Olfactomedin 4- a key regulator of human neutrophil function, role in small intestinal adenocarcinoma.

National Heart, Lung, And Blood Institute

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Abstract

Small intestine adenocarcinoma is a rare intestinal malignancy with distinct clinical, pathological, and molecular characteristics. Recently, a fusion of the intestinal stem-cell marker olfactomedin 4 (OLFM4) and the proto-oncogene RET has been identified in a small intestine adenocarcinoma patient. Here we investigated the biological effects of the OLFM4-RET fusion and whether it can initiate tumorigenesis in small intestine. OLFM4 expression was frequently lost or reduced in human small intestine adenocarcinoma, and its downregulation correlated with high tumor grade and advanced tumor stage. Expression of OLFM4-RET fusion induced cellular transformation in HEK293 cells and blocked RET-induced inhibition of colony growth in HuTu 80 small intestine adenocarcinoma cells. Further, the expression of OLFM4-RET activated the RAS-RAF-MAPK and STAT3 cell signaling pathways in both HEK293 cells and HuTu 80 cells. In addition, OLFM4-RET expression in HEK293 cells upregulated multiple families of genes related to carcinogenesis, cancer progression, and metastasis. Targeted expression of OLFM4-RET in the small intestine led to the development of hyperplasia, adenoma, or adenocarcinoma in transgenic mice. Our study suggests that OLFM4-RET is an oncogenic driver of small intestine tumorigenesis. Therefore, the OLFM4-RET fusion kinase may prove to be a therapeutic target in small intestine adenocarcinoma.