MUC13 Mucin in Colorectal Cancer Health Disparity

 描述（由申请人提供）：结直肠癌（CRC）是美国第二大致命恶性肿瘤，每年影响超过一百万人。在非裔美国人（AA）、美洲印第安人（AI）和高加索人（CA）之间，CRC的发生率、药物反应和死亡率存在显著差异。因此，AA/AI的总体死亡率高于CA。然而，AA/AI这种差异的潜在分子机制尚不清楚。因此，非常有必要了解可用于早期诊断、转移和药物反应的生物标志物的分子基础和鉴定，以减少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的跨膜粘蛋白，MUC 13，这是高度过表达/异常定位在CRC，并参与其发病机制。此外，我们最近的初步数据表明，与CA对应物相比，AA/AI CRC样品中MUC 13的表达显著更高且异常。我们已经证明MUC 13是几种信号转导途径的重要调节剂，并影响参与细胞生长和存活的多种关键蛋白，如Sonic Hedgehog，HER 2和p53。我们已发表的和初步的研究表明，MUC 13的异常表达与CRC的进展和转移有关。基于这些令人信服的证据，我们假设MUC 13和/或MUC 13变体的差异/异常表达是与CRC健康差异相关的潜在因素。此外，我们假设这种差异MUC 13表达受某些microRNA（miR-145和miR-132）和肿瘤微环境产生的炎症介质（例如白细胞介素-6介导的STAT 5 B磷酸化）调节，导致AA/AI人群中的恶性结直肠癌细胞表型。提出了三个具体的目标与综合实验方法来验证这一假设。在目标1中，我们提出研究MUC 13在高加索人、非洲裔美国人和美洲印第安人CRC组织中的表达谱及其与疾病进展、转移和患者生存的相关性。目的2将研究MUC 13剪接变异体/单核苷酸多态性（SNP）的存在及其与化疗耐药性、转移和CRC健康差异的相关性。目的3旨在阐明临床相关CRC组织和细胞系模型中MUC 13调控的分子机制。我们还将研究各种内在因素如何在临床相关的CRC细胞系模型中诱导MUC 13的异常/改变的亚细胞定位，作为异常的 MUC 13的亚细胞定位（细胞质、细胞核）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MUC 13是否可以用作AA和AI中侵袭性和转移性CRC早期检测的分子特征。这项全面的研究将进一步提供关于CRC中MUC 13病因学的重要见解，并有助于设计预防和治疗策略，以降低CRC死亡率和服务不足人群的CRC健康差异。

 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.