中藥抑制HBx所引發之MMP‐9表現及肝癌細胞轉移之研究

慢性B型肝炎是併發肝硬化與肝癌的重要危險因子，也是台灣乃至全球的重要公共衛生議題。目前全球對慢性B型肝炎的治療共識是：（1）現有的藥物尚無法完全治癒；（2）應利用抗病毒藥物持續抑制HBV DNA的複製；以（3）預防或延緩肝纖維化、肝硬化、肝衰竭甚至HCC（hepatocellular carcinoma）的疾病進行過程，提升病人生活品質及延長存活。有鑒於有證據顯示傳統的中醫藥在慢性B型肝炎的治療，能有著協同西醫藥物治療的應用潛力。B型肝炎病毒會造成急性及慢性肝炎，而慢性的感染與人類的肝癌發生率有密切的關係。HBV相關的人類肝癌嵌有病毒的DNA。B型肝炎病毒X蛋白（HBx）會造成肝癌及轉移。雖然HBx不會直接結合到DNA上，但會透過多種順式作用元件（cis-acting elements）來調控細胞基因的轉錄活性（AP-1，AP-2，NF-κB，ATF/CREB，C/EBP，以及Egr-1）。HBx也可能藉由活化Ras/Raf/ERK、c-JUK、Src kinase、PI-3K-AKT/PKB及Jak/STAT（12）等路徑。因此，先前的研究指出HBx可能與HCC的發展有關。MMP-9在HCC的侵襲及轉移上扮演重要的角色，HBx與MMP-9的表現之間的關係也證實，MMP-9基因在具有侵襲潛力HCC中有大量表現。由於MMP-9的啟動子區域具有AP-1及NF-κB的結合位，腫瘤細胞與其刺激物如細胞激素、HBx、TPA 及acetaldehyde，可透過Ras/Raf/ERK，JUK，及PI-3K-AKT/PKB訊息傳遞路徑來調控轉錄因子（AP-1及NF-kB），以達到控制MMP-9表現。在這篇以30種中藥為本次研究主要藥物，我們藉由HBx-transfected來誘發肝癌的轉移作用，篩選可能阻斷其轉移之中藥，並探討其透過其活化路徑所活化的AP-1及NF-κB之分子機制，並觀察中藥是否會透過干擾這些路徑來抑制HCC侵襲轉移相關之MMP-9的表現。接下來會以不同種類的有效中藥進行機制或其有效成分之討探，以期對肝癌轉移的防治提出有效的方式。

關鍵字

慢性B型肝炎；肝癌；轉移

並列摘要

Chronic Hepatitis B is a major risk factor of liver cirrhosis and hepatoma, and is a vital public health issue of Taiwan and world. Present global therapy consensus of chronic hepatitis B are as followed: (1) Incurable outcome by present medication. (2) Persistent inhibition upon duplication of HBV DNA by antiviral drugs. (3) Prevention or prolongation of disease progression of liver fibrosis, liver cirrhosis, hepatic failure and HCC (hepatocellular carcinoma) to elevate patients' quality of life and prolong survival rate. According to evidences of traditional Chinese medicine upon chronic hepatitis B, Chinese herbs are potential in clinical application upon chronic hepatitis B combined with modern medicine. Hepatitis virus B will induce acute and chronic hepatitis, and chronic infection of hepatitis B is closely related with human hepatoma. HBV-related human hepatoma is inlayed with DNA containing hepatitis B virus. X protein of hepatitis B virus (HBx) will cause hepatoma and its metastasis. Although HBx will not combined to viral DNA directly, but it will modulate transcription activity of hepatocyte gene (AP-1, AP-2， NF-κB，ATF/CREB，C/EBP and Egr-1) via multiple cis-acting elements. HBx maybe activate pathways of Ras/Raf/ERK、c-JUK、Src kinase、PI-3K-AKT/PKB and Jak/ STAT. Therefore, previous researches indicate that HBx maybe correlate with disease progression of HCC. MMP-9 plays vital role in invasion and metastasis of HCC. Researches on performance between HBx and MMP-9 demonstrate that MMP-9 gene is presented massively in the potentiality of invasion of HCC. Because promoter regions of MMP-9 gene have binding sites of AP-1 and NF-κB, oncocytes and its stimulators, like cytokines、HBx、TPA and acetaldehyde, can control performance of MMP-9 via message transcription pathways of Ras/Raf/ERK，JUK, and PI-3K-AKT/PKB. 30 Chinese medicinal herbs are selected as major research targets in this article. We screen Chinese medicinal herbs that may block the metastasis of HBx-transfected hepatoma, discuss molecular mechanism of activating pathway of AP-1 and NF-κB, and observe whether Chinese medicinal herbs that will inhibit relevant performance of MMP- 9 via interfering pathways mentioned above to block metastasis of HCC. We will probe into mechanisms and active ingredients of different kinds of effective Chinese medicinal herbs in order to promote effective therapeutically therapy of Chinese medicine to prevent metastasis of hepatoma.

並列關鍵字

Chronic hepatitis B ； HBx ； Hepatoma ； Metastasis ； MMP-9

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