肝癌是世界上第五大癌症。肝臟病變會循序表現出慢性肝炎、脂肪肝，肝纖維化到肝癌。苷氨酸-氮-甲基轉移酶(Glycine N-methyltransferase； GNMT)是一個肝癌抑制基因，在肝發炎和肝癌進展中扮演重要的角色。過去的研究發現在肝癌形成的早期GNMT就消失或去活化。本實驗室發現GNMT基因剔除小鼠都會產生自發性地慢性肝炎，脂肪肝和肝癌。 肝癌衍生生長因子(Hepatoma-derived growth factor; HDGF)是從人類肝癌細胞株的培養液分離出來的生長因子，近十年來的研究指出，HDGF過量表現與許多腫瘤的發生有關，包括肝癌的惡化、腫瘤分化程度、進展(包膜侵犯)、轉移、侵略、血管新生、腫瘤復發以及病患預後有密切關係，分化越完全、預後較差的肝癌患者其HDGF表現量也較多。我們從肝癌患者檢體觀察到，GNMT缺失與HDGF過量表現在肝癌形成過程中有緊密的關聯，但其中詳細機制尚未清楚。而更進一步研究發現，GNMT mRNA表現量在HDGF-/-老鼠的肝臟比野生型多了2.5倍；相反地，HDGF的表現量在GNMT-/-老鼠的肝臟明顯地提高了。在人類肝癌細胞株的實驗中觀察到，外加HDGF蛋白質會抑制GNMT基因表現活性、mRNA與蛋白質表現量。利用攜帶GNMT基因的腺病毒增加GNMT表現量能有效抑制HDGF所誘導的腫瘤效應(tumorigenesis)，包括移行(metastasis)、聚落形成(colony formation)、EMT相關分子誘發、幹細胞相關分子誘發與球體形成(sphere formation)。這些研究結果首次觀察到HDGF會負向調控GNMT表現，而提高GNMT表現量能有效遏止HDGF誘導的癌症惡化現象。

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer worldwide. Chronic hepatitis, steatosis, and liver fibrosis frequently occur before hepatoma development. Glycine N-methyltransferase (GNMT), which is a tumor suppressor gene, plays a central role in hepatic inflammation and liver carcinogenesis. GNMT loss or inactivation occurs at very early stage during liver carcinogenesis. GNMT knockout mice developed chronic hepatitis, fatty liver and HCC spontaneously. Hepatoma-derived growth factor (HDGF) is a novel growth factor identified from human hepatoma cell line. Elevated HDGF expression is associated with hepatic fibrosis and malignancy of HCC cells. HDGF overexpression is correlated with poor prognosis in HCC patients after surgery. Although GNMT depletion and HDGF elevation are involved in liver fibrosis and carcinogenesis, the relationship between GNMT loss and HDGF increment during HCC progression has never been studied. The present study aims to elucidate the probable gene regulation between HDGF and GNMT during liver carcinogenesis. By using 30 pairs of resected human HCC specimens, immunoblot analysis showed that GNMT protein level was reduced in 28 HCC tissues while HDGF protein level was increased in 19 HCC samples. Besides, 18 HCC tissues exhibited concomitant HDGF upregulation and GNMT downregulation. Statistical analysis unveiled a significant correlation between HDGF upregulation and GNMT downregulation in HCC tissues. By using an array of human hepatoma cells, immunoblot analysis also revealed a similar trend of HDGF increment and GNMT reduction in the poorly differentiated hepatoma cells. Adenovirus gene delivery technique was employed to delineate the role of HDGF on GNMT regulation in hepatoma cells. It was found that adenovirus-mediated HDGF overexpression resulted in reduced GNMT expression whereas HDGF knockdown led to increased GNMT expression in various human hepatoma cells (including HepG2, Hep3B and Huh7 cells). Importantly, HDGF modulation suppressed GNMT expression at transcriptional and translational level. Likewise, exogenous supply of HDGF also caused a dose-dependent reduction in GNMT mRNA, protein and promoter activities in hepatoma cells. Finally, expression analysis of HDGF-null mice indicated that HDGF ablation elicited a significant elevation of GNMT mRNA and protein level in the livers. Together, these results uncover the novel pro-oncogenic mechanism of HDGF through GNMT downregulation.
In the second part of this study, we evaluated whether GNMT could reciprocally regulate HDGF expression in HCC cells. By using GNMT knockout mice, immunofluorescence analysis showed that expression of HDGF/nucleolin axis was prominently enhanced in the livers compared with wild type (WT). However, adenovirus-mediated GNMT overexpression suppressed HDGF expression only in HepG2, but not Hep3B or Huh7 hepatoma cells. Despite the incapability to halt HDGF expression, GNMT restoration potently suppress the invasiveness and anchorage-independent growth of hepatoma cells even in the presence of excessive HDGF. Above all, GNMT overexpression significantly inhibited the endogenous and HDGF-stimulated self-renewal capability of hepatoma cells. This was associated with downregulation of epithelial-mesenchymal transition (EMT) markers and hepatic cancer stem cells markers. Thus, GNMT gene therapy may hold potential for HCC through suppressing oncogenic behavior, metastasis and hepatic cancer stemness. In summary, this study unveils the negative GNMT regulation by HDGF during HCC progression. Moreover, GNMT and HDGF may constitute the novel diagnostic and therapeutic targets for HCC.

Verification letter from the Oral Examination Committee -------------------------ⅰ
Acknowledgement ---------------------------------------------------------------------------ⅱ
Chinese Abstract ----------------------------------------------------------------------------ⅲ
English Abstract -----------------------------------------------------------------------------ⅳ
Table of Contents --------------------------------------------------------------------------ⅶ
Abbreviations --------------------------------------------------------------------------------ⅷ
Introduction ------------------------------------------------------------------------------------1
Specific Aims -----------------------------------------------------------------------------------8
Materials and Methods ----------------------------------------------------------------------9
Results -----------------------------------------------------------------------------------------16
Section I. HDGF modulates GNMT expression in HCC in vivo and in vitro. 16
Section II. GNMT restoration reversed the HDGF-induced malignant behaviours. 17
Discussion -------------------------------------------------------------------------------------22
Conclusion ------------------------------------------------------------------------------------25
Future perspectives -------------------------------------------------------------------------26
Figures and legends -------------------------------------------------------------------------27
References ------------------------------------------------------------------------------------61

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