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盐皮质激素受体通过调控miR-338-3p-PKLR轴抑制肝癌的发展和Warburg效应
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激素和它们的受体在生理和病理条件下对代谢的调节起着重要的作用。我们在4株肝癌细胞用siRNA的方法筛选20种激素受体对肝癌细胞的瓦伯格效应(Warburg effect)尤其是乳酸产生的影响。我们发现很多受体的siRNA都影响乳酸的产生。其中盐皮质激素受体(mineralocorticoid receptor, MR) 的siRNA在4株肝癌细胞都表现出增加乳酸的产生。体外和体内实验表明MR影响细胞增殖、细胞周期和凋亡。进一步的机制研究揭示,作为一个转录因子,MR直接调节miR-338-3p的表达,而miR-338-3p又通过靶基因PKLR(pyruvate kinase, liver and red blood,糖酵解途径的关键酶)来抑制肝癌细胞的瓦伯格效应。另外,与癌旁组织相比,有81%的肝癌病人的肝癌组织中MR的表达都发生下调。这种下调是由MR的染色体缺失和去乙酰化引起的。在肿瘤组织中,MR的低表达和病人的预后差相关;miR-338-3p的表达和MR的表达水平呈正相关,和PKLR的表达呈负相关。结论:我们的研究首次揭示了MR通过miR-338-3p/PKLR这个途径抑制肝癌的瓦伯格效应。
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讲师介绍
  • 讲师:张志刚(研究员 博士生导师)

    张志刚,研究组长,2003年毕业于中科院遗传与发育生物学研究所,获博士学位。2003年至2009年在德国科隆大学生物化学研究所作为博士后,主要参与了细胞微环境(细胞外基质蛋白)方面的研究。2009年10月张志刚博士以人才引进方式来上海市肿瘤研究所癌基因及相关基因国家重点实验室工作,现任神经递质与肿瘤微环境研究组组长。国际细胞外基质生物学会成员,中国生理学会基质生物学会副主任委员,中国老年学协会衰老与抗衰老科学委员会理事,中国遗传学会终身会员。担任多个SCI杂志的审稿人。已获得国家重大研究计划、国