Id1/IGF2/IGF1R/PI3K/AKT signaling cascade as functional markers and therapeutic targets in esophageal cancer

Abstract

BACKGROUND: Mounting evidence suggests that growth factors secreted by cancer cells play important roles in cancer progression. Id1 is commonly overexpressed in solid tumors including esophageal squamous cell carcinoma (ESCC). PURPOSE/OBJECTIVE: We aim to determine if the functions of Id1 in promoting cancer progression and chemoresistance are mediated by growth factors, investigate the autocrine/endocrine effects of the key Id1-induced growth factor, and evaluate the treatment efficiency of relevant anticancer therapeutic strategies. MATERIALS AND METHODS: Antibody array-based screening was used to identify differentially secreted growth factors from Id1-overexpressing ESCC cells. In vitro and in vivo assays were performed to confirm the induction of IGF2 by Id1, and to study the autocrine and endocrine effects of IGF2 in promoting ESCC progression. Human ESCC tissue microarray was analyzed for overexpression of IGF2 and its correlation with that of Id1 and p-AKT. Fluorouracil (5-FU)-resistant ESCC sublines were established by treating cells with increasing doses of 5-FU, and gene expression profiles were compared with the parental cells by cDNA microarray. The anti-tumor and anti-metastatic efficacies of IGF2 antibody and PI3K inhibitor wortmannin were evaluated using tumor xenograft and experimental metastasis models. RESULTS: Id1 overexpression induced IGF2 secretion which promoted cancer cell proliferation, survival and invasion by activating AKT in an autocrine manner. IGF2 secreted by Id1-overexpressing ESCC xenograft could instigate the growth of distant esophageal tumors, as well as promote metastasis of circulating cancer cells in an endocrine manner. Tissue microarray data showed overexpression of IGF2 in 21/35 (60%) human ESCC tissues which was associated with up-regulation of Id1 and p-AKT. Moreover, Id1 was identified by cDNA microarray analysis as being up-regulated in 5-FUresistant ESCC sublines; gain- and loss-of-function experiments confirmed its importance in increasing chemoresistance. We found that IGF2 antibody and wortmannin treatment significantly suppressed tumor growth, metastasis, and chemoresistance in mouse models. CONCLUSIONS: Our study demonstrated that the Id1/IGF2/PI3K/AKT signaling cascade plays an important role in esophageal cancer progression and chemoresistance. Blockade of IGF2/PI3K/AKT signaling has therapeutic potential in the management of esophageal cancer.