The Role of MicroRNA in Hepatocarcinogenesis

MicroRNA在肝癌发生中的作用

• 批准号: 7268161
• 负责人: Kalpana Ghoshal
• 金额: $ 13.84万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-13 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268161
• 关键词: 3' Untranslated Regions; Age; Anchorage-Independent Growth; Animals; Anti-Sense Probes; Apoptosis; Base Pairing; Benign; Biological Markers; Biological Process; Caenorhabditis elegans; Cancer Etiology; Cell Cycle; Cell Line; Cell Proliferation; Cell physiology; Cells; Cessation of life; Characteristics; Choline; Development; Diagnostic; Diet; Down-Regulation; Drosophila genus; Etiology; Folate; Folic Acid; Functional RNA; Gene Silencing; Gene Targeting; Genes; Goals; Growth; Growth Factor; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; Human; Institutes; Invertebrates; Lead; Link; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Methionine; MicroRNAs; Microarray Analysis; Mission; Molecular Target; Monitor; Morphology; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Alcohol Abuse and Alcoholism; Neuronal Differentiation; Nodule; Northern Blotting; Nucleotides; Numbers; Oligonucleotides; Oncogenes; Oncogenic; Phenotype; Physiological; Plants; Play; Prevention; Primary carcinoma of the liver cells; Process; Prognostic Marker; Property; Protein Overexpression; Rattus; Regulation; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Role; Site; Small RNA; Time; Tissues; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; Untranslated RNA; Untranslated Regions; Viral Genome; Week; cancer therapy; embryonic stem cell; hepatoma cell; human disease; knock-down; novel; novel therapeutics; tumor

DESCRIPTION (provided by applicant): Our long term objective is to advance our understanding of the role of micro RNAs (miRNAs) in hepatocarcinogenesis. miRNAs are highly conserved -19-25 nucleotides noncoding RNAs some of expressed in plants and animals, are primarily involved in gene silencing. In animals, miRNAs function either by imperfect complimentary base pairing at multiple non-overlapping sites on 3'-UTRs of target genes or by mediating degradation of target mRNAs. The biological function of only a few miRNAs is known. Recent studies have shown that the expression of the miRNAs are differentially regulated in human cancers of different origins and the targets of some of the miRNAs act as oncogenes or tumor suppressor genes. Many miRNAs are expressed in a tissue-specific manner that is markedly altered in human cancers. The objective of this project is to elucidate the role of a liver specific micro RNA (mir-122a) in hepatocarcinogenesis. Hepatocellular carcinoma is the fifth most prevalent cancer in the world and is the third leading cause of cancer related death. Using miRNA microarray analysis we observed differential regulation of some miRNAs during the multistage hepatocarcinogenesis process induced in folate/methyl-deficient rats. Among these the expression of mir-122a, an abundant liver specific miRNA, was significantly down regulated in all tumors. Extension of this study to human primary hepatocellular carcinomas showed dramatic decrease in mir-122 expression in tumors. In the present study we will explore the role of mir-122a in hepatocyte differentiation and hepatocarcinogenesis. The specific aims of the present proposal are to: 1) measure expression of mir- 122a by real time RT-PCR or northern blot analysis in a large number of human HCCs to determine whether its down regulation is characteristic of HCC of specific etiology; 2) determine whether mir-122a is involved in hepatocyte differentiation in mouse ES cells or rat hepatocytes by antisense oligo and 3) investigate whether its overexpression in nonexpressing human hepatocellular carcinoma cell lines inhibits growth in culture and anchorage independent growth or promotes apoptosis. It is hoped that this study could establish mir-122a as a biomarker for hepatocellular carcinomas that can provide novel molecular target for liver cancer therapy. Further, this proposal fits well with the mission/goals set forth by multiple institutes that include NCI, NIDDK and NIAAA n the etiology, prevention and treatment of hepatocellular carcinomas.

描述（由申请人提供）：我们的长期目标是促进我们对微RNA（miRNA）在肝癌发生中的作用的理解。 miRNA是高度保守的-19-25核苷酸非编码RNA，其中一些在植物和动物中表达，主要参与基因沉默。在动物中，miRNA通过在3'-UTRS的靶基因的多个非重叠位点上的不完善基础配对来起作用，或者通过介导靶mRNA的降解。仅知道几个miRNA的生物学功能。最近的研究表明，在不同起源的人类癌症中，miRNA的表达受到差异调节，而某些miRNA的靶标充当了癌基因或肿瘤抑制基因。许多miRNA以组织特异性表达，在人类癌症中明显改变。该项目的目的是阐明肝特异性微RNA（miR-122a）在肝癌发生中的作用。肝细胞癌是世界上第五大癌症，并且是癌症相关死亡的第三主要原因。使用miRNA微阵列分析，我们观察到在叶酸/甲基缺陷型大鼠中诱导的多阶段肝癌发生过程中某些miRNA的差异调节。在这些肿瘤中，miR-122a的表达（一种丰富的肝特异性miRNA）被显着下调。这项研究向人类原发性肝细胞癌的扩展显示，肿瘤中miR-122表达的降低急剧下降。在本研究中，我们将探讨miR-122a在肝细胞分化和肝癌发生中的作用。本建议的具体目的是：1）通过实时RT-PCR或大量人类HCC中的实时RT-PCR或北印迹分析测量miR-122a的表达，以确定其下降调节是否是特定病因的HCC的特征； 2）确定miR-122a是否参与小鼠ES细胞中的肝细胞分化或大鼠肝细胞通过反义寡核酸酯和3）研究它在非X型人类肝细胞癌细胞系中的过表达是否抑制了培养和锚固独立生长或促进凋亡的人类肝细胞癌细胞系。希望这项研究可以将miR-122a建立为肝细胞癌的生物标志物，可以为肝癌治疗提供新颖的分子靶标。此外，该提案非常符合多个机构所提出的任务/目标，包括NCI，NIDDK和NIAAA N NIAAA N的病因，预防和治疗肝细胞癌。