MUC13 Mucin in Colerectal Cancer Health Disparity

 描述(申请人提供)：结直肠癌(CRC)是美国第二大致命性恶性肿瘤，每年影响100多万人。在非裔美国人(AA)、美洲印第安人(AI)和高加索人(CA)之间，结直肠癌的发生、药物反应和死亡率存在显著的健康差异。因此，与CA相比，AA/AI的总体死亡率更高。然而，AA/AI中这种差异的潜在分子机制尚不清楚。因此，了解可用于早期诊断、转移和药物反应的生物标志物(S)的分子基础和鉴定，以缩小这种不可接受的健康差距是非常必要的。我们实验室发现了一种新的跨膜粘蛋白MUC13，它在结直肠癌中高表达/异常定位，并参与其发病机制。此外，我们最近的初步数据显示，与CA对应的部分相比，MUC13在AA/AI CRC样本中的异常表达显著增加。我们已经证明，MUC13是几个信号转导通路的重要调节器，并影响参与细胞生长和生存的多个关键蛋白，如Sonic Hedgehog、HER2和P53。我们已发表的和初步的研究表明，MUC13的异常表达与结直肠癌的进展和转移有关。基于这些令人信服的证据，我们假设MUC13和/或MUC13变异的差异/异常表达是与结直肠癌健康差异相关的潜在因素。此外，我们假设这种差异MUC13表达受某些microRNAs(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STAT5B磷酸化)调节，导致AA/AI人群中的恶性结直肠癌细胞表型。为了验证这一假说，本文提出了三个具体的实验目标和综合实验方法。在目的1中，我们建议研究MUC13在高加索人、非裔美国人和美洲印第安人结直肠癌组织中的表达及其与疾病进展、转移和患者生存的关系。目的2研究MUC13剪接变异体/单核苷酸多态(SNPs)的存在及其与化疗耐药、转移和结直肠癌健康差异的关系。目的3阐明MUC13在临床相关结直肠癌组织和细胞系模型中的调控分子机制。我们还将研究各种内在因素如何在临床相关的大肠癌细胞系模型中诱导MUC13作为异常的亚细胞定位。 MUC13的亚细胞定位(胞浆、胞核)也与疾病分期、预后和转移有关。这项多因素研究的结果将决定MUC13是否可以作为早期检测AA和AI侵袭性和转移性CRC的分子标志。这项全面的研究将进一步提供有关结直肠癌MUC13病因学的重要见解，并有助于设计预防和治疗策略，以减少服务不足人群的结直肠癌死亡率和结直肠癌健康差距。

 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.