The molecular regulation of IGFBP-3 in esophageal epthelial cells

IGFBP-3在食管上皮细胞中的分子调控

• 批准号: 7320953
• 负责人: Hiroshi Nakagawa
• 金额: $ 27.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-07 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320953
• 关键词: Acids; Adenocarcinoma; Apoptosis; Basal Cell; Binding; Biological; Bioluminescence; Cells; Complex; Condition; Data; EGFR Protein Overexpression; Energy Supply; Energy-Generating Resources; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cell Proliferation; Epithelium; Esophageal; Esophageal Neoplasms; Esophagus; Fostering; Gene Transfer; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Hypoxia; Hypoxia Inducible Factor; Image; In Vitro; Infection; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth-Factor-Binding Proteins; Intervention; Invasive; Ischemia; Laboratories; Lesion; Malignant neoplasm of esophagus; Mediating; Messenger RNA; Modeling; Molecular; Oxygen; Pathologic Processes; Peptides; Physiological; Play; Proliferating; Protein Biosynthesis; Protein Overexpression; Proteins; RNA Interference; Radiation; Reflux; Regulation; Research Personnel; Resistance; Response Elements; Role; Signal Pathway; Signal Transduction; Site; Somatomedins; Squamous cell carcinoma; Staging; Surface; System; TP53 gene; Technology; Tetracycline; Tetracyclines; Tissues; Transcriptional Regulation; Transfer RNA; Translating; Translation Initiation; Translations; Transplantation; Tumor Biology; Tumor Suppressor Genes; Tumor Tissue; Xenograft procedure; base; carcinogenesis; chemotherapy; human FRAP1 protein; in vivo; innovation; insight; interest; migration; neoplastic cell; programs; tumor; tumor growth; tumor initiation

DESCRIPTION (provided by applicant): The esophageal epithelium contains proliferating basal cells that undergo differentiation as they migrate towards the luminal surface, where they slough off due to apoptosis. The epithelium is renewed continuously, but it is this constant state of renewal that makes the epithelium so susceptible to injurious insults, such as infection, acid reflux, radiation, chemotherapy, and ischemia. Peptide growth factors such as epidermal growth factor (EGF) and insulin-like growth factor (IGF)-I regulate esophageal epithelial cell proliferation, growth, migration, differentiation, and apoptosis. They also play a critical role in pathological processes such as carcinogenesis. Amongst the IGF binding proteins, IGFBP-3 is a major negative regulator of the bioactivities of IGF. Both IGF-I and IGF-II are implicated in esophageal cancer. The present proposal focuses upon insulin like growth factor binding protein-3 (IGFBP-3). IGFBP-3 binds insulin-like growth factors (IGFs) and regulates their bioactivities. IGFBP-3 is induced by hypoxia and suppressed by EGFR as shown by us. In the esophagus, IGFBP-3 is often upregulated in preneoplastic lesions and frequently overexpressed in invasive adenocarcinomas and squamous cell carcinomas with concurrent EGFR overexpression. However, the biological role(s) of IGFBP-3 and the mode of its regulation are not known in esophageal tumors. Our fundamental hypothesis is that IGFBP-3 plays a critical role in esophageal tumor growth under hypoxic conditions in the microenvironment. When the esophageal epithelium is maintained in a physiological milieu in the presence of growth factors (e.g. EGF) and a normal level of oxygen, IGFBP-3 is inactive and permissive for the full activation of the IGF-signaling pathway. However, in esophageal tumors, hypoxia fosters IGFBP-3 induction. IGFBP-3 gene is transcriptionally activated by hypoxia inducible factor (HIF). IGFBP-3 mRNA is translated in cap-dependent as well as cap-independent manners, while the latter is activated under severe hypoxic conditions to permit selective IGFBP-3 protein synthesis. Once expressed and secreted, IGFBP-3 neutralizes IGF and exerts antiproliferative or proapoptotic effects in tumor cells. However, in a subset of esophageal tumor cells, which have adapted to a hypoxic microenvironment, such tumor cells can proliferate autonomous of IGF even in the presence of IGFBP-3. Inhibition of IGF signaling by IGFBP-3 may benefit tumor cells by suppressing cellular anabolic activities to make them dormant in the absence of sufficient oxygen supply and energy sources. This hypothesis will be pursued through the following interrelated Specific Aims since it is important to understand the role and regulation of IGFBP-3 in esophageal tumor biology: (1) Specific Aim 1: To determine the role of IGFBP-3 in esophageal tumor biology; (2) Specific Aim 2: To elucidate the role of HIF1a in the transcriptional regulation of IGFBP-3; and (3) Specific Aim 3: To determine how hypoxia regulates the translation of IGFBP-3.

描述（由申请人提供）：食管上皮含有增殖的基底细胞，这些细胞在向管腔表面迁移时经历分化，并在管腔表面因细胞凋亡而脱落。上皮不断更新，但正是这种持续的更新状态使得上皮如此容易受到伤害性损伤，例如感染、胃酸反流、放射、化疗和缺血。表皮生长因子（EGF）和胰岛素样生长因子（IGF）-I等肽生长因子调节食管上皮细胞的增殖、生长、迁移、分化和凋亡。它们还在致癌等病理过程中发挥着关键作用。在 IGF 结合蛋白中，IGFBP-3 是 IGF 生物活性的主要负调节因子。 IGF-I 和 IGF-II 均与食道癌有关。目前的提案重点关注胰岛素样生长因子结合蛋白 3 (IGFBP-3)。 IGFBP-3 结合胰岛素样生长因子 (IGF) 并调节其生物活性。正如我们所表明的，IGFBP-3 由缺氧诱导并被 EGFR 抑制。在食管中，IGFBP-3 在癌前病变中经常上调，并且在侵袭性腺癌和鳞状细胞癌中经常过度表达，同时 EGFR 过度表达。然而，IGFBP-3 在食管肿瘤中的生物学作用及其调节模式尚不清楚。我们的基本假设是 IGFBP-3 在微环境缺氧条件下的食管肿瘤生长中发挥着关键作用。当食管上皮在存在生长因子（例如 EGF）和正常氧气水平的情况下维持在生理环境中时，IGFBP-3 处于非活性状态并允许 IGF 信号通路的完全激活。然而，在食管肿瘤中，缺氧会促进 IGFBP-3 的诱导。 IGFBP-3 基因由缺氧诱导因子 (HIF) 转录激活。 IGFBP-3 mRNA 以帽依赖性和帽非依赖性方式翻译，而后者在严重缺氧条件下被激活，以允许选择性 IGFBP-3 蛋白合成。一旦表达和分泌，IGFBP-3 就会中和 IGF，并在肿瘤细胞中发挥抗增殖或促凋亡作用。然而，在已经适应低氧微环境的食管肿瘤细胞亚群中，即使存在 IGFBP-3，此类肿瘤细胞也可以自主增殖。 IGFBP-3 对 IGF 信号传导的抑制可能通过抑制细胞合成代谢活动使肿瘤细胞在缺乏足够的氧气供应和能源的情况下处于休眠状态而有益于肿瘤细胞。由于了解 IGFBP-3 在食管肿瘤生物学中的作用和调节非常重要，因此将通过以下相互关联的具体目标来追求该假设： (1) 具体目标 1：确定 IGFBP-3 在食管肿瘤生物学中的作用； （2）具体目标2：阐明HIF1a在IGFBP-3转录调控中的作用； (3) 具体目标 3：确定缺氧如何调节 IGFBP-3 的翻译。