肝細胞癌是最常見的肝臟原發性癌症且也是因癌症死亡的主要原因之一。手術切除含有腫瘤的肝臟是肝癌的一種重要治療方式，因為肝臟具有獨特的再生能力可以修復損傷，可以在組織受傷後再生成相同質量的器官。因此，剩餘肝臟的再生是手術成功的關鍵。但是大多數肝癌病患既使成功切除腫瘤,仍很快復發並且預後不良。因此，病患切除腫瘤後同時進行營養補充物有效加強肝臟再生功能及找出生物標記物預測手術後B型肝炎相關之肝細胞癌病人的預後是最迫切需要發展之研究主題與方向。本論文中，我們將探討麩醯胺酸對肝臟切除後的肝臟再生影響及肝臟再生中有影響的微小核醣核酸106b (miR-106b)對B型肝炎相關之肝細胞癌病人的影響。第一部分的研究，肝臟再生過程中受到高度調節並且涉及不同細胞型態、複雜的分子機制、肝外訊息傳導路徑以及細胞間交互作用。儘管在過去十年，科學家致力於發展肝臟再生的臨床應用及探索其生理機轉，但目前仍有許多未知存在，其中包括參與肝臟再生機轉的重要分子和機制。首先，我們成功建立了存活率高且個體間差異小的肝切除小鼠模式用以研究肝臟再生的分子機制。在此模式下，麩醯胺酸的補充可以促進肝切除術後小鼠肝臟質量的恢復並增強肝細胞的增殖作用。鳥氨酸轉氨酶 (Ornithine aminotransferase)在肝切除後肝臟再生過程中表現量有增加，在肝門靜脈周邊區域，鳥氨酸轉氨酶的蛋白質及訊息核醣核酸的表現量有顯著增強的情形，但麩醯胺酸的補充與否對鳥氨酸轉氨酶的表現並無相關。另外，我們找出十四個由麩醯胺酸所調控的細胞週期相關基因，並在小鼠及AML-12細胞系統下，證實這些基因的調控在肝臟再生過程中所產生的影響。這些數據顯示，麩醯胺酸的補充可以透過調控細胞週期相關基因的表現而造成肝細胞的迅速增殖。鳥氨酸轉氨酶受到抑制的小鼠系統下，麩醯胺酸對肝臟細胞增生的促進也同樣受到抑制，鳥氨酸轉氨酶對麩醯胺酸在肝臟再生過程中有扮演一定的角色。此外，我們利用HistoIndex的系統，來分析肝臟在生過程中膠原蛋白產生的量、時間點、及位置，發現麩醯胺酸的補充會促進肝臟再生過程中膠原蛋白產生的量進而加速肝臟血管增生形成。第二部分的研究，慢性肝炎如B型肝炎等會會造成肝臟纖維化及肝細胞再生，而肝細胞的增生有可能導致惡性變化。微小核糖核酸會調控基因的表現影響細胞的增生或凋零。因此，研究目的是找出微小核醣核酸106b在B型肝炎相關之肝細胞癌生成及調控的機制。微小核醣核酸106b在B型肝炎相關之肝細胞癌會高度表現，並且B型肝炎病毒X蛋白會增強微小核醣核酸106b的表現。臨床上，B型肝炎相關的肝細胞癌的病人中微小核醣核酸106b大量表現與較差分化及病人預後呈現正相關。臨床上，我們的研究結果將有助於瞭解麩醯胺酸對肝臟受損的病理機制及再生的機制，及miR-106b的表現對於B型肝炎相關的肝細胞癌預測，提供臨床上肝癌病人接受手術及手術後的治療新策略。

Hepatocellular carcinoma (HCC) is primary malignancy type of liver cancers and a leading cause of cancer-related death occurs in the world. Removing tumor by partial hepatectomy is an important treatment for HCC. The liver has the unique ability to regenerate in response to injury and therefore restore its original mass after tissue loss. Thus, the regeneration of remnant liver is a key point for successful surgery. However, HCC patients possibly have the poor survival rate and increased risk of tumor recurrence after curative hepatectomy. Therefore, it is urgently needed to proceed in parallel between nutrient supplements for enhancing liver repair and identification of the potential prognostic biomarkers for HBV-associated HCC after surgery. In this study, the aim of this research is to explore the effect of glutamine (Gln) supplementation during liver regeneration and the role of miR-106b in tumor progression and regulation in HBV-associated HCC. In first topic, liver regeneration is highly regulated and involves in many cell types, complex molecular mechanisms, extra-hepatic signaling pathways, and cellular interactions. Despite the advances in biological understanding and clinical applications of liver regeneration have occurred in the past decades, many gaps are still exist, including the critical factors involved in liver regeneration and how it works in the process of liver regeneration. This study is to clarify the molecular mechanism of liver regeneration post partial hepatectomy (PHx) in the present of Gln supplementation. We have established a reliable 70% PHx mouse model with high survival rate and high reproducible results between individual mice for the studying the liver regeneration. Gln supplementation enhances liver mass restitution and improves hepatic cell proliferation during liver regeneration in mice post PHx. Microarray data is performed to isolate meaningfully different gene categories associated with liver regeneration and provide a comprehensive view on gene modulation by Gln supplementation. 14 crucial Gln-modulated cell cycle-related genes are identified and suggesting that Gln supplementation could promote cell cycle progression through modulation of cell cycle-related gene expression resulting in a rapid proliferation of hepatic cells. Moreover, ornithine aminotransferase (OAT) is identified during the process of liver regeneration. Strikingly, the protein expression of OAT significantly is up-regulated around the portal vein area in liver, but its high expression do not correlate with Gln supplementation. We further find that OAT knockdown results in a decreased hepatocyte proliferation in the presence of Gln. Notably, we find that Gln treatment enhances the synthesis of collagen to promote vessels formation of portal vein and hepatic vein during liver regeneration process after PHx using HistoIndex system. In second topic, chronic hepatitis infection causes liver inflammation damage, followed by fibrosis, liver cell regeneration and liver cell proliferation leading to the malignant transformation of the liver. MicroRNAs (miRNAs) are small non-protein coding genes with important roles in the regulation of gene expression at the post-transcriptional level. MiRNA plays a role in the regulation of cell development, proliferation, cell fate determination and apoptosis. The aim of this study is to clarify the roles of miR-106b in tumor progression and regulation in HBV-associated HCC. These results indicate that miR-106b expression is up-regulated and associated with tumor progression in HBV-associated HCC. In addition, HBx might enhance miR-106b transcription. Up-regulation of miR-106b expression corresponds with poor differentiation and decreased survival time in HBV-associated HCC patients. Thus, miR-106b promotes tumor progression in HBV-associated HCC. Overall, we ultimately provide a new treatment strategy for liver recovery using Gln supplementation and a potential diagnostic marker for HBV-associated HCC patients received hepatectomy.

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