A systematic investigation based on microRNA-mediated gene regulatory network reveals that dysregulation of microRNA-19a/Cyclin D1 axis confers an oncogenic potential and a worse prognosis in human hepatocellular carcinoma

Abstract

MicroRNAs (miRNAs) contribute to a wide variety of human diseases by regulating gene expression, leading to imbalances in gene regulatory networks. To discover novel hepatocellular carcinoma (HCC)-related miRNA-target axes and to elucidate their functions, we here performed a systematic investigation combining biological data acquisition and integration, miRNA-target prediction, network construction, functional assay and clinical validation. As a result, a total of 117 HCC differentially expressed miRNAs were identified, and 728 high confident target genes of these miRNAs were collected. Then, the interaction network of target genes was constructed and 221 key nodes with topological importance in the network were identified according to their topological features including degree, node-betweenness, closeness and K-coreness. Among these key nodes, Cyclin D1 had the highest node-betweenness, implying its bottleneck role in the network. Luciferase reporter assay confirmed that miRNA-19a, which was one of HCC downregulated miRNAs, directly targeted Cyclin D1 in HCC cells. Moreover, miR-19a might play inhibitory roles in HCC malignancy via regulating Cyclin D1 expression. Further clinical evidence also highlighted the prognostic potential of miR-19a/Cyclin D1 axis in HCC. In conclusion, this systematic investigation provides a framework to identify featured miRNAs and their target genes which are potent effectors in the occurrence and development of HCC. More importantly, miR-19a/Cyclin D1 axis might have promising applications as a therapeutic target and a prognostic marker for patients with HCC.

MicroRNA-19a-3p regulates cell growth through modulation of the PIK3IP1-AKT pathway in hepatocellular carcinoma

“…We confirmed miR-19a-3p oncogenic role by depressed PIK3IP1 expression, a negative regulator of PI3K. However, there are one study showed miR-19a was downregulated in HCC by analysis biological data acquisition and integration from literature retrieval and inhibit cyclin D1 expression [12]. Different type of HCC cell lines were used in these studies, and maybe was the reason for the discrepancies of those results.…”

“…Some studies have shown that miR-19a-3p is underexpressed in patients with recurrent HCC compared to the nonrecurrence group [11]. It inhibits cell proliferation and promotes more apoptosis in HCC [12].These data indicate its tumor suppressor function but some studies that have been conducted show the opposite effects of miR-19a-3p in HCC. These studies indicate that miR-19a-3p is upregulated in an HCC tumors compared to respective peritumor adjacent tissues [13] and it promotes tumor growth, metastasis, and chemoresistance [14,15].…”

Blood‐derived DNA methylation predictors of mortality discriminate tumor and healthy tissue in multiple organs

“…Furthermore, pathophysiological, immune infiltrate promoted inflammation in tumor microenvironment is consistent with potential biological functions of the DNAm markers in the MRscore and DNAmPheno-Age. For example, in addition to four CpGs in the MRscore mapped to genes involved in various cancers (cg23665802 in MIR19A, cg08362785 in MKL1, cg19572487 in RARA, cg05575921 in AHRR) [31][32][33][34][35][36][37][38][39], three CpGs in the MRscore (cg05575921, cg06126421, and cg08362785) were identified to correlate with C-reactive protein, a sensitive indicator of chronic inflammation, in a meta-analysis of EWAS [40]. Six CpGs in the MRscore are strongly related to tobacco smoking [12,41,42], a factor with well-established strong effects on inflammation/immune processes [43,44] and 18 types of cancer such as lung, colorectal, and liver cancer [45], [46].…”

Thrombospondin‐1 and microRNA‐1 expression in response to multiwalled carbon nanotubes in alveolar epithelial cells

“…Network interactions are derived from literature curation or direct user submitted information (http://www.ebi.ac.uk/intact/). Numerous studies have used IntAct molecular network interactions . The molecular network interactions include both physical and functional interactions, and novel molecular targets that are reported in the IntAct database.…”

“…Numerous studies have used IntAct molecular network interactions. 35,36 The molecular network interactions include both physical and functional interactions, and novel molecular targets that are reported in the IntAct database.…”