中科大田志剛教授團隊揭示以天然免疫為主導的HBV相關肝癌發病機制

最近，肝病權威學術期刊Hepatology雜誌在線發表了中國科技大學生命科學院田志剛教授團隊的研究成果，揭示了天然免疫應答在HBV相關肝細胞癌（HCC）發生中的重要作用。

乙型肝炎病毒（HBV）是肝細胞癌（HCC）的重要危險因素，目前研究認為，除插入突變和病毒蛋白對宿主基因的激活和反式激活以及其他一些因素外，慢性肝臟損傷和組織再生是導致肝細胞惡性變和發生HCC的重要誘因。但HBV是非細胞毒性病毒，本身並不引起肝細胞損傷，HBV感染時的肝臟損傷主要是由於機體的抗HBV免疫應答引起，因此，免疫應答相關的病理機制對於HBV相關性HCC的發生至關重要。但天然免疫應答在此過程中有何作用並不清楚。

在既往的研究中，團隊曾發現天然免疫系統中的重要組分，NK細胞，在HBV感染時除發揮抗病毒作用外，也參與了肝細胞的損傷。而IFN-γ是其中的重要分子。

在最新發表的這項研究中，研究者給小鼠注射了NK細胞活化劑poly（I∶C），劑量為3 μg/g，2次/周，共8周。6個月後，所有注射了poly（I∶C）的12~13月齡的HBV轉基因（HBs-Tg）小鼠均發生了HCC，發生率達100%，野生型小鼠均未出現HCC。而未經處理的HBs-Tg小鼠中HCC的自然發生率為16.7%（12~13月齡）和40%（24~25月齡）。這提示活化的NK細胞加速了HBV轉基因小鼠中HCC的發生髮展。

poly（I∶C）處理的HBs-Tg小鼠肝內發生炎症和肝細胞損傷，可觀察到淋巴細胞浸潤顯著增加，伴有肝細胞的凋亡和增殖同時增加，肝細胞的上皮-間充質轉化（EMT）加快。研究證實，該模型中的細胞EMT和腫瘤生成依賴於NK細胞--如果去除NK細胞，則HCC發生率顯著降低為28.6%。

而進一步研究發現，肝內的NK細胞高表達IFN-γ，抗-IFN單克隆中和抗體也許可明顯減輕肝炎，肝細胞特異性的IFN-γ表達促進了HCC的發生。如果缺乏IFN-γ，即便有肝臟NK細胞並且被激活，HCC的發生仍可被阻止，提示IFN-γ在NK細胞介導的腫瘤發生中扮演了核心的角色。

Hepatitis B virus (HBV) is a major risk factor for development of hepatocellular carcinoma (HCC) at least partially due to dysfunctional anti‐HBV adaptive immunity; however, the role of innate immune response to HBV in this process is not well understood. In this study, low dose poly (I:C), an NK cell activator (3 μg/g bw, twice/week for 8 weeks) induced HCC in HBV transgenic (HBs‐Tg) mice, with an incidence of 100% after 6 months; while HBs‐Tg mice without treatment only had HCC with an incidence of 16.7%. In HBs‐Tg mice, poly (I:C) induced liver inflammation with markedly increased infiltrating lymphocytes, along with the concurrently increased apoptosis and proliferation of hepatocytes, leading to the accelerated epithelial‐mesenchymal transition (EMT) of hepatocytes shown by the increased expression of the typical transcriptional factors (Slug, Twist and SIP1) and phenotypic proteins (Vimentin and CXCR4). The EMT and tumorigenesis in this model depended on the presence of NK cells since depletion of these cells significantly reduced HCC rate to 28.6%. Further, intrahepatic NK cells highly expressed IFN‐γ, anti‐IFN‐γ neutralizing mAb might obviously alleviate the hepatitis, and hepatocyte‐specific IFN‐γ over‐expression promoted HCC. Moreover, IFN‐γ deficiency in HBs‐Tg mice prevented HCC occurring though hepatic NK cells existed and could be activated, suggesting the critical role of IFN‐γ in NK cell‐mediated tumorigenesis. In vitro experiment, IFN‐γ up‐regulated epithelial cell adhesion molecule (EpCAM) expression via p‐STAT1 pathway, which was followed by EMT, and p‐STAT1 inhibitor might absolutely abolish the expression of EpCAM and EMT in HBsAg‐positive hepatocytes. Conclusion This work demonstrates NK cell‐derived IFN‐γ promotes HCC through EpCAM‐EMT axis in HBs‐Tg mice, revealing the importance of innate immunity in pathogenesis of HBV‐associated HCC.

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