MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors
MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors
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DOI：
10.1172/jci39566
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Dmitrovsky, Ethan
中科院分区：
文献类型：
--
作者：
Liu, Xi;Sempere, Lorenzo F.;Dmitrovsky, Ethan
MicroRNAs(MiRNAs)调节基因表达。已有研究表明，获得miRNA表达谱可以改善肿瘤学中的分类、诊断和预后信息。在这里，我们试图通过对转基因小鼠的正常肺和邻近肺癌进行miRNA微阵列表达谱来全面识别在肺癌中过度表达的miRNAs。我们发现miR-136、miR-376a和miR-31在小鼠肺癌中均显著过表达。实时定量RT-PCR和原位杂交(ISH)分析证实了这些miRNA在来自小鼠和人类的正常和恶性肺组织中的表达谱。MiR-31的工程敲除，但不是其他突出显示的miRNAs，以剂量依赖的方式显著抑制肺癌细胞的生长和致瘤性。利用生物信息学方法，我们鉴定了miR-31靶标mRNAs，并独立地确认它们是人和小鼠肺癌细胞系中的直接靶标。这些靶点包括肿瘤抑制基因大肿瘤抑制因子2(LATS2)和PP2A调节亚基Bα亚基亚型(PPP2R2A)，并且miR-31下调后每种基因的表达均增强。它们的工程抑制可拮抗miR-31介导的生长抑制。值得注意的是，miR-31和这些靶向mRNAs在小鼠和人类肺癌中反向表达，强调了它们的生物学相关性。使用包含正常和恶性人类肺组织的阵列，进一步独立和全面地验证miR-31表达的临床相关性。综上所述，这些发现表明miR-31通过靶向特定的肿瘤抑制因子而在肺癌中发挥致癌miRNA(Oncomir)的作用。
MicroRNAs (miRNAs) regulate gene expression. It has been suggested that obtaining miRNA expression profiles can improve classification, diagnostic, and prognostic information in oncology. Here, we sought to comprehensively identify the miRNAs that are overexpressed in lung cancer by conducting miRNA microarray expression profiling on normal lung versus adjacent lung cancers from transgenic mice. We found that miR-136, miR-376a, and miR-31 were each prominently overexpressed in murine lung cancers. Real-time RT-PCR and in situ hybridization (ISH) assays confirmed these miRNA expression profiles in paired normal-malignant lung tissues from mice and humans. Engineered knockdown of miR-31, but not other highlighted miRNAs, substantially repressed lung cancer cell growth and tumorigenicity in a dose-dependent manner. Using a bioinformatics approach, we identified miR-31 target mRNAs and independently confirmed them as direct targets in human and mouse lung cancer cell lines. These targets included the tumor-suppressive genes large tumor suppressor 2 (LATS2) and PP2A regulatory subunit B alpha isoform (PPP2R2A), and expression of each was augmented by miR-31 knockdown. Their engineered repression antagonized miR-31-mediated growth inhibition. Notably, miR-31 and these target mRNAs were inversely expressed in mouse and human lung cancers, underscoring their biologic relevance. The clinical relevance of miR-31 expression was further independently and comprehensively validated using an array containing normal and malignant human lung tissues. Together, these findings revealed that miR-31 acts as an oncogenic miRNA (oncomir) in lung cancer by targeting specific tumor suppressors for repression.