MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways.

MicroRNAs (miRNAs) have been believed to associate with malignant progression including cancer cell proliferation, apoptosis, differentiation, angiogenesis, invasion and metastasis. However, the functions of miRNAs are intricate, one miRNA can directly or indirectly target multiple genes and function as oncogene or tumor suppressor gene. In this study, we found that miR-21 inhibits PTEN and human sulfatase-1 (hSulf-1) expression in hepatocellular carcinoma (HCC) cells. The hSulf-1 is a heparin-degrading endosulfatase, which can inhibit the heparin binding growth factor-mediated signaling transduction into cells. Therefore, miR-21-mediated suppression of both hSulf-1 and PTEN led to activation of AKT/ERK pathways and epithelial-mesenchymal transition (EMT) in HCC cells, and finally enhance the activity of HCC cell proliferation and movement and promote HCC xenograft tumor growth in mouse models. These findings may provide candidate targets for prevention and treatment of HCC.

Bao L ，Yan Y ，Xu C ，Ji W ，Shen S ，Xu G ，Zeng Y ，Sun B ，Qian H ，Chen L ，Wu M ，Su C ，Chen J ... -  《-》

cPLA2α activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells.

Cytosolic phospholipase A2α (cPLA2α), a key phospholipase that regulates lipid metabolism, plays an important role in tumor progression. In the present study of hepatocellular carcinoma (HCC), cPLA2α was overexpressed in highly metastatic HCC cell lines. Immunohistochemical staining showed increased levels of cPLA2α at the invasive edges of HCC, and a clinicopathological analysis of samples from 111 patients revealed that its expression level was linked with micro-vascular invasion and cirrhosis. Knockdown of cPLA2α inhibited migration, probably due to its role in actin polymerization. Overexpression of cPLA2α promoted cell migration and invasion. Based on the mechanistic analysis, our data suggested that cPLA2α mediate epidermal growth factor (EGF) induced epithelial-mesenchymal transition (EMT) through PI3K/AKT/ERK pathway. cPLA2α activity was required for the transforming growth factor-(TGF)-β-induced EMT. However, cPLA2α inhibited Smad2/3 activation and promoted the activation of the PI3K/AKT/ERK pathway. A xenograft tumor transplant model confirmed the role of cPLA2α in HCC invasion and metastasis. Based on the mechanistic analysis, cPLA2α mediated both EGF- and TGF-β-induced EMT, which are essential for HCC metastasis. cPLA2α is a potentially target for novel therapies of HCC.

Fu H ，He Y ，Qi L ，Chen L ，Luo Y ，Chen L ，Li Y ，Zhang N ，Guo H ... -  《-》

Sulfatase 1 (hSulf-1) reverses basic fibroblast growth factor-stimulated signaling and inhibits growth of hepatocellular carcinoma in animal model.

Xu G ，Ji W ，Su Y ，Xu Y ，Yan Y ，Shen S ，Li X ，Sun B ，Qian H ，Chen L ，Fu X ，Wu M ，Su C ... -  《Oncotarget》

MicroRNA-155-5p promotes hepatocellular carcinoma progression by suppressing PTEN through the PI3K/Akt pathway.

MicroRNA-155-5p (miR-155-5p) has been reported to play an oncogenic role in different human malignancies; however, its role in hepatocellular carcinoma (HCC) progression is not clearly understood. In this study, we used real-time PCR in 20 rats with chemically-induced HCC, 28 human HCC tissues, and the matched paracarcinoma tissues, and HCC cell lines to determine the expression patterns of miR-155-5p and PTEN mRNA. Algorithm-based and experimental strategies, such as dual luciferase gene reporter assays, real-time PCR and western blots were used to identify PTEN as a candidate miR-155-5p target. Gain- and loss-of-function experiments and administration of a PI3K/Akt pathway inhibitor (wortmannin) were used to identify the effects of miR-155-5p and PTEN in MTT assays, flow cytometric analysis, wound healing assays and transwell assays. The results showed that miR-155-5p was highly overexpressed; however, PTEN was underexpressed in the HCC rat models, human HCC tissues and cell lines. In addition, miR-155-5p upregulation and PTEN downregulation were significantly associated with TNM stage (P < 0.05). Through in vitro experiments, we found that miR-155-5p promoted proliferation, invasion and migration, but inhibited apoptosis in HCC by directly targeting the 3'-UTR of PTEN. Western blots showed that miR-155-5p inactivated Bax and caspase-9, but activated Bcl-2 to inhibit apoptosis, and it activated MMP to promote migration and invasion via the PI3K/Akt pathway. A xenograft tumor model was used to demonstrate that miR-155-5p targets PTEN and activates the PI3K/Akt pathway in vivo as well. Our study highlighted the importance of miR-155-5p and PTEN associated with aggressive HCC both in vitro and in vivo.

Fu X ，Wen H ，Jing L ，Yang Y ，Wang W ，Liang X ，Nan K ，Yao Y ，Tian T ... -  《-》

MicroRNA-130b promotes proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling.

Chang RM ，Xu JF ，Fang F ，Yang H ，Yang LY ... -  《-》