2018-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648340摘要：肝癌為全世界第二常見的癌症死亡原因，主因是時下肝癌治療（如：化療、肝動脈栓塞、手術切除和肝臟移植）療效有限，患者易復發並轉移，以致死亡率居高不下。為提升肝癌臨床治療的成功率，了解肝癌惡化並轉移機制實為至關重要。透過免疫組織染色法，我們已在205 個男性肝癌檢體中發現，若其細胞質表現RBMY (RNA-Binding Motif on Y chromosome)癌蛋白，該病人癌症分期常屬晚期(p<0.00005)，易在術後早期復發(p<0.005)並轉移(p< 0.00005)，5 年存活率亦偏低(p<0.0005)。RBMY 原在胎兒肝細胞中表現，隨著肝細胞成熟其表現量逐步消失，並匿蹤於成人肝細胞，但卻在70％的男性肝癌組織中重新被激活。在肝癌細胞質中，RBMY 誘發其快速增殖，強化其細胞幹性(stemness)及藥物抗性。於本計畫，我們將研究RBMY 何以在肝癌細胞大量被活化？其上游調控因子究竟是那些蛋白質？它們又如何接合並影響RBMY 活性。此外，也應用肝癌細胞株、小鼠模式及臨床肝癌組織等轉譯醫學研究法交叉驗證RBMY 在肝癌惡化並轉移過程所扮演的角色，探究其中所牽涉之上皮-間質轉化(epithelial-mesenchymal transition)機制以及其與腸道菌生態失衡之交互作用。鑒於成人正常細胞（除睪丸）均不表現RBMY，唯肝癌組織方測得其基因產物，故就安全性而言，RBMY實為標靶藥設計的理想標的，本計畫將是發展拮抗RBMY 抗癌藥物的前導研究，其重要性由此可見。<br> Abstract: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deathworldwide. The high mortality of HCC is mainly due to the limited efficacy of the currently availableanti-cancer therapies like chemotherapy, hepatic artery embolization, resection and transplantation, leadingto a poor prognosis with high rates of recurrence and metastasis. To achieve clinical success in cancertherapy, advances in understanding the mechanisms of HCC recurrence and metastasis are of criticalimportance. By applying immunohistochemistry on 205 male HCC tissue sections, we had reported on animportant association between cytoplasmic activation of RBMY (RNA-binding motif on Y chromosome)oncoprotein and the poor prognosis of HCC patients after surgical resection. Briefly, we found thatincreasing expression of cytoplasmic RBMY is correlated significantly with advanced tumor stage(p<0.00005), earlier recurrence (p<0.005), metastasis (p< 0.00005) and poor 5-year survival rate (p<0.0005)of HCC patients. Our published work also revealed that RBMY is expressed in the developing fetal liversbut vanished gradually as hepatocyte maturation. It is then silenced in mature hepatocytes; nonetheless,RBMY is reactivated in 70％ male HCC tissues. The cytoplasmic expression of RBMY prompts thetumor cell proliferation, increasing tumor stemness and chemoresistance. In the light of the massiveactivation of RBMY upon hepatocarcinogenesis, in this project we will approach issues of how can it occur;of which upstream factors of RBMY contribute to this effect and how do these factors bind and influent thefunctional activity of RBMY. Besides, a translational medicine approach using a combination of HCC celllines, RBMY-driven HCC mouse models and human HCC tissue samples will be set up for cross-checkingthe role of RBMY in HCC malignancy and metastasis. Additionally, the detail underlying mechanisms ofRBMY involving epithelial–mesenchymal transition and the dysbiosis of gut microbiota will be explored.Taking advantage of the absence of RBMY in normal human tissues (except testis) but is uniquelyexpressed in the cytoplasm of HCC tissues, RBMY will be of great potential for therapeutic drug targetingin term of clinical safety. Hence, this project will be a pilot study prior to conducting the development of aspecific therapeutic inhibitor of RBMY, and its importance is therefore indubitable.肝癌RBMY轉移腸道菌上皮-間質轉化Hepatocellular carcinomaRBMYMetastasisMicrobiotaEpithelial–Mesenchymal Transition