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

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Small intestine adenocarcinoma is a rare intestinal malignancy with a distinct clinical and molecular entity. Recently, the fusion of intestinal stem cell marker OLFM4 (Olfactomedin 4) and the proto-oncogene RET has been reported in a patient with small intestine adenocarcinoma. But this newly discovered fusion genes potential role in carcinogenesis is not known. In our current study, we investigated the biological consequences of a OLFM4-RET fusionconstruct in order to determine whether it can initiate the tumorigenesis in small intestine tissue. First, we show that OLFM4 expression is frequently lost or reduced in small intestine carcinoma and its downregulation is correlated with poor differentiation and advanced tumor stage. Then we investigated whether OLFM4-RET can induce cellular transformation. In HEK293 cells, expression of OLFM4-RET induces early rapid cell proliferation and apoptosis at later stage. The OLFM4-RET fusion protein remains on cell membrane and is constitutively phosphorylated at Y509 and leads to activation of Ras-Raf-MAPK pathway and STAT3 pathway. Multiple cancer-related family of genes including AP1, EGRs, MMPs have been upregulated by OLFM4-RET. Expression of OLFM4-RET in HuTu80 small intestine cancer cells increased activation of MAPK, STAT3 and PI3-Akt pathway and neutralized RET-induced apoptosis and inhibition of colony growth. Finally, we have shown that targeted expression of OLFM4-RET in the small intestine leads to the development of crypt hyperplasia, adenoma and adenocarcinoma in transgenic mice. Our study suggests that OLFM4-RET is an initiator of small intestine carcinogenesis. OLFM4-RET fusion kinase may prove to be a targetable oncogene in small intestine adenocarcinoma.