J Cancer 2020; 11(10):2737-2748. doi:10.7150/jca.36822

Research Paper

The prognostic value of miRNA-18a-5p in clear cell renal cell carcinoma and its function via the miRNA-18a-5p/HIF1A/PVT1 pathway

Huan Wang1*, Zhong-Yi Li2*, Zu-Hao Xu1*, Yuan-Lei Chen1*, Ze-Yi Lu1, Dan-Yang Shen1, Jie-Yang Lu1, Qi-Ming Zheng1, Li-Ya Wang1, Li-Wei Xu1, Ding-Wei Xue1, Hai-Yang Wu1, Li-Qun Xia1, Gong-Hui Li1✉

1. Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China, 310016
2. Department of Urology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China, 310016
*Contributed equally

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Citation:
Wang H, Li ZY, Xu ZH, Chen YL, Lu ZY, Shen DY, Lu JY, Zheng QM, Wang LY, Xu LW, Xue DW, Wu HY, Xia LQ, Li GH. The prognostic value of miRNA-18a-5p in clear cell renal cell carcinoma and its function via the miRNA-18a-5p/HIF1A/PVT1 pathway. J Cancer 2020; 11(10):2737-2748. doi:10.7150/jca.36822. Available from http://www.jcancer.org/v11p2737.htm

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Abstract

Purpose Clear cell renal cell carcinoma(ccRCC) is the most common type of renal cell carcinoma. While it is curable when detected at an early stage, some patients presented with advanced disease have poor prognosis. We aimed to identify key genes and miRNAs associated with clinical prognosis in ccRCC.

Methods The microarray datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were analyzed by using GEO2R. Then, Functional enrichment analysis was performed using the DAVID. A retrospective series of 254 ccRCC patients with complete clinical information was included in this study. Kaplan-Meier analysis and multivariate cox regression analysis were used for prognostic analysis. Wound healing assay and transwell assay were designed to evaluate the migration and invasion ability of ccRCC cell lines.

Results miRNA-18a was identified to be related with prognosis of ccRCC by using Kaplan-Meier analysis and multivariate cox regression analysis demonstrated that the prognostic value of miRNA-18a was independent of clinical features. Further studies showed that up-regulation of miRNA-18a had a positive effect on migration and invasion of ccRCC cells. The target gene (HIF1A) of the miRNA-18a was predicted by using the miRPathDB database. The transcription factors of DEGs were identified by using the i-cisTarget. Luckily, HIF1A was found to be one of the transcription factors of DEGs. Among these DEGs, PVT1 may be regulated by HIF1A and be related with prognosis of ccRCC. Finally, validation of miRNA18a/HIF1A/PVT1 pathway was checked via reverse transcription-polymerase chain reaction (RT-PCR) assay in both cell lines and clinical tumor samples.

Conclusion Our research revealed that miRNA18a/HIF1A/PVT1 pathway might play a crucial role in ccRCC progression, providing novel insights into understanding of ccRCC molecular mechanisms. Importantly, miRNA-18a could serve as a potential diagnostic biomarker and therapeutic targets for ccRCC patients.

Keywords: clear cell renal cell carcinoma, prognosis, biomarker, microarray, molecular pathways