近日，来自美国的研究人员在国际学术期刊JCI上发表了一项最新研究进展，他们发现miR-31在人类肺腺癌中存在过表达，对于促进肺癌发生和进展具有重要作用。这一发现为肺癌靶向治疗药物开发提供了一个新的潜在靶点。
肺癌是导致癌症死亡的重要癌症类型之一，而腺癌是非小细胞肺癌的主要亚型，在肺癌形成和进展过程中存在许多基因调控方面的巨大变化。MicroRNA是一类非编*****RNA，这种RNA主要通过结合3`端非翻译区，导致翻译水平下降或促进靶向mRNA的降解进而调节mRNA表达。
MicroRNA是重要的基因表达调控因子，许多研究已经证明异常的miR表达与癌症发生有关。但是对于参与肺癌发生的miR仍了解较少。
在这项研究中，研究人员发现miR-31在人类肺腺癌中存在过表达现象，并且miR-31的过表达与病人生存率下降存在关联性。他们构建了一个能够在肺部特异性表达miR-31的转移基因小鼠模型用以检测miR-31在肺部的致癌能力。
通过这一模型研究人员观察到诱导miR-31表达能够导致肺部增生，随后出现腺瘤的形成，最终发展为腺癌。除此之外，在小鼠体内诱导表达的miR-31还能够与KRAS突变协同促进肺癌形成。研究表明miR-31能够调节肺上皮细胞生长，同时研究人员还在RAS/MAPK信号途径中鉴定出6个负调控因子是miR-31的直接靶向目标。
这项研究发现miR-31是促进肺癌形成的一个重要推动因素，特别是在促进KRAS突变介导的癌症发生方面作用更加显著，这项研究还证明miR-31能够直接靶向并抑制RAS/MAPK信号途�****************谝幌盗懈旱骺匾蜃拥谋泶铮虼薽iR-31或可成为抑制肺癌发生发展的新靶点。
doi:10.1172/JCI82720
MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer
Mick D. Edmonds1, Kelli L. Boyd1, Tamara Moyo2, Ramkrishna Mitra3, Robert Duszynski1, Maria Pia Arrate1, Xi Chen4, Zhongming Zhao3,5, Timothy S. Blackwell2, Thomas Andl2, and Christine M. Eischen1
MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.
