Abstract
BackgroundRecently, miR-10b is identified as a miRNA highly expressed in many human cancers, promoting cell migration and invasion. However, the specific function of miR-10b in hepatocellular carcinoma (HCC) is unclear at this point.MethodsThe miR-10b expression levels in 60 paired different TNM Stage HCC tumor tissues compared with adjacent non-tumor (ANT) tissues, normal tissue control (8 benign tumor and 7 normal liver tissues), 3 normal liver and 7 HCC cell lines were measured by real-time quantitative RT-PCR and to evaluate their association with HCC clinicopathologic features. Invasion assay, MTT proliferation assay and wound-healing assay were performed to test the invasion and proliferation of HCC cell after transfection. The effect of miR-10b on HCC in vivo was validated by murine xenograft model.ResultsWe found that miR-10b expression was increased in human HCC tissues and cell lines compared with normal control, respectively. The expression of miR-10b was correlated with HCC metastatic ability. Overexpression of miR-10b in MHCC-97L cells increased cell motility and invasiveness, whereas inhibition of miR-10b in MHCC-97H cells reduced cell motility and invasiveness in vitro and in vivo. We also showed that HOXD10 was negatively regulated by miR-10b at the posttranscriptional level, via a specific target site within the 3′UTR by luciferase reporter assay. Furthermore, we found that miR-10b induced HCC cell invasion and migration by modulating the HOXD10 target gene RhoC, uPAR, MMP-2 and MMP-9 expression.ConclusionsOur results suggested that miR-10b was overexpressed in HCC and promoted HCC cell migration and invasion through the HOXD10/ RhoC/ uPAR/ MMPs pathway which may provide a novel bio-target for HCC therapy.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and leading causes of cancer-related death worldwide, especially in Asian Pacific regions, which has a highly invasive malignant behavior and recurrence rate and remains one of the tumors most refractory to treatment [1].MicroRNAs, which encode small non-coding RNAs of approximately 22 nucleotides, are recognized as a very large gene family
All the liver samples were divided into 5 groups: non-metastatic hepatocellular carcinoma (HCC) tissues (NHCC, patients diagnosed as TNM stage I-II, n = 20), low metastatic HCC tissues (LHCC, patients diagnosed as TNM stage III-IVA with intrahepatic metastasis or regional lymph node metastasis, n = 26), high metastatic HCC tissues (HHCC, patients diagnosed as TNM stage IVB with distance metastasis, n = 14), benign tumor tissues (BT, patients diagnosed as hepatic haemangioma, n = 8), and normal liver tissues (NL, n = 7)
When expression levels of miR-10b were compared between subgroups, miR-10b was significantly higher in HCC (NHCC, LHCC and HHCC) groups compared to the normal liver (BT and NL) groups and miR-10b expression was positively correlated with the tumor’s stage (Figure 1b)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and leading causes of cancer-related death worldwide, especially in Asian Pacific regions, which has a highly invasive malignant behavior and recurrence rate and remains one of the tumors most refractory to treatment [1].MicroRNAs (miRNAs), which encode small non-coding RNAs of approximately 22 nucleotides, are recognized as a very large gene family. Recent studies demonstrate that miRNAs may act as activators of tumor metastasis by acting on multiple signaling pathways involved in metastasis [3,4]. Among these miRNAs, miR-10b is first reported to induce breast cancer cell invasion and metastasis [3], which is found to be associated with tumor invasive potential in pancreatic cancer [5], glioma [6], nasopharyngeal carcinoma [7], esophageal cancer [8] and neurofibromatosis [9]. The specific function of miR-10b in hepatocellular carcinoma (HCC) is unclear at this point
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