miR-200 miRNAs repress tumor metastasis in lung adenocarcinoma

项目总结 肺癌是全球癌症死亡的主要原因，很大程度上是由于其高度转移性。 大自然。因此，阐明肿瘤转移的分子机制仍然是目前研究的热点之一。 肺癌研究中最紧迫的挑战。到目前为止，大多数关于癌症转移的研究 都专注于蛋白质编码基因，但越来越清楚的是，非编码基因 RNAs，特别是microRNAs(MiRNAs)，是 肿瘤转移，使用Kras驱动的，p53缺失的肺腺癌小鼠模型，我们 比较了原发和转移性肺肿瘤的miRNA表达谱，以及 发现miR-200 miRNAs是肺癌转移中表达下调最严重的miRNAs。这个 MiR-200家族由位于两个基因组座位的五个同源miRNAs组成：miR-200 200B/200A/429和MIR-200C/141。为了研究miR-200在肺癌转移中的作用， 我们产生了KrasLSL-G12D/+；p53fl/fl；mir-200C/141-/-(KP200cKO)小鼠，它们表现出显著的 短潜伏期内肿瘤转移增加。有趣的是，所有转移的KP200cKO 被检查的肿瘤显示所有miR-200 miRNAs完全沉默，这表明 MiR-200冗余的完全丧失是发生这种癌症转移的关键 模特。基于这些初步发现，我们假设miR-200 miRNAs是关键 Kras基因驱动、P53缺失的肺腺癌中的肿瘤转移抑制因子。vbl.使用 小鼠遗传学，CRISPR基因组编辑，细胞和分子方法，我们建议 综合表征miR-200 miRNAs在肺癌中的重要性 转移，并将阐明管理的潜在分子和细胞机制 MiR-200 miRNAs的生物学功能和转录调控。我们建议的研究将 为抑制肺癌转移的高度可靠的机制提供重要的见解。

Project summary Lung cancer is the leading cause of cancer death worldwide, largely due to its highly metastatic nature. Hence, elucidating the molecular mechanisms for tumor metastasis remains one of the most pressing challenges in lung cancer research. To date, most studies on cancer metastasis have focused on protein-coding genes, yet it has become increasingly clear that non-coding RNAs, particularly, microRNAs (miRNAs), are integral components of the molecular network for cancer metastasis, Using a Kras-driven, p53 deficient lung adenocarcinoma mouse model, we compared the miRNA expression profiles between primary and metastatic lung tumors, and identified miR-200 miRNAs as the most downregulated miRNAs in lung cancer metastases. The miR-200 family consists of five homologous miRNAs located at two genomic loci: mir- 200b/200a/429 and mir-200c/141. To characterize miR-200 functions in lung cancer metastasis, we generated KrasLSL-G12D/+;p53fl/fl; mir-200c/141-/- (KP200cKO) mice, which exhibited a significant increase of tumor metastases within a short latency. Interestingly, all metastatic KP200cKO tumors examined exhibited a complete silencing of all miR-200 miRNAs, suggesting that a complete loss of miR-200 redundancy was essential for developing cancer metastasis in this model. Based on these preliminary findings, we hypothesize that miR-200 miRNAs are key repressors of cancer metastasis in Kras-driven, p53 deficient lung adenocarcinomas. Using mouse genetics, CRISPR genome editing, cell and molecular approaches, we propose to comprehensively characterize the importance of miR-200 miRNAs during lung cancer metastasis, and will elucidate the underlying molecular and cellular mechanisms that govern the biological functions and transcriptional regulation of miR-200 miRNAs. Our proposed studies will provide important insights into a highly robust mechanism to repress lung cancer metastasis.