肝癌（Hepatocellular carcinoma, HCC）是世界上引起人類死亡的重要癌症之一，其主要的致病因子之一，慢性B型肝炎病毒（HBV）感染，目前雖已被廣泛研究，但是其由良性病變轉變成癌症的致病機制仍未明瞭。除了慢性發炎、纖維化、免疫反應細胞激素等機制外，病毒DNA嵌入及病毒蛋白，HBx、HBV突變大表面蛋白的表現可能是導致肝癌的重要路徑。本實驗室先前研究發現，毛玻璃狀肝細胞（Ground glass hepatocytes, GGHs）的內質網中含有HBV pre-S突變株，會造成內質網壓力，並具有誘發導致結節性增生及細胞轉形的能力，為肝癌的前兆病變。本研究在探討HBV pre-S突變株是否會透過誘發細胞激素和生長因子而導致GGHs轉變成肝癌。在本研究中，我們利用microarray分析，發現表現pre-S突變株會誘發許多生長因子的轉錄表現量，例如TGF-βs、FGFs等。進一步用Cytokine/growth factor array，也可觀察到TGF-βs、FGFs、VEGFs等的表現量上升。我們利用ELISA偵測在pre-S表現細胞株的培養液中的細胞激素/生長因子（IL-6、HGF、EGF及TGF-α），結果顯示除了VEGF-A有增強外，pre-S突變株並沒有誘發IL-6、HGF、EGF及TGF-α的分泌增加。因此，VEGF-A很可能是受pre-S突變蛋白調控的一個生長因子。由於血管生成在早期腫瘤發生扮演重要角色，所以我們對VEGF-A進行進一步研究，確認pre-S突變株確實有促進其表現量的增加且可被內質網壓力（ER stress）抑制劑所抑制。因此，pre-S突變蛋白可能經由ER stress來引起VEGF-A的上升。進一步研究發現，其促進肝細胞增生的能力可被VEGF-A的中和抗體所抑制，且培養液也可促進內皮細胞的增生，顯示其可能同時具有autocrine和paracrine的能力。觀察其訊息途徑，發現pre-S突變蛋白可使VEGF receptor-2的表現量增加，且其活化的下游基因Akt及mTOR進一步可被VEGF-A的中和抗體所抑制。此外，我們也證明Ras/Raf-1/ERK的訊息途徑與pre-S突變蛋白的表現無關。經由免疫染色，在GGHs也可看到VEGF-A的表現增加。進一步在比較配對的HCC組織中，增強表現的VEGF-A及活化的Akt/mTOR也可在HBV感染的非腫瘤區的肝組織偵測到。由此可知，pre-S突變蛋白可活化VEGF-A及其受體VEGF receptor-2，經激活Akt/mTOR信息路徑來引發細胞增生。為了更進一步證明這個議題，我們利用pre-S突變株轉基因鼠研究內質網壓力和VEGF-A/Akt/mTOR訊息途徑及其它訊息途徑在肝細胞中不同時期的進展。在三個月大表現pre-S突變株的轉基因鼠中，可看到GRP-78和VEGF-A的表現量及Akt的活化量皆有增加的趨勢。而且，在六個月的轉基因鼠，仍可看到Akt的活化量有更增加的趨勢。由這些結果顯示，VEGF-A在GGHs中的增強表現提供一個在慢性HBV感染中可能導致GGHs轉變成肝癌的可能重要途徑，且藉由轉基因鼠研究觀察不同時期活化的訊息途徑，將有助於未來找到B肝相關肝癌新的治療或化學預防策略。

Hepatocellular carcinoma (HCC) is one of the most important causes of cancer death worldwide. Chronic hepatitis B virus (HBV) infection is a major risk factor for HCC, especially with the presence of HBV pre-S mutants. However, the exact oncogenic mechanism for the progression from a benign precursor lesion to HCC remains to be established. In addition to chronic inflammation, fibrosis and immune response cytokines, HBV DNA integration and viral proteins, HBx or HBV pre-S mutants, may play important roles in HBV-related hepatocarcinogenesis. Previously, we found that ground glass hepatocytes (GGHs) contain pre-S delection mutants may induce ER stress and contribute to nodular proliferation and transforming ability, suggesting that GGHs may represent the precursor neoplastic lesions of HBV-associated HCC. This study was aiming at whether pre-S mutants induced cytokine/growth factors and play a role in the progression from GGHs to HCC. In this study, according to our microarray data, we found that pre-S mutants in HuH-7 hepatoma cell line could induce the expression of many growth factors, like TGF-βs and FGFs. Furthermore, cytokine/growth factor array data also showed that the expression of TGF-βs、FGFs and VEGFs were upregulated by pre-S mutants. We examined the secretion of cytokine/growth factor (VEGF-A, IL-6, HGF, EGF and TGF-α) in hepatocytes expressing pre-S mutants by ELISA. The production of VEGF-A was upregulated by pre-S mutants 48 hours post-transfection, but IL-6, HGF, EGF and TGF-α showed no detectable changes by pre-S mutants as compared to control. Thus, VEGF-A was selected for studies in details due to its critical role in angiogenesis at the early stage of tumorigenesis. We confirmed that the expression of VEGF-A was enhanced by pre-S mutants and could be suppressed by ER stress inhibitor vomitoxin. Further, the VEGF-A secreted from pre-S mutant-expressing HuH-7 hepatocytes could not only enhance the proliferation of endothelial cells but also promote the proliferation of HuH-7 cells, which could be inhibited by neutralization of VEGF-A. This indicated that VEGF-A may not only act as paracrine growth factor but also as an autocrine. Furthermore, we observed that pre-S mutants could upregulate the expression of VEGF receptor II and activation of Akt/mTOR signaling, which could be inhibited by neutralization of VEGF-A. Otherwise, we also demonstrated that Ras/Raf-1/ERK signal pathway was independent to the expression of pre-S mutants. By immunohistochemistry, both type I and type II GGHs showed enhanced expression of VEGF-A. Consistent with this notion, the enhanced expression of VEGF-A and the activation of Akt/mTOR signaling were also detected in HBV-related non-tumorous livers as compared to the levels of paired HCC tissues. To further address these issues, we used the transgenic mouse model to study the stepwise progression of ER stress and VEGF-A/Akt/mTOR signals at different time point. By Western blot assay, the data revealed that the expression of GRP-78 and VEGF-A and the activation of Akt were enhanced in 3-month-old transgenic livers harboring pre-S mutants as compared to control livers. Moreover, the activation of Akt was increased at the age of 6 month. Based on these results, the enhanced expression of VEGF-A in GGHs provides potential mechanism to explain the progression from pre-neoplastic GGHs to HCC in chronic HBV infection and may provide novel therapeutical strategies or chemoprevention via this study of the stepwise activation of signaling pathways in the transgenic mice.

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