MicroRNA-214-3p inhibits proliferation and cell cycle progression by targeting MELK in hepatocellular carcinoma and correlates cancer prognosis

Cancer Cell International, Nov 2017

Chunhua Lu, Huan Deng, Ningning Dong, Qian Xie, Suihai Wang, Yanjun Gao, Yao Chen, You Li, Yue Li

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MicroRNA-214-3p inhibits proliferation and cell cycle progression by targeting MELK in hepatocellular carcinoma and correlates cancer prognosis

Li et al. Cancer Cell Int MicroRNA-214-3p inhibits proliferation and cell cycle progression by targeting MELK in hepatocellular carcinoma and correlates cancer prognosis Yue Li 1 You Li 0 Yao Chen 1 Qian Xie 1 Ningning Dong 1 Yanjun Gao 1 Huan Deng 1 Chunhua Lu 0 Suihai Wang 1 0 Department of Biotechnology, College of Life Science and Technology, Guangxi University , No. 100, Daxue Road, Nanning 530004, Guangxi Province , China 1 Institute of Antibody Engineering, Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University , No. 1838, Guangzhou Avenue North, Guangzhou 510515 , China Background: MicroRNAs are considered as potential regulators in various biological pathways and contribute to the diagnosis and prognosis of cancers. MicroRNA-214-3p (miR-214-3p) was proved to be correlated with various cancers in recent studies. However, the biological functions of miR-214-3p in hepatocellular carcinoma (HCC) and its association with the prognosis of HCC after liver transplantation are still unevaluated. Here we intended to elucidate the functional implication of miR-214-3p in regulation of cell proliferation and apoptosis and its potential prediction of clinical prognosis of HCC patients. Methods: Expressions of miR-214-3p in 98 HCC patients and three HCC cell lines were detected by quantitative reverse transcription PCR (qRT-PCR) to explore the association of miR-214-3p expression and clinicopathological characteristics. The effects of miR-214-3p on cell proliferation and apoptosis were examined by proliferation and flow cytometry assay, respectively. The direct target gene of miR-214-3p was also detected by luciferase reporter assay. Results: The effects of miR-214-3p on cell proliferation and apoptosis were examined by proliferation and flow cytometry assay, respectively. The direct target gene of miR-214-3p was also detected by luciferase reporter assay. The results showed that miR-214-3p expression was downregulated in primary HCC samples compared with normal liver tissues, and was decreased in HCC recurrence species compared with non-recurrence controls (P = 0.001). Low miR214-3p level was associated with poor overall survival (OS) (Log rank P = 0.003) and recurrence-free survival (RFS) (Log rank P = 0.007). Moreover, miR-214-3p precursor transfection resulted in decreased cell proliferation, cell cycle arrest at G1 phase, and enhanced cell apoptosis in HepG2 and HUH-7 cells. Further investigation showed that miR-214-3p could regulate its target gene maternal embryonic leucine zipper kinase (MELK) by directly binding to MELK-3′-UTR. Conclusions: miR-214-3p suppresses HCC progression by directly down-regulating MELK expression, indicating a potential therapeutic target for the treatment and prognosis of HCC patients. microRNA-214-3p; MELK; Hepatocellular carcinoma; Recurrence; Proliferation; Apoptosis; Cell cycle arrest Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide with poor survival and unsatisfied prognosis [ 1–3 ]. Over decades, the incidence of HCC has been dramatically increased especially in hepatitis B or C virus (HBV or HCV) infection induced phenotype [ 4 ]. Until now, surgical hepatic resection and liver transplantation are still the main curative treatment for HCC patients. Although great advances have been made in treatment and diagnosis, the prognosis of HCC remains limited, with its survival rates under 20% at 5  years [ 5 ]. Therefore, it’s an urgent need to understand the molecular mechanisms responsible for the pathogenesis of HCC and to identify effective treatment strategies. However, tumor recurrence rates remain a major concern for the exhibition of active hepatitis or cirrhosis in surrounding non-tumor liver tissues, even in patients who have received curative treatments [ 6, 7 ]. A better understanding of the molecular mechanisms that can distinguish progressive from non-progressive HCC is indispensable for exploring novel prognostic markers and therapeutic targets which may guide the surveillance after liver transplantation. Recent evidences support that microRNAs (miRNAs) serve as potential indicators for diagnosis and prognosis of cancers [ 8 ]. miRNAs are small noncoding RNAs, which contain 20 ~ 23 nucleotides, processed from primiRNAs and contribute to post-transcriptional regulation of target gene expression through binding directly to the specific sequences of target genes’ 3′-UTRs [ 8 ]. Researches show that miRNAs have effects on cell proliferation, migration, and apoptosis via making a difference in the stability or translation of target mRNA. Additionally, miRNAs are considered as crucial participators in tumor progression through influencing multiple biological functions and pathways [ 9 ]. Previous study has demonstrated that miR-214-3p is correlated with tumor onset and progression [ 10 ]. It has been reported that miR-214-3p is downregulated in HCC tissues and closely rela (...truncated)


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Chunhua Lu, Huan Deng, Ningning Dong, Qian Xie, Suihai Wang, Yanjun Gao, Yao Chen, You Li, Yue Li. MicroRNA-214-3p inhibits proliferation and cell cycle progression by targeting MELK in hepatocellular carcinoma and correlates cancer prognosis, Cancer Cell International,