据香港文汇报报道,肝癌为香港最常见的癌症,男性发病率更较女性高出3倍,惟个中原理一直为未解之谜。香港中文大学以3年时间研究,发现男性荷尔蒙能诱发一种导致肝癌的基因“CCRK”,令肝脏细胞异常快速繁殖,促成肿瘤的形成,完整解释男性较易患肝癌的原因。
研究又发现,70%肝癌病人“CCRK”高于正常水平,若降低“CCRK”或阻碍其分子信息通路,能有效减慢肿瘤生长。中大校长沈祖尧表示,“CCRK”很可能为治癌标靶,今次发现有助开发新药造福病人。
肝癌男性发病率较女性高的谜团终被解开。中大医学院消化疾病研究所由2008年起,以基因组定位技术及生物信息学分析,从逾17,000个人类基因中,找出一个名为“细胞周期相关性激素”(CCRK)的基因,并证实其与男性荷尔蒙受体,以及肝癌有密切关系。
消化疾病研究所研究副教授郑诗乐表示,男士如患有乙型肝炎,其男性荷尔蒙受体会被激活,与男性荷尔蒙结合后,会入侵肝细胞的细胞核,启动并增加“CCRK”的含量,继而引发一连串名为分子信息通路的化学反应,激发细胞异常快速繁殖,并转化形成肿瘤细胞,导致肝癌的发生。
研究所为逾50名肝癌病人验测,发现70%患者的“CCRK”远高于正常水平,而“CCRK”高的肝癌病人较多为末期患者,其术后存活率3年已大跌50%,反之“CCRK”低的患者,6年存活率仍达100%。小鼠实验更进一步证实,降低肝癌细胞“CCRK”的含量,以及阻碍“CCRK”分子信息通路,均能有效减慢肿瘤形成的速度。
研究主管兼莫庆尧医学讲座教授沈祖尧解释,每个人体内也有“CCRK”基因,但含量高低各有不同,医学界过去只知“CCRK”对脑部有一定作用,今次研究则首次发现“CCRK”对肝脏有所反应,“荷尔蒙会唤醒沉睡的基因,令不正常细胞快速增长”。
中大下一步会把“CCRK”与小鼠自身基因结合,让小鼠从出世已带有“CCRK”,看其会否发展成为肝癌,亦会研究针对“CCRK”的标靶治疗,冀能开发肝癌新标靶药物。有关研究结果已刊载于权威生物医学刊物《临床调查杂志》7月份网上版。(生物谷 Bioon.com)
生物谷推荐原文出处:
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.