Study on the Role of Dlk1/Pref-1 in Endometrial and Ovarian Adenocarcinomas

Dlk1/Pref-1 is a transmembranous protein belonging to the epidermal growth factor (EGF)-like homeotic superfamily. It was initially known as an inhibitor of adipogenesis. A series of subsequent studies have found that it is a regulator of cell differentiation, most likely a differentiation inhibitor. It has also been considered that Dlk1/Pref-1 is a marker of the progenitor cells of the liver. Some reports showed that Dlk1/Pref-1 may functionally interact with Notch1, leading to the regulation of differentiation processes modulated by Notch1 activation and signaling. In the previous study, we have demonstrated that exogenous Dlk1/Pref-1 increased the expression of Notch1 and its downstream transcriptional factor Hes1, and induced the phosphorylation of ERK1/2 and p38 MAPK in the endothelial cells, to play a role on angiogenesis. Recently, there have been emerging evidences to show the relationships 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. It was also claimed that Dlk1/Pref-1 may be involved in an important stem cell pathway to regulate cancer stem cell-like functionality and tumorigenesis. In our preliminary study, we found that 24.6% (17/69) ovarian adenocarcinomas are positive for Dlk1/Pref-1 immunostaining. By the search on the website of the Human Protein Atlas, endometrial cancer is the most frequent cancer with Dlk1/Pref-1 expression, and ovarian cancer is the fourth one, only next to endometrial cancer, glioma and liver cancer. Interestingly, our study on a 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, which may imply the presence of tumor stem cells. Accordingly, we propose this project to study the role of Dlk1/Pref-1 in endometrial and ovarian adenocarcinomas. This study will answer the following questions. 1) Which subtype of endometrial/ovarian adenocarcinomas has the highest expression of Dlk1/Pref-1? 2) What is the impact of Dlk1/Pref-1 over-expression or knock-down to the tumor cells? 3) Is Notch signaling pathway related to Dlk1/Pref-1 on endometrial and ovarian adenocarcinomas? 4) Does Dlk1/Pref-1 play the role as a tumor stem cell on tumorigenesis of endometrial and ovarian adenocarcinomas? The results of this study would be able to clarify the role of Dlk1/Pref-1 as either a differentiation regulator or tumor stem cell in endometrial and ovarian adenocarcinomas. The information will be potentially helpful for the development of anti-cancer strategies for the treatment of endometrial and ovarian adenocarcinomas in the future.

Project ID:PC10108-0917
External Project ID:NSC101-2320-B182-009