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G-quadruplex in Translational Regulation and Cancer Therapy

G-四联体在翻译调控和癌症治疗中的应用

基本信息

批准号：
8494599
负责人：
HONG LU
金额：
$ 16.3万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494599
关键词：
5&apos Untranslated Regions Abbreviations Address Antineoplastic Agents Area Binding Bioinformatics CCAAT-Enhancer-Binding Proteins Cancer Patient Cause of Death Cell physiology Chemicals DNA Data Development Differentiation Therapy Disease Foundations Functional disorder G-Quartets Genes Genetic Transcription Goals Grant Hepatocarcinogenesis Hepatocyte Human Incidence Knowledge Ligands Literature Liver Liver Cirrhosis Liver Fibrosis Liver diseases Malignant Neoplasms Malignant neoplasm of liver Normal Cell Oncogenes Oncogenic Physiology Play Polyamines Porphyrins Primary carcinoma of the liver cells Protein C Proteins Reporting Resistance Role Solid Testing Toxic effect Translational Regulation Translations Tumor Suppressor Genes Tumor Suppressor Proteins United States Work analog cancer cell cancer therapy cytotoxic design hepatic nuclear factor 1 histone deacetylase 3 human NCOR1 protein improved innovation killings liver function novel novel strategies nucleic acid structure promoter protein expression protoporphyrin IX restoration small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long term goal is to develop novel therapy for liver cancer through simultaneously treating liver cancer and improving liver function, because most liver cancer patients have liver cirrhosis. A group of liver-enriched transcription factors (TFs) are master regulators of liver development and liver function, and they are tumor- suppressors down-regulated during liver carcinogenesis. Literature reports strongly suggest that restoration of the master regulator HNF4? can treat not only liver cancer, but also liver fibrosis. However, like many important oncogenes and tumor-suppressors, HNF4? is a TF that lacks known activating ligand; how to modulate "undruggable" TFs to treat cancer is a huge challenge. Chemicals have been developed to silence "undruggable" oncogenes via stabilizing a special nucleic acid structure, G-quadruplex (G4) in gene promoter. However, the lack of selectivity of G4-stabilizing chemicals toward normal cells is a bottleneck in developing G4-stabilizing chemicals as novel anticancer drugs. Our preliminary data strongly suggest that G4 motif within 5' untranslated region (UTR) is critical in suppressing protein translation of HNF4? and certain liver- enriched essential TFs. The objective of this proposal is to elucidate the importance of G4 motif within 5' UTR in translational regulation of liver-enriched TFs and cancer therapy. The central hypothesis is that G4 motifs in 5' UTR of these master regulators play a key role in suppressing their protein expression. Thus, we can increase protein expression of these master regulators using small molecules or G4 DNA oligos to destabilize G4 within 5' UTR or competitively inhibit G4-interacting proteins. This will be an exciting innovative approach to trea liver cancer and improve liver function simultaneously. This central hypothesis will be tested in 3 specific aims. Aim 1 will determine mechanism of suppression of protein expression of HNF4?1 by its 5' UTR. The working hypothesis is that formation of G4 motif within 5' UTR is essential in inhibiting protein expression. Aim 2 will determine role of G4 motif within 5' UTR of human HNF1?, HNF3?, C/EBP?, C/EBP?, HDAC3, NCOR1, and p53 in regulating protein expression. The working hypothesis is that G4 motif within 5' UTR is essential in suppressing protein expression of these TFs. Aim 3 will determine effects of G4-interacting chemicals and G4 oligos from 5' UTR of above 8 human TFs on protein expression of these TFs. The working hypothesis is that TMPYP4, polyamines, and protoporphyrin IX inhibits, whereas certain G4 DNA oligos increase protein expression of these TFs in hepatoma/hepatocytes. This study is highly novel, because it is the first to address the importance of an important nucleic acid structure, G4 in regulating the protein expression of a group of essential liver-enriched TFs. This study is highly significant, because results from this study will not only provide important novel knowledge, but also greatly aid the rational design of G4- interacting anticancer drugs, and help to develop a paradigm-shift approach to coordinately target otherwise "undruggable" essential liver-enriched TFs to simultaneously treat liver cancer and improve liver function.

描述（申请人提供）：长期目标是通过同时治疗肝癌和改善肝功能来开发新的肝癌治疗方法，因为大多数肝癌患者都有肝硬化。富肝转录因子是肝脏发育和肝功能的主要调控因子，是肝癌发生过程中下调的抑瘤因子。文献报道强烈建议恢复主调控因子HNF4？不仅能治疗肝癌，还能治疗肝纤维化。