ERRP is downregulated in colon cancer, and is a potential anti-tumor agent.

Abstract

3791

EGF-Receptor Related Protein (ERRP), a novel “negative regulator” of EGFR, possesses ∼90% homology to the extracellular domain of the receptor. ERRP binds EGFR ligands forming inactive heterodimers leading to inhibition of EGFR signaling. Here, we examined ERRP expression in benign colon, tubular adenomas and adenocarcinomas. We also investigated in vitro and in vivo effects of ERRP on tumor growth. SCID mice were xenotransplanted with colon cancer HCT-116 cells and treated with recombinant ERRP or vehicle. For in vitro studies, HCT-116 cells were exposed to recombinant ERRP or vehicle, followed by determination of cell cycle and apoptosis. 35 cases of colonic adenocarcinoma and 10 adenomatous polyps were examined with anti-ERRP antibodies. Normal colonic mucosa demonstrated strong supranuclear and membranous staining for ERRP. The tumors showed a diffused cytoplasmic staining which was inversely associated with tumor grade. The staining score was significantly lower in the high-grade carcinoma compared to well-differentiated carcinomas; the intramucosal carcinomas displayed weaker staining. Low-grade dysplastic adenomas retained strong staining when compared with the high grade dysplastic areas. Exposure of HCT-116 cells to recombinant ERRP demonstrated a G0/G1 arrest and increased apoptosis. ERRP treatment of SCID mice bearing HCT-116 derived tumors showed significant tumor growth retardation. The apoptotic rate in the ERRP treated tumor was significantly higher than the controls, as evidenced by reduced phospho-Akt and elevated levels of activated caspase 3. In addition, MAP kinase activation was down-regulated in ERRP treated tumors. In conclusion, ERRP is differentially expressed in colonic adenocarcinomas, with diminished expression in high-grade carcinomas. ERRP causes apoptosis and cell cycle arrest and tumor growth delay in vivo. We propose that ERRP is a potential therapeutic agent for colorectal cancer.