Understanding the regulatory role and therapeutic potential of long non-coding RNAs in metastatic colorectal cancer

项目摘要/摘要 这项建议的总体研究目标是阐明推动mcrc更好地评估 发现生物标记物和靶向治疗的迫切需要。虽然早期结直肠癌 癌症(CRC)可以通过手术和辅助治疗治愈，转移性CRC(MCRC)通常是致命的。尽管 原发结直肠癌致癌机制的研究进展 转移并导致患者死亡的特点很差。此外，缺乏可靠的生物标志物 预测多发性结直肠癌的发展和选择进一步治疗的患者是一个关键障碍。要解决这个问题 关键的知识差距，我们的建议试图了解非编码RNA(LncRNAs)能够使 原发肿瘤的侵袭和转移，以发展改进的诊断和治疗方法。因此，我们 对37例匹配的正常、原发和远处转移性结直肠癌患者进行转录组分析 癌症组织发现148个与转移相关的差异表达(DE)RNA(RAMS)。值得注意的是， 最高上调的新候选基因RAMS11，(I)与低存活率有关，(Ii)在体外诱导侵袭 在体内，(Ii)增加对拓扑异构酶抑制剂的抵抗力，(Iii)与染色盒同源4相互作用 (CBX4)，和(Iv)，并可在体外与锁定的核酸靶向。这就是我们的 RAMS11可能通过相互作用作为预后生物标志物与不良预后相关的假说 使用CBX4对基因进行表观调控，并可作为治疗mCRC的靶点。为了证明这一点， AIM 1将评估RAMS11作为与不良长期结果相关的预后生物标记物。目标2将 表征RAMS11依赖的CBX4调控。最后，AIM 3将评估RAMS11的治疗潜力。 这项提案将确立RAMS11作为促进结肠的主要表观遗传调节因子的重要性 癌症转移。此外，这项研究通过评估预测和预测，具有翻译影响 锁定核酸反义寡核苷酸直接靶向RAMS11的治疗潜力

Project Summary/Abstract The overall research goal of this proposal is to elucidate the mechanisms driving mCRC to better assess the critical need for discovery of biomarkers and targeted therapies. Although early stage colorectal cancer (CRC) is curable with surgery and adjuvant therapy, metastatic CRC (mCRC) is usually lethal. Despite advances in our understanding of primary CRC oncogenesis, the mechanisms by which CRC becomes metastatic and leads to patient death is poorly characterized. In addition, the lack of reliable biomarkers to predict development of mCRC and select patients for further treatment is a critical barrier. To address this critical knowledge gap, our proposal seeks to understand how long non-coding RNAs (lncRNAs) enable primary tumors to invade and metastasize to develop improved diagnostics and therapeutics. Therefore, we performed transcriptome analysis of 37 patient matched normal, primary, and distant metastatic colorectal cancer tissues to discover 148 differentially expressed (DE) RNA Associated with Metastasis (RAMS). Notably, the top up-regulated novel candidate, RAMS11, (i) is associated with poor survival, (ii) induces invasion in vitro and in vivo, (ii) increases resistance to topoisomerase inhibitors, (iii) interacts with chromobox homology 4 (CBX4), and (iv) and can be targeted with locked nucleic acids in vitro. This serves as the rationale for our hypothesis that RAMS11 may serve as a prognostic biomarker associated with poor outcome by interacting with CBX4 to epigenetically regulate genes and can be therapeutically targeted in mCRC. To demonstrate this, Aim 1 will evaluate RAMS11 as a prognostic biomarker associated with poor long-term outcome. Aim 2 will characterize RAMS11-dependant CBX4 regulation. Lastly, Aim 3 will evaluate RAMS11 therapeutic potential. This proposal will establish the importance of RAMS11 as a master epigenetic regulator to promote colon cancer metastasis. Furthermore, this research is of translational impact by evaluating the prognostic and therapeutic potential of targeting RAMS11 directly with locked nucleic acid antisense oligonucleotides.