在慢性B型肝炎病毒感染的病人血清中常可發現有自然產生的pre-S表面蛋白的突變株。在我們實驗室先前的研究中顯示 pre-S突變株的發生可能與病程的發展及肝癌有關。因此, 本研究的主要目標是要瞭解不同的pre-S突變株在生物學上的意義及肝細胞在表現這些突變蛋白後的影響。由於在臨床上 肝組織中的毛玻璃細胞被當為慢性B型肝炎病毒感染的指標 因此 我們先利用雷射細胞微量截取儀來分離組織中不同型式的毛玻璃細胞以進行分析。結果我們發現, 在慢性肝炎的早期 可在第一型的毛玻璃細胞中分離出在pre-S1序列有缺失的突變株 而在第二型毛玻璃細胞中卻可分離到在pre-S2序列有缺失的突變株。在此 我們對於pre-S2突變株特別有興趣 因為第二型毛玻璃細胞在組織中常成叢集增生, 並且主要出現在肝硬化或是在肝癌附近的肝組織。此外, pre-S2突變株可能具有逃脫免疫攻擊的特性。我們接著在HuH-7細胞中表現pre-S突變基因並且發現pre-S突變的大表面蛋白會堆積在細胞內質網中, 並且造成內質網壓力 因而導致內質網蛋白GRP78/94的表現 JNK訊息的活化及過氧化物的產生。我們進一步分析發現突變大表面抗原蛋白在細胞內會促使許多基因活化 進而影響細胞生理週期及訊息傳遞。其中我們進一步發現pre-S2突變大表面蛋白能夠增強cyclin A的表現並可能藉著對細胞調節因子的調控(cyclin D1/CDK, 及cyclin A) 對細胞因受到外界壓力而死亡的機制有保護的作用。在細胞轉型的能力方面 我們也發現只有pre-S2突變大表面蛋白能促使肝癌細胞(HuH-7)及正常肝細胞(HH4)在洋菜膠中的生長。因此 為了進一步瞭解pre-S2突變大表面蛋白對細胞生理功能及細胞轉型的影響, 我們建立了表現pre-S2突變大表面抗原蛋白的老鼠實驗動物模式。在我們所建立的基因轉殖鼠中, pre-S2突變大表面抗原蛋白主要表現在肝門靜脈周圍的肝細胞 並且明顯造成肝細胞的增大及細胞核的變異。肝細胞的生長在早期也在基因轉殖鼠有較高的表現。在組織學的檢測中, 我們發現在基因轉殖肝細胞所觀察到的肝細胞變性(liver cell dysplasia)在臨床上常可在癌症發生早期可以觀察到。此外 我們在基因轉殖鼠上也發現pre-S2突變大表面蛋白會造成的肝細胞死亡及小型發炎反應。綜合以上結果, 本實驗首先證明了在病人血清內所測得的pre-S突變株在肝細胞中有不同的表現及分佈型態。我們的實驗結果也顯示 在缺乏實際病毒感染時所造成的免疫反應的刺激之下 pre-S2突變大表面蛋白能夠藉由調控基因的表現及細胞訊息傳遞來造成細胞的轉型, 這樣的作用可能在肝癌的發展中扮演輔助的角色。我們的實驗結果顯示 在慢性B型肝炎病毒感染的過程中 pre-S突變株對肝癌的發生有促進的作用。而在慢性B型肝炎病人血清中 pre-S突變株的出現與否可能可以做為臨床上較差預後的指標。

Naturally occurring pre-S mutants can be frequently isolated from serum of patients with chronic hepatitis B virus (HBV) infection. In our previous studies, we have demonstrated that the prevalence of pre-S mutants may associate with disease progression to hepatocellular carcinoma. This study therefore is to study biological characteristics of different pre-S mutants and potential physiological impacts on hepatocytes with pre-S mutant proteins. With the application of laser capture microdissection, we first identified different pre-S mutants from liver tissues from different types of ground glass hepatocytes (GGHs), which is the histologic hallmark of chronic HBV infection. Two major types of pre-S truncated mutants, one with a deletion over pre-S1 region (DS1) in type I GGHs and the second with a deletion at pre-S2 region (DS2) in type II GGHs, were identified. The DS2 mutants was of particular interest, because type II GGHs harboring this mutant usually cluster in groups, clonally proliferate, and prevail in cirrhotic nodules and non-tumor regions adjacent to hepatoma tissues. Besides, the HBV pre-S2 mutants may represent immune escape mutants. The expression of pre-S mutant proteins on HuH-7 cells leads to intracellular ER accumulation, which can be further supported by the observation of co-localization of surface proteins with ER marker on GGHs. The ER accumulation of pre-S mutant proteins subsequently leads to induction of ER stress signal, which activates ER chaperones GRP78/94, JNK pathways, and increases reactive oxygen intermediates. Several groups of genes involving in cell cycle regulation, kinases and transcription were found to be up-regulated by pre-S mutants. Here we have further demonstrated that DS2-LHBs could specifically increase cyclin A expression and could protect cells from ER-stress-induced cell cycle arrest through the regulation of cyclin D1/CDK and cyclin A. Soft agar assay on HuH-7 and non-transformed HH4 cells next showed an enhanced transforming ability of DS2 mutant proteins. To further evaluate the potential carcinogenic effects of DS2 mutant protein, a transgenic mice model of DS2-mutant was next established. The DS2-mutant surface protein (DS2-LHBs) expressed predominantly on the area around central vein and resulted in enlarged hepatocytes and nuclear abnormality. Hepatocyte proliferation was elevated on transgenic mice at early stage. By histological examinations, we have detected liver cell dysplasia on most transgenic livers which usually represented a preneoplastic lesion of hepatocellular carcinoma. In addition, the demonstration of necrotic inflammation and apoptotic cell death on transgenic livers indicate that DS2-LHBs might induce liver damages. In conclusion, our data demonstrated the association of pre-S mutants in human serum with distinct surface protein expression patterns on liver hepatocytes. Our data suggest that in the absence of immune attack, the biological effects of DS2-LHBs protein might be sufficient for inducing liver cell dysplasia but might not be sufficient for supporting liver cell regeneration and tumor formation thereafter. Therefore, we believed that the presence of HBV pre-S mutants in patients with chronic hepatitis B infection may contribute to hepatocarcinogenesis and link to a poor disease outcome.

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