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.
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