10月26日,，國(guó)際學(xué)術(shù)期刊Journal of Molecular Cell Biology在線發(fā)表了中科院上海生科院生物化學(xué)與細(xì)胞生物學(xué)研究所李伯良研究組和宋保亮研究組最新合作研究論文A specific cholesterol metabolic pathway is established in a subset of HCCs for tumor growth。該論文報(bào)道一條肝癌特異性的膽固醇代謝途徑,，他們的工作闡明該途徑在肝癌生長(zhǎng)中發(fā)揮的重要作用,。
肝癌是世界常見惡性腫瘤,， 五年存活率僅為7%，高居癌癥致死原因的第三位,。肝癌在亞洲尤其是我國(guó)發(fā)病率極高,，中國(guó)每年有11萬(wàn)人死于肝癌，幾乎占全球肝癌死亡率的一半,。肝臟在體內(nèi)膽固醇代謝平衡中發(fā)揮極重要作用,。氧化型膽固醇是一類重要的膽固醇代謝產(chǎn)物，參與許多生物學(xué)過(guò)程,。但是過(guò)量的氧化型膽固醇具有比膽固醇自身更大的細(xì)胞毒性,。因此，在生理?xiàng)l件下，全身來(lái)源的氧化型膽固醇被轉(zhuǎn)運(yùn)到肝臟進(jìn)行進(jìn)一步的代謝,。肝癌使肝臟功能受到極大的損傷,，導(dǎo)致包括膽固醇代謝在內(nèi)的許多代謝過(guò)程出現(xiàn)病理性變化。然而,，膽固醇代謝變化在肝癌發(fā)生發(fā)展中的作用還不清楚,。
博士后魯明和博士研究生胡西旵等研究人員通過(guò)對(duì)肝癌病人的組織樣本以及肝癌細(xì)胞株的研究發(fā)現(xiàn)，在一部分肝癌里存在一條特異性的膽固醇代謝途徑,，其包括ACAT2基因的誘導(dǎo)高表達(dá)與ACAT2介導(dǎo)的過(guò)量氧化型膽固醇的酯化分泌過(guò)程,。肝癌細(xì)胞通過(guò)這條代謝途徑消除過(guò)量氧化型膽固醇的細(xì)胞毒性。進(jìn)一步的研究顯示,，在肝癌細(xì)胞株或肝癌移植瘤中,，利用ACAT2特異性抑制劑阻斷該特異性膽固醇代謝途徑，可導(dǎo)致游離氧化型膽固醇的累積而抑制肝癌細(xì)胞株或肝癌移植瘤的生長(zhǎng),。深入的機(jī)制研究表明,，ACAT2基因啟動(dòng)子區(qū)域的低甲基化，在肝癌細(xì)胞誘導(dǎo)高表達(dá)ACAT2中發(fā)揮至關(guān)重要的作用,。該研究發(fā)現(xiàn)一條肝癌自身生長(zhǎng)特異的膽固醇代謝途徑,，對(duì)肝癌特別是晚期肝癌的臨床治療具有重要的意義。
該研究課題得到了國(guó)家科技部和國(guó)家自然科學(xué)基金委的資助,。（生物谷Bioon.com）
生物谷推薦的英文摘要
Journal of Molecular Cell Biology doi: 10.1093/jmcb/mjt039
A specific cholesterol metabolic pathway is established in a subset of HCCs for tumor growth
Ming Lu1,， Xi-Han Hu1， Qin Li1,， Ying Xiong1， Guang-Jing Hu1,， Jia-Jia Xu1,， Xiao-Nan Zhao1， Xi-Xiao Wei1,， Catherine C. Y. Chang2,， Yin-Kun Liu3， Fa-Jun Nan4,， Jia Li4,， Ta-Yuan Chang2， Bao-Liang Song1,，* and Bo-Liang Li1
The liver plays a central role in cholesterol homeostasis. It exclusively receives and metabolizes oxysterols,， which are important metabolites of cholesterol and are more cytotoxic than free cholesterol， from all extrahepatic tissues. Hepatocellular carcinomas (HCCs) impair certain liver functions and cause pathological alterations in many processes including cholesterol metabolism. However,， the link between an altered cholesterol metabolism and HCC development is unclear. Human ACAT2 is abundantly expressed in intestine and fetal liver. Our previous studies have shown that ACAT2 is induced in certain HCC tissues. Here,， by investigating tissue samples from HCC patients and HCC cell lines， we report that a specific cholesterol metabolic pathway,， involving induction of ACAT2 and esterification of excess oxysterols for secretion to avoid cytotoxicity,， is established in a subset of HCCs for tumor growth. Inhibiting ACAT2 leads to the intracellular accumulation of unesterified oxysterols and suppresses the growth of both HCC cell lines and their xenograft tumors. Further mechanistic studies reveal that HCC-linked promoter hypomethylation is essential for the induction of ACAT2 gene expression. We postulate that specifically blocking this HCC-established cholesterol metabolic pathway may have potential therapeutic applications for HCC patients.
