-3613-5p gene expression and Kidney renal clear cell carcinoma (KIRC). Utilizing several bioinformatics tools, we examined the expression level and clinicopathological value of hsa-miR-3613-5p in patients with KIRC compared to normal tissues. Other bioinformatic measures, including survival analysis, diagnostic merit of hsa-miR-3613-5p, downstream target prediction, potential upstream lncRNAs, network construction, and functional enrichment analysis of hsa-miR-3613-5p, were performed. We observed that overexpression of hsa-miR-3613-5p in KIRC tissues had valuable diagnostic merit and was significantly correlated with the poor overall survival of KIRC patients. We also realized a correlation between abnormal expression of hsa-miR-3613-5p and several clinical parameters such as pathological stage, race, age, and histological grades in patients with KIRC. Moreover, we constructed the most potential regulatory network of hsa-miR-3613-5p in KIRC with 17 different axes, including four pseudogenes, two lncRNAs, and three mRNAs. Besides, we uncovered six variants in the mature form of hsa-miR-3613-5p. Finally, pathway enrichment analysis demonstrated that the top-ranked pathways for hsa-miR-3613-5p are cell cycle, cell adhesion molecules (CAMs), and hepatocellular carcinoma pathways. The present report suggests that the higher expression of hsa-miR-3613-5p is associated with the progression of KIRC. Therefore, it may be considered a valuable indicator for the early detection, risk stratification, and targeted treatment of patients with KIRC.

Ahmadi M ，Najari-Hanjani P ，Ghaffarnia R ，Ghaderian SMH ，Mousavi P ，Ghafouri-Fard S ... -  《-》

A microRNA-clinical prognosis model to predict the overall survival for kidney renal clear cell carcinoma.

Numerous studies have shown that microRNA (miRNA) serves as key regulatory factors in the origin and development of cancers. However, the biological mechanisms of miRNAs in kidney renal clear cell carcinoma (KIRC) are still unknown. It is necessary to construct an effective miRNA-clinical model to predict the prognosis of KIRC. In this study, 94 differentially expressed miRNAs were found between para-tumor and tumor tissues based on the Cancer Genome Atlas (TCGA) database. Seven miRNAs (hsa-miR-21-5p, hsa-miR-3613-5p, hsa-miR-144-5p, hsa-miR-376a-5p, hsa-miR-5588-3p, hsa-miR-1269a, and hsa-miR-137-3p) were selected as prognostic indicators. According to their cox coefficient, a risk score formula was constructed. Patients with risk scores were divided into high- and low-risk groups based on the median score. Kaplan-Meier curves analysis showed that the low-risk group had a better survival probability compared to the high-risk group. The area under the ROC curve (AUC) value of the miRNA model was 0.744. In comparison with clinical features, the miRNA model risk score was considered as an independent prognosis factor in multivariate Cox regression analysis. In addition, we built a nomogram including age, metastasis, and miRNA prognostic model based on the results of multivariate Cox regression analysis. The decision curve analysis (DCA) revealed the clinical net benefit of the prognostic model. Gene set enrichment analysis (GSEA) results suggested that several important pathways may be the potential pathways for KIRC. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for the target genes of 7 miRNAs revealed that miRNAs may participate in KIRC progression via many specific pathways. Additionally, the levels of seven prognostic miRNAs showed a significant difference between KIRC tissues and adjacent non-tumorous tissues. In conclusion, the miRNA-clinical model provides an effective and accurate way to predict the prognosis of KIRC.

Zhan Y ，Zhang R ，Li C ，Xu X ，Zhu K ，Yang Z ，Zheng J ，Guo Y ... -  《Cancer Medicine》

LncRNA MALAT1 modified progression of clear cell kidney carcinoma (KIRC) by regulation of miR-194-5p/ACVR2B signaling.

This investigation was purposed to extrapolate whether and how lncRNA MALAT1, miR-194-5p, and ACVR2B altered development of clear cell kidney carcinoma (KIRC). We totally gathered 318 pairs of KIRC tissues and adjacent normal tissues, and also purchased human KIRC cell lines and normal human proximal tubular epithelial cell line. Besides, si-MALAT1, pcDNA-MALAT1, miR-194-5p mimic, miR-194-5p inhibitor, and negative control (NC) were, respectively, transfected into KIRC cells. The viability, proliferation, and apoptosis of the cells were determined with CCK-8 assay, colony formation assay, and flow cytometry. Dual-luciferase reporter gene assay was implemented to validate the targeted relationships between MALAT1 and miR-194-5p, as well as between miR-194-5p and ACVR2B. The results showed that highly expressed MALAT1, ACVR2B, and lowly expressed miR-194-5p were associated with larger tumor size (≥4 cm), advanced TNM stage and poor prognosis of KIRC patients, when, respectively, compared with lowly expressed MALAT1, ACVR2B, and highly expressed miR-194-5p (P < 0.05). Transfection of pcDNA-MALAT1, miR-194-5p inhibitor, and pcDNA-ACVR2B conferred the KIRC cells with promoted viability and proliferation, as well as reduced apoptosis (P < 0.05). Treatment of rats with pcDNA-MALAT1, miR-194-5p inhibitor, or pcDNA-ACVR2B also contributed to larger tumor size growing in them (P < 0.05). Moreover, MALAT1 could directly target miR-194-5p to suppress its expression, and ACVR2B was the targeted molecule of miR-194-5p (P < 0.05). Finally, ACVR2B could reverse the effects exerted by miR-194-5p on viability, proliferation, and apoptosis of KIRC cells (P < 0.05). In conclusion, LncRNA MALAT1/miR-194-5p/ACVR2B signaling was regarded as a candidate pathway for modulating KIRC progression.

Ye Y ，Zhang F ，Chen Q ，Huang Z ，Li M ... -  《-》

Comprehensive analysis of PTEN-related ceRNA network revealing the key pathways WDFY3-AS2 - miR-21-5p/miR-221-3p/miR-222-3p - TIMP3 as potential biomarker in tumorigenesis and prognosis of kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is one of the most common malignancies, and there is still a lack of effective biomarkers for early detection and prognostic prediction. In here, we compared the characteristics of RNA sequencing data sets of KIRC samples based on the tumor suppressor gene phosphatase and tensin homolog (PTEN). The 1016 long noncoding RNAs, 48 microRNAs (miRNAs), and 2104 messenger RNAs associated with PTEN were identified and these genes were differentially expressed between tumor and paracancerous tissues. The most relevant pathway was found to be WDFY3-AS2 - miR-21-5p/miR-221-3p/miR-222-3p - TIMP3 according to the rules of competing endogenous RNA (ceRNA) regulation. WDFY3-AS2 and TIMP3 expression were positively correlated and reduced in KIRC samples, while miR-21-5p, miR-221-3p, and miR-222-3p were relatively highly expressed. The relatively low expression of WDFY3-AS2 and TIMP3 in KIRC were associated with poor prognosis in KIRC patients, while higher expression of miR-21-5p, miR-221-3p, and miR-222-3p predicted reduced survival (p < 0.05). Univariate and multivariate Cox regression analysis showed that lower expression of WDFY3-AS2 and TIMP3 was significantly related to tumor grade, tumor size, lymph node metastasis, distant metastasis, and TNM stage. The expression of TIMP3 in KIRC tissues was also verified by immunohistochemistry, and the results were consistent with our analytical data. In summary, this study constructed a new model with clinical predictive value and identified the WDFY3-AS2/TIMP3 pathway that was closely associated with the prognosis of KIRC, which could serve as a promising biomarker for the diagnosis and treatment of KIRC.

Zhou X ，Liu G ，Xu M ，Ying X ，Li B ，Cao F ，Cheng S ，Xiao B ，Cheng M ，Liang L ，Jia M ，Li W ，Liu J ，Li Z ... -  《-》

Epigenetic inactivation of ACAT1 promotes epithelial-mesenchymal transition of clear cell renal cell carcinoma.

Acetyl-CoA acyltransferase 1 (ACAT1) is a key enzyme catalyzing the production of mitochondrial ketone bodies. We have shown that ACAT1 is down-regulated in kidney renal clear cell carcinoma (KIRC) previously. To investigate the reasons for downregulation of ACAT1 in KIRC and explore the underlying mechanisms involved in metastatic inhibition regulated by ACAT1. The Gene Expression Omnibus (GEO) database was queried for meta-analysis of ACAT1 mRNA expression in KIRC. The UALCAN website was used to compare the methylation levels of the ACAT1 promoter region in KIRC and normal tissues. RT-qPCR was used to quantitate ACAT1 transcription levels. The GCBI and Tarbase V.8 databases were used to predict miRNAs that may target the mRNA of ACAT1. The correlation between mRNA expression of ACAT1, MMP7 (matrix metallopeptidase 7), CDH1 (E-cadherin), EpCAM (epithelial cell adhesion molecule), and VIM (vimentin) was analyzed. Extracellular MMP7 protein was quantitated using an ELISA assay. The methylation level of the ACAT1 promoter region in KIRC was significantly higher than that in the normal kidney tissues. The ACAT1 mRNA expression in the KIRC cell lines was restored after treatment with 5-aza-dC (p < 0.05). MiR-21-5p is a conserved microRNA targeting ACAT1. It is expressed at a significantly higher level in KIRC than in normal tissues (p < 0.001). MiR-21-5p miRNA expression negatively correlates with ACAT1 mRNA expression. The expression of miR-21-5p is higher at the T3-T4 stages and in the histologic grades G3-G4. Patients with high miR-21-5p expression tended to have lower overall survival, suggesting that miR-21-5p could serve as a potentially valuable diagnostic biomarker for KIRC (AUC = 0.957; p < 0.001). A mimetic of miR-21-5p inhibited the expression of ACAT1 mRNA and protein. In addition, ACAT1 mRNA expression positively correlates with CDH1 and EpCAM but is negatively correlated with VIM. Overexpression of ACAT1 suppresses the secretion of MMP7 in KIRC cells. Expression of ACAT1 in KIRC is controlled at two levels, firstly by the hypermethylation of the ACAT1 promoter region and secondly by overexpression of miR-21-5p. Downregulation of ACAT1 expression correlates with epithelial-mesenchymal transition (EMT).

Han P ，Wu S ，Li L ，Li D ，Zhao J ，Zhang H ，Wang Y ，Zhong X ，Zhang Z ，Li P ，Matskova L ，Zhou X ... -  《-》