Abstract
Metastasis is one of the causes of cancer death. Functions and mechanisms of microRNAs (miRNAs) involved in hepatocellular carcinoma (HCC) metastasis are largely unknown. Here, a miRNA microarray analysis was performed in MHCC-97L, MHCC-97H and HCC-LM3 cells with gradually increasing metastatic potential to disclose crucial miRNAs involved in HCC metastasis. miR-192 expression decreased and negatively correlated with vascular invasion in HCC specimens. Gain and loss of function studies revealed that miR-192 significantly suppressed metastasis of HCC cells in vitro and in vivo. Solute carrier family 39 member 6 (SLC39A6) was identified as a direct and functional target of miR-192. In addition, SLC39A6 negatively correlated with miR-192 in HCC samples and promoted HCC cell migration and invasion. Moreover, miR-192 decreased SLC39A6 expression, subsequently downregulating SNAIL and upregulating E-cadherin expression. Suppression of migration and invasion caused by miR-192 overexpression was alleviated by exogenous Snail expression. Intriguingly, lower miR-192 expression and higher SLC39A6 expression significantly contributed to poorer outcomes in HCC patients. Multivariate analysis indicated that miR-192 was an independent and significant predictor of HCC patient overall survival. In conclusion, we newly determined that miR-192 targeted the SLC39A6/SNAIL pathway to reduce tumor metastasis in HCC cells. This axis provided insights into the mechanism underlying miRNA regulation of HCC metastasis and a novel therapeutic target for HCC treatment.
Highlights
Primary liver cancer, hepatocellular carcinoma (HCC), continues to be a growing global health problem and is the third most common cause of cancer-related deaths worldwide, accounting for over800,000 deaths per year [1, 2]
The results showed that miR-574 did not affect HCC cell migration (Supplementary Figure 1A)
Clinical significance analysis of The Cancer Genome Atlas (TCGA) data showed that miR-192 expression levels were lower in HCC patients with vascular cell invasion compared with HCC patients without vascular cell invasion (Figure 1D)
Summary
Hepatocellular carcinoma (HCC), continues to be a growing global health problem and is the third most common cause of cancer-related deaths worldwide, accounting for over800,000 deaths per year [1, 2]. Hepatocellular carcinoma (HCC), continues to be a growing global health problem and is the third most common cause of cancer-related deaths worldwide, accounting for over. Among the causes of cancer-related deaths, metastasis accounts for 90% of cancer mortality [4,5,6]. A number of reports have demonstrated that multiple signaling pathways are www.impactjournals.com/oncotarget involved in tumor metastasis, the molecular mechanisms governing the metastatic cascades of HCC are complex, and our current knowledge regarding these mechanisms remains limited [4, 7]. MiRNAs can function as oncogenes or tumor suppressors, and their dysfunctions are involved in the development and progression of various human cancers [11, 12]. The functions and mechanisms of miRNAs involved in HCC metastasis are largely unknown
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