Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3

Abstract

Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most upregulated gene. IGFBP-3 regulates cell proliferation through both insulinlike growth factor-dependent and independent mechanisms. We found that IGFBP-3 mRNA and protein expression was increased in EGFRoverexpressing primary and immortalized human esophageal cells. IG-FBP-3 was also up-regulated in EGFR-overexpressing cells in organotypic culture and in EGFR transgenic mice. Furthermore, IGFBP-3 mRNA was overexpressed in 80% of primary esophageal squamous cell carcinomas and 60% of primary esophageal adenocarcinomas. Concomitant upregulation of EGFR and IGFBP-3 was observed in 60% of primary esophageal squamous cell carcinomas. Immunohistochemistry revealed cytoplasmic localization of IGFBP-3 in the preponderance of preneoplastic and neoplastic esophageal lesions. IGFBP-3 was also overexpressed in esophageal cancer cell lines at both mRNA (60%) and protein (40%) levels. IGFBP-3 secreted by cancer cells was capable of binding to insulinlike growth factor I. Functionally, epidermal growth factor appeared to regulate IGFBP-3 expression in esophageal cancer cell lines. Finally, suppression of IGFBP-3 by small interfering RNA augmented cell proliferation, suggesting that IGFBP-3 may inhibit tumor cell proliferation as a negative feedback mechanism. In aggregate, we have identified for the first time that IGFBP-3 is an aberrantly regulated gene through the EGFR signaling pathway and it may modulate EGFR effects during carcinogenesis.

Interplay between microRNA-17-5p, insulin-like growth factor-II through binding protein-3 in hepatocellular carcinoma

“…miR-17-5p was markedly downregulated ( Figure 1A) while IGFBP-3 was significantly upregulated ( Figure 1B) in the nonmetastatic liver tissues of HCC patients compared to healthy controls. This goes in line with previous studies showing IGFBP-3 to be highly expressed in breast and esophageal cancer [21,22] . But on the other hand, it contradicts other studies that reported reduced IGFBP-3 mRNA expression and protein levels in metastatic HCC patients [12,13] .…”

Aberrant promoter methylation of insulin‐like growth factor binding protein‐3 gene in human cancers

“…34 One explanation for the overexpression of IGFBP-3 in malignancies is that IGFBP-3 may inhibit tumor cell proliferation via a negative feedback mechanism. 37,[39][40][41][42] Another possibility is that unknown defects in IGFBP-3 receptor function may lead to IGFBP-3 overexpression in these tumors. 22 Overall, the expression and function of IGFBP-3 may differ according to the type of malignancy.…”

Growth Factors, Signal Transduction Pathways, and Tumor Suppressor Genes in Esophageal Cancer

“…The EGFR family composes of four members: EGFR (HER-1, erbB-1), HER2 (erbB-2, Neu), HER3 (erbB-3) and HER4 (erbB-4) [4,18], all of which are tyrosine kinase receptors that are activated by ligand-induced homo or hetero dimerization. Overexpression of EGFRs is common in esophageal cancer and has been reported in several cell lines of SCCE, 29-92% of tumor samples of SCCE [19,20] and 80% of patients with adeno and squamous cell carcinoma [21,22]. EGFR upregulation correlates with poor prognosis, low survival rate and minimal response to chemotherapy [20,[23][24][25].…”