第二軍醫(yī)大學(xué)孫樹漢教授課題組使用Arraystar Human LncRNA芯片研究肝癌,，連續(xù)發(fā)表了兩篇Hepatology文章；近期,，其課題組的研究成員應(yīng)用Arraystar Mouse LncRNA芯片,，首次發(fā)現(xiàn)了能抑制肝癌轉(zhuǎn)移的新LncRNA——Dreh，該研究成果刊登在國際著名肝病研究雜志Hepatology上,。（所有Arraystar LncRNA芯片均由康成提供技術(shù)服務(wù)）
研究背景：
乙型病毒性肝炎是華人人群中肝癌的首要因素,。乙肝病毒表達(dá)的HBx蛋白能促進(jìn)肝臟腫瘤的形成，但其分子機制仍不清楚,。孫樹漢教授課題組本次研究目的在于揭示HBx和熱點分子——非編碼RNA之間的關(guān)聯(lián),。
研究思路：
應(yīng)用美國Arraystar公司Mouse LncRNA V2.0芯片，研究人員分別對6只HBx轉(zhuǎn)基因小鼠和對照組小鼠肝臟的LncRNA表達(dá)譜進(jìn)行研究,，篩選出差異表達(dá)的長鏈非編碼RNA,，其中LncRNA.Dreh(AK050349)表達(dá)量在所有年齡和性別的轉(zhuǎn)基因小鼠中都顯著下調(diào)，因此研究者將目標(biāo)鎖定在該分子上,。
研究者對LncRNA.Dreh進(jìn)行深入的功能分析，發(fā)現(xiàn)其能抑制細(xì)胞的增殖和遷移,；進(jìn)一步的研究發(fā)現(xiàn)LncRNA.Dreh抑癌作用背后的分子機制：它能結(jié)合中間絲蛋白并抑制其表達(dá),，通過改變細(xì)胞骨架結(jié)構(gòu)和形態(tài)，阻止癌細(xì)胞的轉(zhuǎn)移,。
由于LncRNA.Dreh的保守性很高,，在對50例臨床樣本(肝癌組織v.s.癌旁組織)的研究中發(fā)現(xiàn)：該分子在癌組織中表達(dá)量比正常組織低,，并且和病人的預(yù)后相關(guān)；LncRNA.Dreh表達(dá)量高的病人復(fù)發(fā)率低并且生存期長,。
研究意義：
該研究首次將乙肝病毒自身表達(dá)的HBx蛋白和肝臟組織中的LncRNA關(guān)聯(lián)起來,。發(fā)現(xiàn)了LncRNA對細(xì)胞骨架結(jié)構(gòu)的調(diào)控作用，由此來抑制癌細(xì)胞的轉(zhuǎn)移,。找到了新的肝癌預(yù)后標(biāo)志物,，其研究有著重大的臨床意義。(生物谷Bioon.com)
DOI: 10.1002/hep.26195
PMC:
PMID:
HBx-related lncRNA Dreh inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin
Jin-feng Huang1,†, Ying-jun Guo1,†, Chen-xi Zhao1, Sheng-xian Yuan2, Yue Wang1, Guan-nan Tang1, Wei-ping Zhou2, Shu-han Sun1,‡,*
The hepatitis B virus X protein (HBx) has been implicated as an oncogene in both epigenetic modifications and genetic regulation during hepatocarcinogenesis, but the underlying mechanisms are not entirely clear. Long non-coding RNAs (lncRNAs), which regulate gene expression with little or no protein-coding capacity, are involved in diverse biological processes and in carcinogenesis. We asked whether HBx could promote hepatocellular carcinoma (HCC) by regulating the expression of lncRNAs. In this study, we investigated the alteration in expression of lncRNAs induced by HBx using microarrays and real-time quantitative PCR. Our results indicate that HBx transgenic mice have a specific profile of liver lncRNAs compared with wild-type mice. We identified an lncRNA, down-regulated expression by HBx (termed lncRNA-Dreh), which can inhibit HCC growth and metastasis in vitro and in vivo, act as a tumor suppressor in the development of HBV-HCC. LncRNA-Dreh could combine with the intermediate filament protein vimentin and repress its expression, further change the normal cytoskeleton structure to inhibit tumor metastasis. We also identified a human ortholog RNA of Dreh (hDREH) and found that its expression level was frequently down-regulated in HBV-related HCC tissues in comparison with the adjacent noncancerous hepatic tissues, and its decrement significantly correlated with poor survival of HCC patients. Conclusion: Our findings support a role of lncRNA-Dreh in tumor suppression and survival prediction in HCC patients. Our discovery contributes to a better understanding of the importance of the deregulated lncRNAs by HBx in HCC and provides a rationale for the potential development of lncRNA-based targeted approaches for the treatment of HBV-related HCC.
