miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma.
miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma.
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DOI：
10.1158/0008-5472.can-12-2001
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发表时间：
2012-11-01
期刊：
影响因子：
11.2
通讯作者：
Slack FJ
中科院分区：
文献类型：
--
作者：
Kasinski AL;Slack FJ
肺癌是全球癌症死亡的首要原因，且在绝大多数病例中，当前的疗法无法治愈这种疾病。RAS和p53通路是肺癌中最常发生改变的两条通路，这些改变导致对当前疗法失去反应以及患者生存率下降。微小RNA - 34（miR - 34）基因家族成员是p53的下游转录靶点，并且在p53突变的肿瘤中miR - 34表达降低；因此，我们假设用miR - 34治疗突变的Kras；p53肿瘤将是一种抑制肺癌发生的强有力的新疗法。为此，我们研究了具有治疗抗性的KrasLSL - G12D/+；Trp53LSL - R172H/+小鼠肺癌模型。我们对这些小鼠在肺特异性转基因激活后的肿瘤进展进行了特征分析，发现早在激活后10周就出现肿瘤，到22周时出现严重的肺部炎症。从这些肺中获取的肿瘤致癌微小RNA miR - 21和miR - 155水平升高；缺乏p53调控的微小RNA；并且miR - 34靶基因（如Met和Bcl - 2）表达增强。在存在外源性miR - 34的情况下，源自这些肿瘤的上皮细胞显示出增殖和侵袭能力降低。体内用miR - 34a治疗可阻止KrasLSL - G12D/+；Trp53LSL - R172H/+小鼠的肿瘤形成和进展。在转基因激活的同时感染表达miR - 34a的慢病毒的动物几乎没有肿瘤发生的迹象，并且慢病毒诱导的miR - 34a还阻止了已形成肿瘤的进一步进展。这些数据支持将miR - 34用作肺癌预防和肿瘤抑制药物。
Lung cancer is the leading cause of cancer deaths worldwide, and current therapies fail to treat this disease in the vast majority of cases. The RAS and p53 pathways are two of the most frequently altered pathways in lung cancers, with such alterations resulting in loss of responsiveness to current therapies and decreased patient survival. The microRNA-34 (mir-34) gene family members are downstream transcriptional targets of p53, and miR-34 expression is reduced in p53 mutant tumors; thus, we hypothesized that treating mutant Kras;p53 tumors with miR-34 would represent a powerful new therapeutic to suppress lung tumorigenesis. To this end we examined the therapeutically resistant KrasLSL-G12D/+;Trp53LSL-R172H/+ mouse lung cancer model. We characterized tumor progression in these mice following lung-specific transgene activation and found tumors as early as 10 weeks post-activation, and severe lung inflammation by 22 weeks. Tumors harvested from these lungs have elevated levels of oncogenic miRNAs miR-21 and miR-155; are deficient for p53-regulated miRNAs; and have heightened expression of miR-34 target genes, such as Met and Bcl-2. In the presence of exogenous miR-34, epithelial cells derived from these tumors show reduced proliferation and invasion. In vivo treatment with miR-34a prevented tumor formation and progression in KrasLSL-G12D/+;Trp53LSL-R172H/+ mice. Animals infected with mir-34a-expressing lentivirus at the same time as transgene activation had little to no evidence of tumorigenesis, and lentivirus-induced miR-34a also prevented further progression of pre-formed tumors. These data support the use of miR-34 as a lung tumor-preventative and tumor-static agent.