Functional Analysis of DLK1/Pref-1 Expression on Epithelial-Mesencymal Transition and Cancer Stemness in Ovarian Cancer

DLK1/Pref-1, a transmembranous protein belonging to the epidermal growth factor (EGF)-like superfamily, was initially identified as secreted factor that inhibit adipogenesis. Subsequent studies found that DLK1/Pref-1 is a regulator of cell differentiation, most likely a differentiation inhibitor, and a marker of the progenitor cells of the liver. DLK1/Pref-1 may functionally interact with Notch1, leading to the regulation of differentiation processes modulated by Notch1 activation and signaling. Our pilot study has demonstrated that exogenous DLK1/Pref-1 supply stimulated migration of endothelial cells and increased the expression of Notch1 and its downstream transcriptional factor Hes1, thereby promoting the angiogenesis in vitro and in vivo. Recently, emerging evidences support the relationship between DLK1/Pref-1 and tumorigenesis. DLK1/Pref-1 has been reported to express in tumors with neuroendocrine features, malignant glioma, hepatoblastoma, and a subset of hepatoma, adenocarcinoma of colon and pancreatic islet carcinoma. In addition, given the importance of Notch signaling, DLK1/Pref-1 may be involved in regulation of cancer stem cells. Our preliminary studies found that 24.6% (17/69) ovarian adenocarcinomas are positive for DLK1/Pref-1 immunostaining. The search of Human Protein Atlas website reveals ovarian cancer is the fourth most frequent cancer with DLK1/Pref-1 expression, only next to endometrial cancer, glioma and liver cancer. An interesting case of malignant mixed mullerian tumor showed strong DLK1/Pref-1 immunoreactivity in some clusters of poorly differentiated neoplastic epithelial cells but completely negative in the adjacent well differentiated neoplastic epithelial cells, implying the presence of tumor stem cells. Accordingly, we propose to study the role of DLK1/Pref-1 in ovarian adenocarcinomas in this 3-year project as follows: 1) DLK1/Pref-1 expression and secretion profiles in ovarian cancer (1st Year) 2) DLK1/Pref-1 expression on oncogenic behaviors and epithelial-mesenchymal transition (EMT) of ovarian cancer (2nd Year) 3) DLK1/Pref-1 expression on chemoresistance and cancer stemness of ovarian cancer (3rd Year) The results from this study would help to clarify the prognostic role of DLK1/Pref-1 as well as the oncogenic function of DLK1/Pref-1 in ovarian carcinogenesis. Moreover, the information will assist the development of anti-cancer strategies for the treatment of ovarian adenocarcinomas in the future.

Project ID:PC10207-0415
External Project ID:NSC102-2320-B182-011