Molecular Mechanism of miR-140 in Colon Cancer

miR-140在结肠癌中的分子机制

• 批准号: 8185001
• 负责人: JINGFANG JU
• 金额: $ 41.2万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185001
• 关键词: Binding; CD44 gene; CXCL12 gene; Cancer Patient; Cell Cycle Regulation; Cell Proliferation; Cells; Chondrocytes; Colon Carcinoma; Development; Diagnostic Neoplasm Staging; Extracellular Matrix; Failure; Fluorouracil; Functional RNA; Genes; Goals; Growth; Growth Factor; Human; IGFBP5 gene; Immunoprecipitation; In Vitro; Individual; Insulin-Like Growth Factor Binding Protein 5; Interleukin-1; Interleukin-4; Lead; Malignant Neoplasms; Messenger RNA; Metastatic Neoplasm to the Liver; Methotrexate; MicroRNAs; Mission; Molecular; Molecular Target; Mus; National Cancer Institute; Neoplasm Metastasis; Oligonucleotides; Pathway interactions; Patients; Pharmaceutical Preparations; Population; RNA; Regulation; Resistance; Systemic Therapy; Systemic disease; Therapeutic; Transcript; Transcriptional Activation; Translations; Tumor Biology; Tumor Cell Invasion; Tumor stage; Western Blotting; base; cancer cell; cancer stem cell; cell motility; cellular transduction; chemokine; chemotherapy; cytokine; cytotoxic; digital; follow-up; human HDAC4 protein; improved; in vivo; knock-down; migration; mouse model; next generation; novel; novel strategies; oxaliplatin; resistance mechanism; stem; stem cell population; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): The ultimate goal of this project is to elucidate the molecular and cellular regulatory mechanisms of miR-140 in colon cancer. Human colon cancer is highly heterogeneous, and systemic drug treatment is almost never able to cure individuals with late stage tumors. One major reason for the failure of chemotherapy is the resistant cancer stem cell population: current chemotherapeutics target rapidly dividing cancer cells, but cancer stem cells divide slowly, and thus are relatively resistant to cytotoxic systemic therapies. Our recent studies showed that several non-coding miRNAs are involved in the resistance mechanism in colon cancer stem cells. In particular, we demonstrated that the cell proliferation of differentiated colon cancer cells was significantly reduced by over- expressing miR-140. As a result, these cells became more resistant to 5-fluorouracil (5-FU) or methotrexate (MTX) treatment. We further revealed that the expression of miR-140 was elevated in a small population of CD133+HICD44+HI colon cancer stem-like cells. These cells are highly resistant to 5-FU treatment, and by blocking miR-140 activity using anti-miR140 oligonucleotides, we were able to increase chemosensitivity to 5-FU (1). We also discovered that one of the key targets of miR-140 is histone deacetylase 4 (HDAC4), implying that miR-140 could potentially modulate transcriptional activation of genes involved in cell cycle control through HDAC4. Given the potential of this new paradigm whereby miRNAs, acting post-transcriptionally, can impact pathways leading to cancer growth and altered chemosensitivity, to offer new options for treatment, it is essential to follow up and extend our findings: We therefore propose three specific aims: (1) To investigate the mechanisms of miR-140 in contributing to proliferation, differentiation and chemoresistance in CD133+HICD44+HI colon cancer stem cells in vitro and in vivo; (2) To investigate the impact of miR-140 on colon cancer metastasis; and (3) To define the molecular targets and interaction networks impacted by miR-140, taking advantage of a powerful new approach, TrIP-Seq, to identify miRNA regulation at the translational level, even in small stem cell populations. This proposed project will provide the molecular basis for developing miR-140-based therapeutic strategies to overcome chemoresistance in colon cancer stem cells and to improve patient survival. PUBLIC HEALTH RELEVANCE: This project will help to develop a new paradigm in our current understanding of the tumor biology as it relates to miR-140 function. This, in turn, may lead to the development of novel targeted therapies to colon cancer stem cells and enhance our understanding of chemoresistance in cancer, which fits the scope of the National Cancer Institute's mission to eliminate cancer.

描述（由申请人提供）：本项目的最终目标是阐明miR-140在结肠癌中的分子和细胞调控机制。人类结肠癌是高度异质性的，并且全身性药物治疗几乎永远无法治愈患有晚期肿瘤的个体。化疗失败的一个主要原因是耐药的癌症干细胞群体：目前的化疗药物靶向快速分裂的癌细胞，但癌症干细胞分裂缓慢，因此对细胞毒性全身治疗相对具有抗性。我们最近的研究表明，几个非编码miRNA参与了结肠癌干细胞的耐药机制。特别地，我们证明了分化的结肠癌细胞的细胞增殖通过过表达miR-140而显著降低。结果，这些细胞变得对5-氟尿嘧啶（5-FU）或甲氨蝶呤（MTX）治疗更具抗性。我们进一步揭示了miR-140的表达在一小群CD 133 + CD 44 +HI结肠癌干细胞样细胞中升高。这些细胞对5-FU治疗具有高度抗性，通过使用抗miR-140寡核苷酸阻断miR-140活性，我们能够增加对5-FU的化疗敏感性（1）。我们还发现，miR-140的关键靶点之一是组蛋白脱乙酰酶4（HDAC 4），这意味着miR-140可能通过HDAC 4调节参与细胞周期控制的基因的转录激活。鉴于这种新范式的潜力，即转录后作用的miRNA可以影响导致癌症生长和改变化学敏感性的途径，为治疗提供新的选择，因此有必要跟进和扩展我们的发现：因此，我们提出了三个具体目标：（1）研究miR-140促进细胞增殖的机制，（2）探讨miR-140对结肠癌转移的影响;（3）利用TrIP-Seq方法，在翻译水平上确定miR-140调控的分子靶点和相互作用网络，即使是在小的干细胞群体中。 该项目将为开发基于miR-140的治疗策略提供分子基础，以克服结肠癌干细胞的耐药性并提高患者的生存率。 公共卫生关系：该项目将有助于在我们目前对肿瘤生物学的理解中开发一种新的范式，因为它与miR-140功能有关。反过来，这可能会导致开发针对结肠癌干细胞的新型靶向疗法，并增强我们对癌症耐药性的理解，这符合美国国家癌症研究所消除癌症的使命的范围。