2013-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660891摘要：肝癌是世界五大癌症死因之一,在亞非地區尤其嚴重。雖然肝癌好發於成人,但亞非地區肝癌細胞癌與B型肝炎關係密切，其癌症之發生多數種因於兒童時期之B型肝炎病毒感染。我們過去的研究雖顯示台灣全民B型肝炎預防注射降低了兒童B型肝炎與肝細胞癌的發生率。但對於發生率高遠高於兒童之成人肝癌，是否能被B型肝炎預防注射預防,至今世界文獻資料仍然闕如。隨著全民預防注射實施時間已超過二十五年，本計畫將比較在全民B型肝炎預防注射實施前與後出生之兒童及年輕成人（於6歲至29歲時）肝細胞癌發生率之變化。其中27至29歲之年輕成人在嬰兒時並未注射B肝疫苗。本計畫並將進一步探討全民B型肝炎預防注射後出生的肝癌患者（6至27歲者）其肝細胞癌預防失敗之原因。肝母細胞癌是一種源自胚胎肝母(幹)細胞之兒童肝癌。當兒童肝細胞癌發生率在B肝預防注射實施後明顯降低之際, 本計畫將探討肝母細胞癌之發生率是否確實逐漸昇高。若屬實,將進一步探討其可能因子。其診斷年齡與預後之關係也將一併探討。本研究並將回顧B肝預防接種方案之成效，採用投資報酬率作為分析架構，整合公務預算投入該政策在健康及經濟面的效益。並以馬可夫模型模擬該政策的長期效益，將對應的HBsAg陽性率轉換為健康生活品質校正人年(QALYs)與終生醫療費用的預測。再透過國內研究對生命價值的衡量作為換算基準，B型肝炎疫苗預防接種方案的淨現值(NPV)將得以呈現。可作為政策評估重要參考。兒童及成人中男性好發肝癌但機轉仍不甚明瞭。我們發現男性特有的RNA結合蛋白RBMY基因在36%的男性肝細胞癌及67%的男性肝母細胞瘤之腫瘤組織中被活化表現，並在基因轉殖鼠模式中證明RBMY具有引發肝癌形成能力，且RBMY被降解的肝癌細胞株其轉形能力減弱。在分子機轉方面發現RBMY表現與否和雄激素受器(AR45)，SSX1，及EpCAM等基因的轉錄物合成量成正或負相關，且RBMY與GSK3β及MAP2K2等蛋白激酶交互作用。為了解RBMY在男性肝癌中的致癌機轉，本計劃將針對其標的RNA的轉錄調控以及其交互蛋白之訊息傳導路徑進行深入的研究。第一目標是要探討RBMY在SSX1，AR，及EpCAM等肝癌相關基因的製造與活性中扮演的角色及調控機制。第二目標是要探討RBMY是否藉由GSK3β蛋白激酶調控Wnt pathway。由於細胞黏著分子EpCAM是幹細胞的重要標記，第三目標是要探討RBMY陽性EpCAM陽性細胞是否具有腫瘤幹細胞的特性，並檢驗該細胞的移轉能力。RNA結合蛋白已被報導在微小核醣核酸(microRNA)的合成扮演調控角色，第四目標是要探討RBMY是否參與特定的microRNA合成。第五目標是評估RBMY表現在男性肝癌患者的臨床結果預測之價值。藉由完成以上目標，我們期待揭露RBMY活化在男性肝癌形成的角色，藉以評估其在臨床應用的可能性。本研究也將探討具肝幹細胞標記之人類胚胎肝細胞在發育過程增生分化之特質, 與具相同肝幹細胞標記之肝癌細胞比較,以了解胚胎肝臟發育與肝細胞癌化過程之異同;並比較前二者微小核醣核酸表現差異, 以了解肝幹細胞癌化過程中微小核醣核酸扮演的可能機轉, 並藉由肝癌細胞株驗證其在功能上的影響。<br> Abstract: Liver cancer is one of the five top causes of cancer death. Although adults have much higher incidence of hepatocellular carcinoma (HCC) than children, evidence is lacking regarding whether adult HCC can be prevented by hepatitis B virus (HBV) immunization. We will investigate the epidemiologic changes of HCC from before to 27 years after the HBV vaccination program in 6-29 years old adults and children. The risk factors of HCC prevention failure will be analyzed. Hepatoblastoma (HB) is a liver cancer of embryonal/fetal origin mainly in children of 0-5 years old. While HCC incidence is reduced in children after HBV immunization program, the changes of the incidence of HB will be analyzed. If the incidence is indeed increased, the possible causes will be investigated. The outcome also will be correlated with the age at diagnosis. We will summarize all the available information, including government spending over these years. An analytic framework of return on investment (ROI) will be adopted to evaluate the potential returns on both economic and clinical outcomes of HBV immunization program from a healthcare perspective. The net present value (NPV) of HBV immunization program will be calculated as a future reference point for the international public policy. The oncogenic mechanism of male predominance in liver cancer in both children and adults is not fully understood. Our previous study proved that the male germ-specific RNA binding motif at Y chromosome (RBMY) gene expression is specifically activated in 36% male HCC and 67% male HB. The liver tumor promoting effect of RBMY activation has been further proved in RBMY transgenic mice. The transformation ability of RBMY knockdown hepatoma cells HepG2 has significantly decreased. RBMY expression level is associated with the transcript levels of epithelial cell adhesion molecule (EpCAM), but inversely associated with that of androgen receptor variant AR45 (an AR inhibitor) and synovial sarcoma X breakpoint 1 (SSX1). RBMY interacts with protein kinases GSK3β involved in Wnt signaling pathway. In this project, we will investigate (1) the regulation of RBMY on the transcription of candidate RNA targets, including SSX1, AR 45, EpCAM;(2) if RBMY can regulate Wnt signaling pathway through interaction with GSK3β; (3) if RBMY+ EpCAM+ cells behave like cancer stem cells, and their metastatic ability;(4) RBMY associated microRNAs, and RBMY effect on candidate microRNA synthesis; (5) the clinical outcome predictive value of RBMY expression in HCC patients. We will also compare the expression levels of microRNA of human fetal hepatocytes versus liver cancer cells with the same stem cell markers. Functional assay of identified microRNA will be conducted in hepatoma cell lines for possible oncogenic mechanisms through stem cell pathways.肝細胞癌肝母細胞瘤肝臟幹細胞標記Y染色體上RNA結合蛋白糖蛋白合成？激？