Abstract
MicroRNA-218 (miR-218) is considered a tumor suppressor in human cancer. In the present study, miR-218 expression was found to be significantly lower in human hepatocellular carcinoma (HCC) than in normal tumor-adjacent tissues. miR-218 was clearly silenced or downregulated in five HCC cells (HepG2, Hep3B, SMMC-7721, Huh7 and Bel-7402) compared with normal hepatocytes (LO2). The low expression of miR-218 conferred a poor 5-year survival in HCC patients. Multivariate Cox regression analysis indicated that miR-218 was an independent prognostic factor in HCC. Ectopic expression of miR-218 inhibited proliferation and promoted apoptosis in HepG2 and SMMC-7721 cells. In tumor bearing mice, miR-218 slowed down tumor growth by inducing apoptosis and growth arrest. Restoring miR-218 expression resulted in downregulation of B lymphoma Mo-MLV insertion region1 homolog (BMI-1) mRNA and protein level in HepG2 and SMMC-7721 cells. In addition, BMI-1 mRNA expression in HCC was significantly higher than that in non-cancerous tissues. BMI-1 mRNA was inversely correlated with miR-218 expression in HCC tissues. In conclusion, miR-218 may serve as a prognostic biomarker and induce apoptosis and growth arrest by downregulating BMI-1 in HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the second leading cause of cancer-related mortality in China [1]
Several studies reported that miRNAs regulate carcinogenesis-related gene expression, suggesting a new mechanism involved in HCC initiation and development
We primarily detected miR-218 expression in 60 samples of paired HCC and normal tumor-adjacent tissues using quantitative reverse transcription-PCR (qRT-PCR); our data indicated that miR-218 level in the cancer tissues was significantly lower than that in the noncancerous tissues
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the second leading cause of cancer-related mortality in China [1]. MicroRNAs (miRNAs) are a large class of evolutionarily conserved non-coding RNAs 18-25 nucleotides in length that negatively regulate genes involved in many fundamental cell processes including development, differentiation, proliferation, survival and death [3]. Recent studies have shown that miRNAs play key roles in the initiation and progression of cancer [4]. Deregulation of miRNAs has been reported in various types of human cancers including lymphoma, colorectal and breast cancer, glioblastoma, lung cancer, papillary thyroid carcinoma and HCC, suggesting it is a hallmark of cancer [5]. Specific miRNAs have been shown to regulate known oncogenes or tumor suppressor genes or function as so called onco-miRs or tumor suppressor-miRs by directly targeting other genes involved in cell differentiation, proliferation, invasion, apoptosis and angiogenesis in various types of cancer [4]
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