The role of RAMS11 in colorectal cancer progression and treatment resistance

项目概要/摘要 尽管早期结直肠癌（CRC）可以通过手术治愈，但迫切需要对高风险人群进行分层 早期患者可以从辅助治疗中受益。与早期 CRC 相比，晚期 CRC 转移性结直肠癌 (mCRC) 通常是致命的，迫切需要为患者匹配治疗方式 基于分子表型分析。为了解决这些未满足的临床需求，拟议的研究旨在 了解原发性 CRC 转移的分子机制，长期目标是 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lncRNA，现有的大规模测序项目主要由原发性肿瘤组成 没有匹配的转移样本。这代表了研究涉及的 lncRNA 的一个关键障碍 原发性疾病进展为转移性疾病。为了解决这一差距，我们进行了首次荟萃分析 CRC 患者的正常组织、原发组织和远处转移组织，以鉴定差异表达的 RNA 与转移（RAMS）相关。我们优先考虑以前未表征的核定位lncRNA， RAMS11，因为：（1）其表达与转移进展相关，（2）其表达与转移进展相关 多个独立患者队列的无病生存率较差，并且（3）它促进了致癌性 体外和体内的表型。此外，随后的机械实验证明了 RAMS11- 依赖招募 Chromobox 蛋白 4 (CBX4) 以转录激活拓扑异构酶 II α （TOP2α）。这为我们的假设提供了强有力的理由，即 RAMS11 与 CBX4 相互作用 表观遗传调节基因以促进致癌表型和治疗耐药性。本研究将重点 剖析 RAMS11 依赖性 CBX4 靶基因调控如何在体外赋予致癌表型 和体内。我们还将评估 RAMS11 是否可以帮助识别高危 CRC 患者及其在 化疗耐药。总体而言，我们的提案将通过以下方式显着推进 lncRNA 肿瘤生物学领域： 提供 RAMS11 表观遗传调控的机制见解，以促进 mCRC。我们的研究有 通过评估 RAMS11 对 CRC 患者进行高风险分层的潜在作用来评估转化影响 受益于特定辅助治疗的复发/转移性疾病。

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.