MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy
MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy
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DOI：
10.1158/0008-5472.can-07-2858
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Slack, Frank J.
中科院分区：
文献类型：
--
作者：
Weidhaas, Joanne B.;Babar, Lmran;Slack, Frank J.
肿瘤细胞使用预先存在的促生存信号通路来逃避抗癌药物的损伤和细胞毒性作用。放射治疗是细胞毒性抗癌治疗的主要形式，但成功改变体内放射反应的药物缺乏。MicroRNAs （miRNA）是全球性的基因调控因子，在肿瘤发生中起关键作用，并被发现调节促生存途径。然而，对于细胞miRNA表达如何影响癌症对细胞毒性治疗的反应和最终结果，人们知之甚少。let-7家族的miRNAs调节癌基因的表达，如RAS，并且在许多癌症亚型中特异性下调。事实上，低水平的let-7预示着肺癌的不良预后。在这里，我们报告了let-7家族的miRNAs在一类miRNAs中被过度代表，这些miRNAs在辐射反应中表现出表达改变。更引人注目的是，当选择let-7家族的mirna在体外肺癌细胞和体内秀丽隐杆线虫辐射诱导细胞死亡模型中过表达时，我们还可以创建一个辐射敏感状态，而降低它们的水平会导致辐射抗性。在秀丽隐杆线虫中，我们发现这部分是通过控制原癌基因同源物let-60/RAS和DNA损伤反应途径中的基因实现的。这些发现是第一个直接证据，表明miRNAs可以抑制抗癌细胞毒性治疗的耐药性，这是癌细胞的共同特征，并表明miRNAs可能是增强当前癌症治疗的可行工具。
Tumor cells use preexisting prosurvival signaling pathways to evade the damaging and cytotoxic effects of anticancer agents. Radiation therapy is a primary form of cytotoxic anticancer treatment, but agents that successfully modify the radiation response in vivo are lacking. MicroRNAs (miRNA) are global gene regulators that play critical roles in oncogenesis and have been found to regulate prosurvival pathways. However, there is little understanding of how cellular miRNA expression affects the response of a cancer to cytotoxic therapy and ultimately outcome. The let-7 family of miRNAs regulates expression of oncogenes, such as RAS, and is specifically down-regulated in many cancer subtypes. In fact, low levels of let-7 predict a poor outcome in lung cancer. Here, we report that the let-7 family of miRNAs is overrepresented in a class of miRNAs exhibiting altered expression in response to radiation. More strikingly, we also can create a radiosensitive state when the select let-7 family of miRNAs is overexpressed in vitro in lung cancer cells and in vivo in a Caenorhabditis elegans model of radiation-induced cell death, whereas decreasing their levels causes radioresistance. In C. elegans, we show that this is partly through control of the protooncogene homologue let-60/RAS and genes in the DNA damage response pathway. These findings are the first direct evidence that miRNAs can suppress resistance to anticancer cytotoxic therapy, a common feature of cancer cells, and suggest that miRNAs may be a viable tool to augment current cancer therapies.