Background:The role of long noncoding RNA (lncRNA) highly up-regulated in liver cancer (HULC) in hepatocarcinogenesis mediated by hepatitis B virus X protein (HBx) remains unclear. Results: Up-regulation of HULC by HBx promotes hepatoma cell proliferation via down-regulating p18. Conclusion: HULC contributes to HBx-related hepatocarcinogenesis through suppressing p18. Significance: The finding provides insight into the roles of lncRNAs in HBx-associated hepatocarcinogenesis.

Rationale Abnormal phenotypic switch of vascular smooth muscle cell (VSMC) is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. MicroRNAs (miRNAs) have emerged as important regulators for VSMC function, and we recently identified miR-663 as critical for controlling human aortic smooth muscle cell proliferation. Objective To investigate whether miR-663 plays a role in human VSMC phenotypic switch and the development of neointima formation. Methods and Results By using quantitative reverse-transcription polymerase chain reaction, we found that miR-663 was significantly downregulated in human aortic VSMCs on platelet-derived growth factor treatment, whereas expression was markedly increased during VSMC differentiation. Furthermore, we demonstrated that overexpression of miR-663 increased expression of VSMC differentiation marker genes, such as smooth muscle 22α, smooth muscle α-actin, calponin, and smooth muscle myosin heavy chain, and potently inhibited platelet-derived growth factor-induced VSMC proliferation and migration. We identified the transcription factor JunB and myosin light chain 9 as downstream targets of miR-663 in human VSMCs, because overexpression of miR-663 markedly inhibited expression of JunB and its downstream molecules, such as myosin light chain 9 and matrix metalloproteinase 9. Finally, we showed that adeno-miR-663 markedly suppressed the neointimal lesion formation by ≈50% in mice after vascular injury induced by carotid artery ligation, specifically via decreased JunB expression. Conclusions These results indicate that miR-663 is a novel modulator of human VSMC phenotypic switch by targeting JunB/myosin light chain 9 expression. These findings suggest that targeting miR-663 or its specific downstream targets in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.

These results indicate that miR-638 is a key molecule in regulating human VSMC proliferation and migration by targeting the NOR1/cyclin D pathway and suggest that specific modulation of miR-638 in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.

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Hepatitis B virus X protein (HBx) plays critical roles in the pathogenesis of hepatocellular carcinoma (HCC). Here, we were interested in knowing whether the oncogene Lin28A and its homolog Lin28B are involved in the hepatocarcinogenesis mediated by HBx. We showed that the expression levels of Lin28A and Lin28B were increased in clinical HCC tissues, HepG2.2.15 cell line and liver tissues of p21-HBx transgenic mice. Interestingly, the expression levels of HBx were positively associated with those of Lin28A/Lin28B in clinical HCC tissues. Moreover, the overexpression of HBx resulted in the upregulation of Lin28A/Lin28B in hepatoma HepG2/H7402 cell lines by transient transfection, suggesting that HBx was able to upregulate Lin28A and Lin28B. Then, we examined the mechanism by which HBx upregulated Lin28A and Lin28B. We identified that the promoter region of Lin28A regulated by HBx was located at nt -235/-66 that contained Sp-1 binding element. Co-immunoprecipitation showed that HBx was able to interact with Sp-1 in HepG2-X cells. Moreover, chromatin immunoprecipitation (ChIP) demonstrated that HBx could bind to the promoter of Lin28A, which failed to work when Sp-1 was silenced. Electrophoretic mobility shift assay (EMSA) further identified that HBx was able to interact with Sp-1 element in Lin28A promoter via transcription factor Sp-1. In addition, we found that c-Myc was involved in the activation of Lin28B mediated by HBx. In function, Lin28A/Lin28B played important roles in HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. In conclusion, HBx activates Lin28A/Lin28B through Sp-1/c-Myc in hepatoma cells. Lin28A/Lin28B serves as key driver genes in HBx-induced hepatocarcinogenesis.

Hepatitis B virus X protein (HBx) contributes to the development of hepatocellular carcinoma (HCC) through inducing dysregulation of lipogenesis. However, the mechanism by which HBx induces the abnormal lipogenesis is not well known. In this study, we report that the oncogene Rab18, a member of Ras family, enhances the HBx-induced hepatocarcinogenesis through inducing dysregulation of lipogenesis and proliferation. Our data showed that the expression levels of Rab18 were positively associated with those of HBx in clinical HCC tissues. HBx was able to upregulate the expression of Rab18 in p21-HBx transgenic mice and hepatoma cell lines. Next, we identified the mechanism by which HBx upregulated Rab18. The results demonstrated that cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) were able to stimulate Rab18 promoter through activating transcription factor activator protein 1 (AP-1) and cyclic adenosine 3',5'-monophosphate response element-binding (CREB). In addition, we identified another pathway that HBx activated Rab18. We found that miR-429 was able to directly target the 3' untranslated region of Rab18, suggesting that Rab18 is one of the target genes of miR-429. Then, we found that HBx was able to downregulate miR-429 in hepatoma cells. The oil red O staining showed that HBx resulted in the dysregulation of lipogenesis through Rab18. Moreover, Rab18 contributed to the HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. HBx enhances hepatocarcinogenesis through leading to the dysregulation of lipogenesis and proliferation of hepatoma cells, involving two pathways such as HBx/COX-2/5-LOX/AP-1/CREB/Rab18 and HBx/miR-429/Rab18.

Tumor angiogenesis plays an important role in the development of cancer. Previously, we reported that hepatitis B X-interacting protein (HBXIP) functioned as an oncoprotein in breast cancer. However, the role of HBXIP in angiogenesis in breast cancer remains poorly understood. In the present study, we show that the oncoprotein HBXIP plays crucial roles in the event. We observed that the expression levels of HBXIP were positively correlated with those of fibroblast growth factor 8 (FGF8) or vascular endothelial growth factor (VEGF) in clinical breast cancer tissues. Then, we demonstrated that HBXIP was able to upregulate FGF8 through activation of its promoter involving direct binding to cAMP response element-binding protein (CREB) in breast cancer cells and thereby increased its secretion. Strikingly, we identified another pathway that HBXIP upregulated FGF8 and VEGF through inhibiting miRNA-503, which directly targeted 3' untranslated region of FGF8 or VEGF mRNA in the cells. Moreover, we revealed that HBXIP-induced FGF8 could upregulate VEGF expression through activating phosphoinositide 3-kinase (PI3K)/Akt/hypoxia-inducible factor 1-alpha (HIF1α) signaling and increase its secretion. In function, matrigel angiogenesis assay and hemoglobin content analysis uncovered that HBXIP-enhanced FGF8/VEGF boosted tumor angiogenesis and growth in breast cancer in vitro and in vivo in a paracrine/autocrine manner. Thus, we conclude that HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. Our finding provides new insights into the mechanism of tumor angiogenesis in breast cancer. Therapeutically, HBXIP may serve as a novel target of tumor angiogenesis.