Abstract
Many miRNAs are associated with the carcinogenesis of hepatocellular carcinoma (HCC) and some exhibit potential prognostic value. In this study, to further confirm the prognostic value of miRNAs in HCC, we employed miRNA-sequencing data of tumor tissues of 372 HCC patients released by The Cancer Genome Atlas (TCGA) and identified 3 miRNAs including miR-22, miR-9-1 and miR-9-2 could be used as independent predictors for HCC prognostic evaluation. As a tumor-suppressive miRNA, miR-22 was down-regulated in HCC tissues. This down-regulation correlated with tumor vascular invasion, Edmondson–Steiner grade, TNM stage, and AFP level. Moreover, biofunctional investigations revealed that miR-22 significantly attenuated cellular proliferation, migration and invasion of HCC cells. Additionally, through gene expression profiles and bioinformatics analysis, YWHAZ was identified to be a direct target of miR-22 and its overexpression partially counteracted the inhibitory effects of miR-22 on HCC cells. Finally, molecular studies further confirmed that miR-22 promoted the accumulation of FOXO3a in nucleus and subsequently reversed invasive phenotype of HCC cells by repressing YWHAZ-mediated AKT phosphorylation. Taken together, these data demonstrate that miR-22 exhibits tumor-suppressive effects in HCC cells by regulating YWHAZ/AKT/FOXO3a signaling and might be used as an independent prognostic indicator for HCC patients.
Highlights
A steadily growing number of studies have confirmed that miRNAs play pivotal roles in tumorigenesis, either acting as oncogenes or tumor suppressors to modulate growth, angiogenesis, drug or chemo-resistance, invasion and metastasis of malignant cells [1, 2]
To further confirm the prognostic value of miRNAs in hepatocellular carcinoma (HCC), we employed miRNA-sequencing data of tumor tissues of 372 HCC patients released by The Cancer Genome Atlas (TCGA) and identified 3 miRNAs including miR-22, miR-9-1 and miR-9-2 could be used as independent predictors for HCC prognostic evaluation
MiR-22 is an independent predictor of overall survival of HCC patients
Summary
A steadily growing number of studies have confirmed that miRNAs play pivotal roles in tumorigenesis, either acting as oncogenes or tumor suppressors to modulate growth, angiogenesis, drug or chemo-resistance, invasion and metastasis of malignant cells [1, 2]. It has been suggested that miRNAs play a critical role in regulating tumorigenesis and metastasis of HCC [9,10,11], and some of them have been characterized to correlate with prognosis or accepted as potential therapeutic targets [12, 13]. Enforced expression of miR-26a suppressed tumor angiogenesis, growth and metastasis of HCC cells through multiple pathways, including HGF-cMet signaling [14], IL-6-Stat www.impactjournals.com/oncotarget signaling [15] or directly targeting cyclins [16]. Systemic administration of miR-26a in a mouse HCC model dramatically suppressed tumorigenesis and protected mice from disease progression without toxicity [16]
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