MUC13 Mucin in Colorectal Cancer Health Disparity

MUC13 粘蛋白在结直肠癌健康差异中的作用

• 批准号: 9313845
• 负责人: Subhash C. Chauhan
• 金额: $ 35.15万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313845
• 关键词: 3' Untranslated Regions; Adenomatous Polyps; Affect; African American; American Indians; Applications Grants; Benign; Binding; Caucasians; Cell Line; Cell Nucleus; Cell Survival; Cell membrane; Cells; Colorectal Cancer; Cytoplasm; Data; Diagnosis; Disease; Disease Progression; ERBB2 gene; Early Diagnosis; Etiology; Functional disorder; Genetic Polymorphism; IL6 gene; Individual; Inflammation Mediators; Interleukin-6; Intrinsic factor; Investigation; JAK2 gene; Laboratories; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mucins; Neoplasm Metastasis; Neoplastic Polyp; Nuclear; Outcome Study; Oxidative Stress; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Population; Predisposition; Prevalence; Preventive; Proteins; Publishing; RNA Splicing; Regulation; Research; Risk stratification; Role; SHH gene; STAT5B gene; Sampling; Signal Pathway; Signal Transduction Pathway; Single Nucleotide Polymorphism; Stat5 protein; TP53 gene; Testing; Therapeutic; Tissue Sample; Tissues; Underserved Population; Validation; Variant; base; biomarker identification; cancer cell; cancer health disparity; caucasian American; cell growth; clinically relevant; clinically significant; cohort; colon cancer cell line; cytokine; design; differential expression; experience; health disparity; improved; innovation; insight; metastatic colorectal; mortality; next generation; novel; novel marker; outcome forecast; overexpression; public health relevance; response; transcription factor; transcriptome sequencing; treatment planning; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most lethal malignancy in the USA and affects over a million people every year. A significant CRC health disparity exists between African Americans (AA), American Indians (AI) and Caucasians (CA) in relation to its occurrence, drug response and mortality. Due to this, the overall mortality is highr among AA/AI compared to CA. However, the underlying molecular mechanisms of this disparity in AA/AI are not known. Therefore, it is highly imperative to understand the molecular basis and the identification of biomarker(s) that can be used for early stage diagnosis, metastasis and drug response to reduce this unacceptable health disparity. Our laboratory has identified a novel transmembrane mucin, MUC13, which is highly overexpressed/aberrantly localized in CRC and is involved in its pathogenesis. Additionally, our recent preliminary data suggest a markedly higher and aberrant expression of MUC13 in AA/AI CRC samples compared to CA counter parts. We have shown that MUC13 is an important modulator of several signal-transduction pathways and affects multiple key proteins involved in cell growth and survival, such as sonic hedgehog, HER2 and p53. Our published and preliminary studies have suggested an aberrant expression of MUC13 which has implications in CRC progression and metastasis. Based on these compelling evidence, we hypothesize that the differential/aberrant expression of MUC13 and/or MUC13 variants are underlying factors associated with CRC health disparity. In addition, we hypothesize this differential MUC13 expression is regulated by certain microRNAs (miR-145 and miR-132) and inflammatory mediators produced by the tumor microenvironment (e.g. interleukin-6 mediated STAT5B phosphorylation) resulting in malignant colorectal cancer cells phenotypes among AA/AI populations. Three specific aims with comprehensive experimental approach are proposed to test this hypothesis. In Aim 1, we propose to study the expression profile of MUC13 in Caucasians, African Americans and American Indians CRC tissues and its correlation with disease progression, metastasis and patient survival. Aim 2 will investigate the presence of MUC13 spliced variants/single nucleotide polymorphisms (SNPs) and their association with chemoresistance, metastasis and CRC health disparity. Aim 3 intends to elucidate the molecular mechanisms of MUC13 regulation in clinically relevant CRC tissues and cell line models. We will also investigate how various intrinsic factors can induce aberrant/ altered subcellular localization of MUC13, in clinically relevant CRC cell line models, as aberrant subcellular localization (cytoplasmic, nuclear) of MUC13 has also been associated with disease stage, prognosis and metastasis. The results of this multi factorial study will determine if MUC13 can be used as a molecular signature for early detection of aggressive and metastatic CRC in AA and AI. This comprehensive study will further provide important insights regarding MUC13 etiology in CRC and help in designing preventive and therapeutic strategies to reduce CRC mortality and CRC health disparity in underserved populations.

 描述（由适用提供）：结直肠癌（CRC）是美国第二大致命的恶性肿瘤，每年影响超过一百万。非洲裔美国人（AA），美国印第安人（AI）和高加索人（CA）之间存在重大的CRC健康差异，就其发生，药物反应和死亡率而言。因此，与CA相比，AA/AI的总死亡率很高。但是，尚不清楚这种差异的这种差异的基本分子机制。因此，必须理解可用于早期诊断，转移和药物反应的分子基础和生物标志物的鉴定，以降低这种不可接受的健康差异。我们的实验室已经确定了一种新型的跨膜粘蛋白MUC13，该粘蛋白高表达/异常位于CRC中，并参与其发病机理。此外，我们最近的初步数据表明，与CA计数器相比，AA/AI CRC样品在AA/AI CRC样品中的MUC13表达明显更高和异常。我们已经表明，MUC13是几种信号转导途径的重要调节剂，并且会影响与细胞生长和生存有关的多种关键蛋白，例如Sonic Hedgehog，Her2和p53。我们发表的初步研究表明，MUC13的异常表达对CRC的进展和转移具有影响。基于这些令人信服的证据，我们假设MUC13和/或MUC13变体的差异/异常表达是与CRC健康差异相关的基本因素。此外，我们假设这种差异MUC13表达受某些microRNA（miR-145和miR-132）和由肿瘤微环境产生的炎症介质（例如，脑介导的STAT5B光疗法）在AA/AI群中产生的恶性结论性癌细胞现象。提出了三个特定的目标，以全面的实验方法来检验这一假设。在AIM 1中，我们建议在高加索人，非裔美国人和美国印第安人CRC组织中研究MUC13的表达曲线及其与疾病进展，转移和患者生存的相关性。 AIM 2将研究MUC13剪接变体/单核肽多态性（SNP）的存在及其与化学抗性，转移和CRC健康差异的关联。目标3旨在阐明临床相关的CRC组织和细胞系模型中MUC13调控的分子机制。我们还将研究各种固有因素如何诱导MUC13的异常/改变临床相关的CRC细胞系模型的亚细胞定位，因为异常 MUC13的亚细胞定位（细胞质，核）也与疾病阶段，预后和转移有关。这项多因素研究的结果将确定MUC13是否可以用作分子特征，以早日检测AA和AI中的攻击性和转移性CRC。这项全面的研究将进一步提供有关CRC中MUC13病因的重要见解，并有助于设计预防和治疗策略，以降低服务不足人群中CRC死亡率和CRC健康差异。