9月11日,， Cancer Cell雜志在線發(fā)表了美國Duke大學(xué)王小凡實(shí)驗(yàn)室和營養(yǎng)所謝東實(shí)驗(yàn)室合作的研究成果,，發(fā)現(xiàn)miR-34a 在抑制肝癌肝內(nèi)轉(zhuǎn)移及門靜脈癌栓形成中發(fā)揮重要作用。
肝癌是嚴(yán)重影響人類健康的疾病,，居世界腫瘤相關(guān)死因的第三位,。肝癌門靜脈栓的形成是影響肝癌預(yù)后的重要因素。迄今為止,，肝癌門靜脈栓形成的原因尚不清楚,。
王小凡實(shí)驗(yàn)室博士后楊鵬遠(yuǎn)、張?jiān)坪椭x東實(shí)驗(yàn)室博士生馮宇雄,、鄧躍臻,、趙江沙等經(jīng)過三年多的合作研究，發(fā)現(xiàn)TGF-β通過影響miR-34a 和趨化因子CCL22 的表達(dá)而調(diào)控調(diào)節(jié)性T細(xì)胞（Treg 細(xì)胞）的招募,，進(jìn)而影響肝癌的肝內(nèi)轉(zhuǎn)移及門靜脈癌栓（PVTT）的形成,。研究結(jié)果表明，在從原位癌向門靜脈癌栓肝內(nèi)轉(zhuǎn)移過程中,，乙肝病毒（HBV）的持續(xù)感染導(dǎo)致TGF-β信號(hào)通路活性的提高,，從而抑制miR-34a的表達(dá)，進(jìn)而上調(diào)miR-34a下游靶基因趨化因子CCL22的表達(dá),。CCL22的上調(diào)有利于T-reg免疫細(xì)胞的招募,，從而幫助腫瘤細(xì)胞逃脫免疫細(xì)胞的攻擊（免疫逃逸）。該研究工作利用大量的臨床樣本和動(dòng)物模型,，從腫瘤微環(huán)境的角度,，闡明了HBV感染和TGF-β-miR-34a-CCL22 信號(hào)通路激活以及對(duì)Treg 細(xì)胞的招募在肝癌門靜脈癌栓形成過程中的重要作用,，揭示肝癌門靜脈癌栓形成的新機(jī)制,，為肝癌的治療提供新的潛在靶點(diǎn)。
該研究得到科技部的肝癌重大專項(xiàng)和重大基礎(chǔ)項(xiàng)目的支持,。（生物谷Bioon.com）
doi:10.1016/j.ccr.2012.07.023
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TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma
Pengyuan Yang, Qi-Jing Li, Yuxiong Feng, Yun Zhang, Geoffrey J. Markowitz, Shanglei Ning, Yuezhen Deng, Jiangsha Zhao, Shan Jiang, Yunfei Yuan, Hong-Yang Wang, Shu-Qun Cheng, Dong Xie, Xiao-Fan Wang
Portal vein tumor thrombus (PVTT) is strongly correlated to a poor prognosis for patients with hepatocellular carcinoma (HCC). In this study, we uncovered a causative link between hepatitis B virus (HBV) infection and development of PVTT. Mechanistically, elevated TGF-β activity, associated with the persistent presence of HBV in the liver tissue, suppresses the expression of microRNA-34a, leading to enhanced production of chemokine CCL22, which recruits regulatory T (Treg) cells to facilitate immune escape. These findings strongly suggest that HBV infection and activity of the TGF-β-miR-34a-CCL22 axis serve as potent etiological factors to predispose HCC patients for the development of PVTT, possibly through the creation of an immune-subversive microenvironment to favor colonization of disseminated HCC cells in the portal venous system.
