PNAS:miRNA抢镜mda-7的抗癌通路,新型疗法一触即发!

2019-03-28 Michael 转化医学网

科学家对mda-7 / IL-24基因进行了十多年的研究表明,它有助于抑制大多数常见的癌症类型,目前,科学家们正在探索上游基因是如何通过影响microRNA来推动这一抑制过程的。

导语

科学家对mda-7 / IL-24基因进行了十多年的研究表明,它有助于抑制大多数常见的癌症类型,目前,科学家们正在探索上游基因是如何通过影响microRNA来推动这一抑制过程的。

来自弗吉尼亚联邦大学(VCU)分子医学研究所的Paul B. Fisher及其研究团队发现mda-7 / IL-24或能通过影响相应microRNA的表达情况,来诱导细胞凋亡和细胞自噬,最终抑制肿瘤的进展。同时,这一过程可能对一些血管和神经退行性疾病产生影响。这一研究的最新进展发表于近期的《PNAS》杂志。

mda-7 / IL-24基因最初由Fisher发现,他和他的同事们已经对这一基因发表了许多研究报告,详细说明了该基因是如何通过直接影响细胞死亡的两种重要机制:细胞凋亡和细胞自噬来抑制癌症的进展的。同时,他们还开发了mda-7 / IL-24病毒基因治疗、纯化蛋白治疗和T细胞传递治疗。经研究发现,利用这些治疗手段可选择性杀死癌细胞。

Fisher 教授表示,“MicroRNA在包括癌症在内的多种疾病中发挥着决定性作用。本研究首次表明mda-7 / IL-24可通过影响microRNA合成过程中的关键酶从而发挥其抗癌疗效,这一发现可提供利用这一机制开发新的治疗方案的思路”。

我们知道,DICER酶主要影响具有特定细胞功能的microRNA的产生,研究人员发现,mda-7 / IL-24可以降低DICER酶的表达,并且这种降低作用发生在肿瘤细胞内。在前列腺癌、乳腺癌和脑癌细胞系小鼠模型的实验中,研究人员发现DICER的过表达载体转化的小鼠可有效抵抗mda-7 / IL-24介导的细胞死亡作用,进而导致肿瘤细胞逃避mda-7 / IL-24机制的清除作用。

研究人员发现微小眼病相关性转录因子(MITF)是这一过程的关键介质分子。 MITF分子可调节细胞对活性氧(ROS)的反应,活性氧是ROS正常代谢的天然副产物,是细胞信号传导的重要组成部分。在细胞应激时,ROS水平会急剧增加并导致疾病的发生。此次,研究人员们首次表明mda-7 / IL-24通过下调MITF,下调了MITF的靶蛋白DICER,进而介导了肿瘤的死亡机制。

先前的实验显示这一通路具有明显的旁观者效应,其中mda-7 / IL-24不仅可以杀死原发肿瘤部位的癌细胞,而且还可以杀死未直接靶向的远端继发性肿瘤。目前,对这一旁观者效应的理解尚不全面,但其部分原因是由mda-7 / IL-24的有效免疫激活和抗生长特性来介导的。这些发现有助于解释为什么肿瘤“自杀”机制会出现这种旁观者效应。

Fisher教授表示,“他们计划继续探索的mda-7 / IL-24和ROS 、 MITF 、DICER之间未知的联系。这项研究可能会开辟新的治疗方法,监测这些关键成分的信息或可提供重要的生物标志物,进而辅助预测mda-7 / IL-24疗法的有效性”。

虽然microRNA的许多机制已经被发现,但其与上游和下游核酸及分子的关系还有待开发。了解这其中蕴藏的机制,或可帮助研究人员开发出新型的抗肿瘤方案。

原始出处:Pradhan AK1, Bhoopathi P1, Talukdar S1, et al. MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF. PNAS. 2019 Mar 19

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    2019-08-10 smallant2002
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    2019-05-11 drwjr
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    2019-06-19 wetgdt
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    2019-03-30 Homburg