KRAS突变调控miR-139-5p介导结直肠癌恶性生物学行为的功能与机制研究

超过30%的结直肠癌患者存在KRAS突变，是预后不良的重要因素。miRNA在肿瘤发生发展中发挥重要作用，但受KRAS突变调控的miRNA及调控机制罕有报道。我们前期发现miR-139-5p在KRAS突变结直肠癌细胞系及临床标本中表达降低，过表达miR-139-5p抑制KRAS突变癌细胞的增殖和侵袭能力，提示KRAS突变调控miR-139-5p表达，在结直肠癌恶性生物学行为中发挥重要作用。本研究拟通过体内外功能实验，阐明miR-139-5p在KRAS突变结直肠癌中发挥的作用；联合应用基因芯片和蛋白质组iTRAQ，阐明miR-139-5p调控的关键靶分子和信号网络；探索KRAS突变致miR-139-5p表达下调的转录机制及表观遗传学机制；在结直肠癌PDX小鼠模型及organoid模型中进一步验证，探索miRNA治疗可行性。本研究将深入对KRAS突变结直肠癌的认识，为其治疗提供新靶点新策略。

Over 30% of patients with colorectal cancer (CRC) harbor KRAS mutation, which indicates the poor prognosis in patients with CRC. microRNAs (miRNAs) play essential roles in gene expression regulation during carcinogenesis; however, miRNAs dysregulation in KRAS-mutant colorectal cancer has not been fully explored. We previously found that miR-139-5p was down-regulated in KRAS mutant CRC cell lines and tissues compared with their wild-type KRAS counterparts and overexpression of miR-139-5p in KRAS mutant CRC cells inhibited the proliferation, migration, and invasion of CRC cells. All above results indicated that that miR-139-5p plays an important role in KRAS mutation CRC. In this study, we aim to demonstrate the function of miR-139-5p in KRAS mutant CRC through in vitro and in vivo functional studies. In addition, we will utilize high-throughput methods including cDNA microarray and iTRAQ analysis to reveal the target molecules of miR-139-5p and the related signaling pathways. Mechanically, we investigate the role and mechanism of KRAS in regulation of miR-139-5p expression at both transcriptional and post-transcriptional levels. Finally, we will explore the therapeutic potential and application values of miR-139-5p administration in CRC PDX and organoid models, which may provide a potential therapeutic strategy for colon cancers exhibiting aberrant KRAS pathway activation.