Ovarian carcinoma is the most lethal type of gynecologic malignancies. Alterations of Notch pathway are prevalent in ovarian carcinogenesis. This study investigated the expression profile and function of delta-like 1 homolog (DLK1), a non-canonical Notch ligand, during ovarian carcinogenesis. Tissue microarray (TMA) consisting of surgically resected samples from 221 patients with ovarian carcinoma was constructed for DLK1 expression. DLK1 overexpression or knockdown was achieved by adenovirus gene delivery to evaluate the effect of DLK1 on the oncogenic behaviors in ovarian cancer cells and in xenografted tumors. TMA analysis revealed that elevated DLK1 expression was correlated with stages, lymph node metastasis and E-cadherin downregulation. Despite no influence on survival among ovarian carcinoma patients, DLK1 overexpression was specially associated with overall survival and progression free survival in high-grade serous carcinoma (HGSC) patients, constituting an independent prognostic factor for these patients. By adenovirus gene delivery, it was found modulation of cellular DLK1 level regulated the tumorigenic behaviors and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Immunohistochemical analysis further showed that DLK1 overexpression resulted in escalated proliferation, angiogenesis, EMT and Notch activities. Application of recombinant DLK1 extracellular domain (rDLK1-EC) recapitulated the tumorigenic behaviors of DLK1 in ovarian cancer cells. By using neutralizing antibody or pharmaceutical inhibitor, blockade of Notch signaling attenuated the tumorigenic behaviors evoked by DLK1 overexpression. The present study indicates that DLK1 overexpression participates in ovarian carcinogenesis through Notch activation and EMT induction. Moreover, DLK1 may constitute a novel diagnostic biomarker and therapeutic target for HGSC.
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Conception and design: C.C.H., S.H.C., and M.H.T. Development of methodology: C.C.H., S.H.C., M.L.K., and T.H.U. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.C.H., C.H.W., W.Y.L., and J.S.W. Administrative, technical, or material support: C.C.H., S.H.C., C.H.W., M.L.K., T.H.C., S.T.H., C.T.F., and S.C.H. Writing, review, and/or revision of the manuscript: C.C.H., S.H.C., C.H.W., and M.H.T. Study supervision: C.C.H., and M.H.T.
This work was supported by grants from the Ministry of Science and Technology, Taiwan (NSC101-2320-B-182-009, NSC102-2320-B-182-011, MOST103-2320-B-182-005-MY3 to C.C.H., and MOST105-2325-B-110-001 to M.H.T.). We thank Chang Gung Medical Foundation Kaohsiung Chang Gung Memorial Hospital Tissue Bank (CLRPG8E0161 and CLRPG8F1701), and the Kaohsiung Armed Forces General Hospital, Taiwan (107-10) for technical support.
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Huang, C., Cheng, S., Wu, C. et al. Delta-like 1 homologue promotes tumorigenesis and epithelial-mesenchymal transition of ovarian high-grade serous carcinoma through activation of Notch signaling. Oncogene 38, 3201–3215 (2019). https://doi.org/10.1038/s41388-018-0658-5