MicroRNA and colorectal cancer chemoprevention

MicroRNA 与结直肠癌化学预防

• 批准号: 9313603
• 负责人: Yaguang Xi
• 金额: $ 33.4万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313603
• 关键词: Address; Adenomatous Polyposis Coli; Adverse effects; American Cancer Society; Amides; Angiogenesis Inhibition; Animal Model; Antineoplastic Agents; Apoptosis; Apoptotic; Aspirin; BCL2 gene; BIRC4 gene; Benzylamines; Biological Assay; Biological Markers; Biological Process; Breast Cancer Cell; Cancer Patient; Cause of Death; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Chemoprotection; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Colonic Neoplasms; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Data; Development; E-Cadherin; Epidemiologic Studies; Epithelial; Gene Expression; General Population; Genes; Health; Human; Image; Immunohistochemistry; In Situ Hybridization; In Vitro; Incidence; Individual; Induction of Apoptosis; Inhibition of Apoptosis; Malignant Neoplasms; Measures; Mediating; Mediation; Mesenchymal; Meta-Analysis; Metastasis Induction; MicroRNAs; Molecular; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Play; Premalignant; Prevention; Prostaglandin-Endoperoxide Synthase; Publications; RNA Processing; Randomized Controlled Clinical Trials; Regulator Genes; Reporting; Research; Risk; Role; Signal Pathway; Snails; Sulindac; Sulindac Sulfide; System; Technology; Tissue Microarray; Toxic effect; Transcription Repressor/Corepressor; Tumor Cell Invasion; Tumor Suppressor Proteins; United States; Untranslated RNA; adenoma; advanced disease; anticancer activity; base; cancer cell; cancer chemoprevention; cancer initiation; cancer statistics; cell growth; chromatin immunoprecipitation; clinically relevant; colon cancer patients; colorectal cancer prevention; cytotoxic; effective therapy; genome editing; improved; in vitro Model; in vivo; mouse model; neoplastic cell; new therapeutic target; novel; pre-clinical; preclinical study; prevent; response; tumor; tumor progression

DESCRIPTION (provided by applicant): According to the latest report of cancer statistics by American Cancer Society, colorectal cancer remains a leading cause of death from cancer in the United States. Therefore, there is still an unmet need to develop safer and more efficacious agents for treatment and prevention of colorectal cancer. Numerous studies report that the nonsteroidal anti-inflammatory drug (NSAID), sulindac is highly effective for the treatment of precancerous adenomas in individuals with familial adenomatous polyposis and shows promising anticancer activity in preclinical animal models; however, the adverse side effects resulting from cyclooxygenase (COX) inhibition limit the long-term use of sulindac for chemoprevention. Our previous studies reported that two non- COX inhibitory derivatives, sulindac sulfide amide (SSA) and sulindac benzylamine (SBA), can inhibit colorectal tumor cell growth with better potency and improved efficacy when compared to sulindac sulfide (SS).These results imply that anticancer activity of sulindac might attribute to other underlying mechanisms distinct from COX inhibition. In this application, we will aim at anticancer activity of SSA and SBA in prevention of colorectal tumor progression and metastasis, and focus on mechanism of action. Our recent results show that SS at sub-cytotoxic concentrations can efficiently inhibit the invasion of human colon tumor cells, which suggest that this drug may inhibit biological processes associated with metastasis. The mechanism of action appears to involve microRNAs (miRNAs), which are a set of small non-coding RNA molecules acting as master regulators of gene expression. A tumor suppressor miRNA, miR-200, was found to be up-regulated by SS and its non-COX inhibitory derivatives through the signaling pathway mediated by the transcriptional repressor snail. Given the documented tumor suppressive roles in promotion of apoptosis and inhibition of metastasis, we hypothesize that miR-200 is a key factor to mediate the non-COX anticancer activity of SSA and SBA for prevention of colorectal cancer. Three specific aims are proposed to address this hypothesis are: (1) to study the mechanistic basis of miR-200 in mediation of anticancer activities of SSA and SBA in vitro; (2) to study the role of miR-200 in mediating anticancer activities of sulindac in vivo; (3) to assess the clinical relevance of snail/miR-200/E-cadherin to human colorectal cancer progression. This application is being submitted in response to PA-12-213 and will address two research objectives: "determine the molecular pathways targeted by non-coding RNAs (ncRNAs) that predispose to cancer initiation or progression" and "determine whether interfering with oncogenic ncRNAs processing, target selection, or associated pathways prevent cancer progression". The proposed studies have the potential to impact human health by: 1) providing a mechanistic rationale in support of an ongoing national clinical trial studying prevention of colorectal cancer metastasis by sulindac; 2) evaluating novel non-COX inhibitory directives of sulindac to accelerate their preclinical development; and 3) identifying new therapeutic targets and/or biomarkers for clinical trials.

描述(申请人提供)：根据美国癌症协会最新的癌症统计报告，结直肠癌仍然是美国癌症死亡的主要原因。因此，开发更安全、更有效的治疗和预防结直肠癌药物的需求仍然没有得到满足。大量研究报道，非甾体抗炎药舒林酸对家族性腺瘤性息肉病患者的癌前病变有很高的治疗效果，并在临床前动物模型中显示出良好的抗癌活性；然而，环氧合酶(COX)抑制所产生的副作用限制了舒林酸用于化学预防的长期使用。我们以前的研究报道了两种非COX抑制衍生物，舒林酸硫胺(SSA)和舒林酸苯甲胺(SBA)，与舒林酸硫化物(SS)相比，可以更有效地抑制结直肠癌细胞的生长。这些结果表明，舒林酸的抗癌活性可能归因于其他不同于COX抑制的潜在机制。在本申请中，我们将针对抗癌活性 SSA和SBA在预防结直肠癌进展和转移中的作用，并重点阐述其作用机制。我们最近的研究结果表明，在亚细胞毒性浓度下，SS可以有效地抑制人结肠肿瘤细胞的侵袭，这表明该药物可能抑制与转移相关的生物学过程。其作用机制似乎涉及到microRNAs(MiRNAs)，这是一组作为基因表达主要调节因子的非编码小RNA分子。肿瘤抑制因子miR-200被发现通过转录抑制因子Snail介导的信号通路被SS及其非COX抑制衍生物上调。鉴于已知的肿瘤抑制作用在促进细胞凋亡和抑制转移方面的作用，我们假设miR-200是介导SSA和SBA预防结直肠癌的非COX抗癌活性的关键因素。针对这一假设，我们提出了三个具体的目标：(1)研究miR-200在介导SSA和SBA体外抗癌活性中的机制；(2)研究miR-200在介导舒林酸体内抗癌活性中的作用；(3)评估Snail/miR-200/E-cadherin与结直肠癌进展的临床相关性。这项申请是应PA-12-213的要求提交的，将涉及两个研究目标：“确定非编码RNA(NcRNAs)靶向的、易导致癌症发生或进展的分子途径”和“确定干扰致癌ncRNAs的处理、靶点选择或相关途径是否能阻止癌症进展”。拟议中的研究有可能通过以下方面影响人类健康：1)为正在进行的研究舒林酸预防结直肠癌转移的全国性临床试验提供机制基础；2)评估舒林酸的新的非COX抑制指令，以加速其临床前开发；以及3)为临床试验确定新的治疗靶点和/或生物标记物。