據(jù)香港文匯報(bào)報(bào)道，肝癌為香港最常見的癌癥,，男性發(fā)病率更較女性高出3倍,，惟個(gè)中原理一直為未解之謎。香港中文大學(xué)以3年時(shí)間研究,，發(fā)現(xiàn)男性荷爾蒙能誘發(fā)一種導(dǎo)致肝癌的基因“CCRK”,，令肝臟細(xì)胞異常快速繁殖,，促成腫瘤的形成,，完整解釋男性較易患肝癌的原因。
研究又發(fā)現(xiàn),，70%肝癌病人“CCRK”高于正常水平,，若降低“CCRK”或阻礙其分子信息通路，能有效減慢腫瘤生長,。中大校長沈祖堯表示,，“CCRK”很可能為治癌標(biāo)靶，今次發(fā)現(xiàn)有助開發(fā)新藥造福病人,。
肝癌男性發(fā)病率較女性高的謎團(tuán)終被解開,。中大醫(yī)學(xué)院消化疾病研究所由2008年起，以基因組定位技術(shù)及生物信息學(xué)分析,，從逾17,000個(gè)人類基因中,，找出一個(gè)名為“細(xì)胞周期相關(guān)性激素”(CCRK)的基因,，并證實(shí)其與男性荷爾蒙受體，以及肝癌有密切關(guān)系,。
消化疾病研究所研究副教授鄭詩樂表示,，男士如患有乙型肝炎，其男性荷爾蒙受體會(huì)被激活,，與男性荷爾蒙結(jié)合后,，會(huì)入侵肝細(xì)胞的細(xì)胞核，啟動(dòng)并增加“CCRK”的含量,，繼而引發(fā)一連串名為分子信息通路的化學(xué)反應(yīng),，激發(fā)細(xì)胞異常快速繁殖,，并轉(zhuǎn)化形成腫瘤細(xì)胞,，導(dǎo)致肝癌的發(fā)生。
研究所為逾50名肝癌病人驗(yàn)測(cè),，發(fā)現(xiàn)70%患者的“CCRK”遠(yuǎn)高于正常水平,，而“CCRK”高的肝癌病人較多為末期患者，其術(shù)后存活率3年已大跌50%,，反之“CCRK”低的患者,，6年存活率仍達(dá)100%。小鼠實(shí)驗(yàn)更進(jìn)一步證實(shí),，降低肝癌細(xì)胞“CCRK”的含量,，以及阻礙“CCRK”分子信息通路，均能有效減慢腫瘤形成的速度,。
研究主管兼莫慶堯醫(yī)學(xué)講座教授沈祖堯解釋,，每個(gè)人體內(nèi)也有“CCRK”基因，但含量高低各有不同,，醫(yī)學(xué)界過去只知“CCRK”對(duì)腦部有一定作用,，今次研究則首次發(fā)現(xiàn)“CCRK”對(duì)肝臟有所反應(yīng)，“荷爾蒙會(huì)喚醒沉睡的基因,，令不正常細(xì)胞快速增長”,。
中大下一步會(huì)把“CCRK”與小鼠自身基因結(jié)合，讓小鼠從出世已帶有“CCRK”,，看其會(huì)否發(fā)展成為肝癌,，亦會(huì)研究針對(duì)“CCRK”的標(biāo)靶治療，冀能開發(fā)肝癌新標(biāo)靶藥物,。有關(guān)研究結(jié)果已刊載于權(quán)威生物醫(yī)學(xué)刊物《臨床調(diào)查雜志》7月份網(wǎng)上版,。(生物谷 Bioon.com)
生物谷推薦原文出處：
The Journal Of Clinical Investigation doi:10.1172/JCI45967.
Cell cycle–related kinase is a direct androgen receptor–regulated gene that drives β-catenin/T cell factor–dependent hepatocarcinogenesis
Hai Feng, Alfred S.L. Cheng, Daisy P. Tsang, May S. Li, Minnie Y. Go, Yue S. Cheung, Gui-jun Zhao, Samuel S. Ng, Marie C. Lin, Jun Yu1,, Paul B. Lai, Ka F. To and Joseph J.Y. Sung
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is more prevalent in men than women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling — cell cycle–related kinase (CCRK) — that drives hepatocarcinogenesis via a signaling pathway dependent on β-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding to the androgen-responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of CCRK in immortalized human liver cells activated β-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active β-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and β-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of β-catenin/TCF signaling.
