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　　來自南開大學生命科學學院的研究人員在新研究中證實：乙型肝炎病毒X蛋白（hepatitisBvirusXprotein，HBx）通過CREB介導YAP癌基因促進了肝癌細胞生長。相關論文發表在12月的國際著名肝臟疾病雜志Hepatology上（最新影響因子11.665）上。

　　南開大學生命科學學院的張曉東（XiaodongZhang）教授和葉麗虹（LihongYe）為這篇論文的共同通訊作者。前者的主要研究領域為腫瘤分子生物學，開展乙肝病毒致癌分子機制和乳腺癌轉移分子機制研究，篩選抗腫瘤藥物。后者的研究方向是腫瘤發生、發展和轉移的分子機制；抗腫瘤藥物篩選。

　　乙型肝炎病毒(HBV)慢性感染是我國肝細胞肝癌(HCC)發生的主要原因之一。一些體內外研究發現，HBx可誘導肝細胞的惡性轉化及癌變，成為目前研究乙肝相關性肝細胞癌生機制的熱點。近來在HBx與抑癌基因，如p53的新成員p73以及p16，p21等之間的相互作用及其對肝細胞惡性轉化與癌變的影響等方面的研究也取得初步成果，但其關系錯綜復雜，這方面不斷的深入研究將有助于進一步揭示HBx致肝細胞癌發生的分子機制，對探尋乙肝相關性肝癌新的防止策略具有重要意義。

　　在這篇文章中，研究人員證實HBx介導YAP參與了肝癌形成。研究人員發現臨床肝癌樣本、乙肝病毒感染肝癌HepG2.2.15細胞系及HBx轉基因小鼠的肝癌組織中的YAP表達均顯著增高。同時，他們發現HBx過表達導致了HBx穩定轉染的HepG2/H7402肝癌細胞系中YAP表達上調，而在上述細胞系中采用HBxRNA干擾則以劑量依賴性的方式減少了YAP的表達，這表明HBx可以正調控YAP。

　　隨后，研究人員解析了HBx上調YAP的潛在分子機制。熒光素酶報告基因檢測揭示HBx對YAPnt-232/+115這一包含cAMP反應元件結合蛋白(CREB)元件的啟動子區域進行了調控。通過染色質免疫沉淀法(ChIP)，研究人員證實HBx能夠結合到YAP的啟動子上，但當CREB沉默時它不能發揮作用。此外，借助于電泳遷移率實驗（EMSA）和熒光素酶報告基因檢測，他們也證實HBx激活了YAP啟動子。在體內外實驗中，研究人員還證實YAP短干擾RNA（shortinterfering RNA）能夠顯著阻斷HBx增進肝癌細胞生長的效應。

　　這些結果表明YAP是HBx誘導肝癌形成中的一個關鍵驅動基因，其或可作為一種治療乙肝病毒相關肝癌的新靶點。

 　　Hepatitis B virus X protein modulates oncogene yes-associated protein by CREB to promote growth of hepatoma cells

　　Tao Zhang1, Junping Zhang1, Xiaona You1, Qian Liu2, Yumei Du1, Yuen Gao1, Changliang Shan1, Guangyao Kong1, Youliang Wang3, XiaoYang3, Lihong Ye2,,*, Xiaodong Zhang1,§,*

　　Hepatitis B virus X protein (HBx) plays critical roles in the development of hepatocellular carcinogenesis (HCC). Yes-associated protein (YAP), a downstream effector of the Hippo-signaling pathway, is an important human oncogene. In the present article, we report that YAP is involved in the hepatocarcinogenesis mediated by HBx. We demonstrated that the expression of YAP was dramatically elevated in clinical HCC samples, hepatitis B virus (HBV)-infected hepatoma HepG2.2.15 cell line, and liver cancer tissues of HBx-transgenic mice. Meanwhile, we found that overexpression of HBx resulted in the up-regulation of YAP in stably HBx-transfected HepG2/H7402 hepatoma cell lines, whereas HBx RNA interference reduced YAP expression in a dose-dependent manner in the above-mentioned cell lines, suggesting that HBx up-regulates YAP. Then, we investigated the mechanism underlying the up-regulation of YAP by HBx. Luciferase reporter gene assays revealed that the promoter region of YAP regulated by HBx was located at nt -232/+115 containing cyclic adenosine monophosphate response element-binding protein (CREB) element. Chromatin immunoprecipitation (ChIP) demonstrated that HBx was able to bind to the promoter of YAP, whereas it failed to work when CREB was silenced. Moreover, we confirmed that HBx activated the YAP promoter through CREB by electrophoretic mobility shift assay and luciferase reporter gene assays. Surprisingly, we found that YAP short interfering RNA was able to remarkably block the HBx-enhanced growth of hepatoma cells in vivo and in vitro. Conclusion: YAP is a key driver gene in HBx-induced hepatocarcinogenesis in a CREB-dependent manner. YAP may serve as a novel target in HBV-associated HCC therapy.