The role of RAMS11 in colorectal cancer progression and treatment resistance

项目摘要/摘要 虽然早期结直肠癌(CRC)可以通过手术治愈，但仍有必要对高危人群进行分层。 早期患者将受益于辅助治疗。与早期阶段的CRC相比，晚期的 转移性结直肠癌(Mcrc)通常是致命的，迫切需要将治疗方法与患者相匹配。 基于分子表型。为了解决这些未得到满足的临床需求，拟议的研究旨在 了解使原发癌转移的分子机制，并实现以下长期目标 合理指导治疗决策。虽然转录组测序提供了一种公正的方法 发现lncRNAs，现有的大规模测序项目主要由原发肿瘤组成 没有匹配的转移样本。这是研究参与LncRNAs的关键障碍 原发疾病向转移性疾病的进展。为了解决这一差距，我们进行了第一次元分析 结直肠癌患者的正常、原发和远处转移组织识别差异表达的RNA 与转移相关(公羊)。我们优先考虑了一种以前未定性的核局部化的lncRNA， RAMS11，因为：(1)它的表达与转移进展有关，(2)它的表达与 在多个独立的患者队列中的无病生存率较低，以及(3)它促进了致癌 体外和体内的表型。此外，随后的机械实验证明了RAMS11- 依赖于Chromobox蛋白4(CBX4)的募集来转录激活拓扑异构酶IIα (Top2α)。这为我们的假设提供了一个强有力的理由，即RAMS11与CBX4相互作用 表观遗传学调节基因以促进致癌表型和治疗耐药性。这项研究将集中于 体外解剖RAMS11依赖的CBX4靶基因调控致癌表型 在活体内。我们还将评估RAMS11是否可以帮助识别高危CRC患者，以及它在 化疗耐药。总体而言，我们的建议将极大地推动lncRNA肿瘤生物学领域的发展 提供对RAMS11表观遗传调控的机械性见解，以促进mCRC。我们的研究已经 通过评估RAMS11对高危结直肠癌患者分层的潜在作用的翻译影响 复发/转移性疾病，将受益于特定的辅助治疗。

PROJECT SUMMARY/ABSTRACT Although early stage colorectal cancer (CRC) is curable with surgery, there is a critical need to stratify high-risk early stage patients that would benefit from adjuvant treatment. In contrast to early stage CRC, late-stage metastatic CRC (mCRC) is usually lethal presenting a critical need to match treatment modalities to patients based on molecular phenotyping. To address these unmet clinical needs the proposed study aims to understand the molecular mechanisms enabling primary CRCs to metastasize with the longer-term goal of rationally guiding treatment decisions. While transcriptome sequencing has provided an unbiased method for discovering lncRNAs, existing large-scale sequencing projects are comprised of predominantly primary tumors without matched metastatic samples. This represents a critical barrier to studying lncRNAs involved in the progression of primary to metastatic disease. To address this gap, we conducted the first meta-analysis of normal, primary, and distant metastatic tissues across CRC patients to identify differentially expressed RNAs Associated with Metastasis (RAMS). We prioritized a previously uncharacterized nuclear localized lncRNA, RAMS11, since: (1) its expression correlated with metastatic progression, (2) its expression associated with poor disease-free survival across multiple independent patient cohorts, and (3) it promoted oncogenic phenotypes in vitro and in vivo. Further, subsequent mechanistic experiments demonstrated RAMS11- dependent recruitment of Chromobox protein 4 (CBX4) to transcriptionally activate Topoisomerase II alpha (TOP2α). This provides a strong rationale for our hypothesis that RAMS11 interacts with CBX4 to epigenetically regulate genes to promote oncogenic phenotypes and treatment resistance. This study will focus on dissecting how RAMS11 dependent CBX4 target gene regulation confers oncogenic phenotypes in vitro and in vivo. We will also assess whether RAMS11 can help identify high-risk CRC patients and its role in chemotherapy resistance. Overall, our proposal will significantly advance the lncRNA tumor biology field by providing mechanistic insight into RAMS11 epigenetic regulation to promote mCRC. Our research has translational impact by evaluating the potential role of RAMS11 to stratify CRC patients at high-risk of develop recurrent/metastatic disease that would benefit from specific adjuvant therapies.