Evaluation of Dlk1 as a Prognostic and Chemoresistance Biomarker of Ovarian Serous Carcinomas

Ovarian cancer is a gynecological cancer with poor prognosis and high mortality rate. The high-grade serous carcinoma (HGSC) accounts for 70% of ovarian cancers. HGSCs are initially sensitive to platinum-based chemotherapy, but tend to relapse shortly after an initial response, in approximately 70–80% of cases. Thus, to date, the early diagnosis of ovarian cancer and the recurrence after chemotherapy are still a thorny issue. Delta-like 1 homolog (DLK1) was initially found to function as an inhibitor of adipocyte differentiation. Recently, emerging evidences supported its role in cell differentiation and the relationship between DLK1 and tumorigenesis is also noted. In the previous studies, we have accomplished the proposed goals: (1) tissue microarray analysis revealed a high prevalence (78.9%; 194 among 246) of DLK1 overexpression (immunostaining score ? 2+) in ovarian adenocarcinomas. (2) DLK1 over-expression could predict the survival and recurrence in patients with serous ovarian carcinomas. (3) The in vitro and in vivo experiments and tissue arrays showed a correlation between DLK1 and EMT/CD44. (4) knockdown of DLK1 expression by using a lentiviral shRNA sensitized SKOV-3 cells to Taxol and induced apoptosis. The above findings support that DLK1 plays an important role in ovarian carcinogenesis and possibly in responsiveness to cancer therapy. In addition, by reviewing the literature, we have known that microRNAs (miRNAs) may potentially serve as diagnostic and prognostic markers for ovarian cancer. Among them, several DLK1-targeted miRNAs have been shown to decline in recurrent tumor tissues and in Taxol-resistant cells. Thus, this 3-year project aims to delineate the potential of DLK1 as a novel prognostic biomarker for HGSC as well as an index to evaluate the responsiveness of chemotherapeutic treatment. The 3-year project is outlined as follows: The first year: We will collect the ovarian cancer specimens (tissues) from Kaohsiung Chang Gung Tissue Bank and analyze by in situ hybridization, real-time PCR, and microarray to detect the expression of the DLK1-targeted miRNAs and analyze the results with the patient prognostic data. Simultaneously, in vivo experiments will be set up to clarify the relevant miRNAs in the regulation of ovarian cancer. The second year: We will develop the fully human DLK1 antibody to set up ELISA platform and bio-chip. ELISA platform and bio-chip will be used to evaluate the secretion of DLK1 as a biomarker for chemotherapy response in chemo-resistant ovarian cancer cell xenografts mice and human serum. The third year: To investigate the potential of targeting DLK1 strategies (DLK1 antibody or the combination of DLK1 antibody and chemotherapy drugs) in chemo-resistant ovarian cancer cell xenografts mice. The results from this study will be helpful to clarify the role of miRNA/DLK1 axis during ovary carcinogenesis and development of chemoresistance during chemotherapy. Moreover, the DLK1-based scFV and fully human DLK1 antibody will constitute the novel modalities for diagnosis and therapeutic intervention for refractory ovarian cancer in the future.

Project ID:PC10901-0203
External Project ID:MOST107-2320-B182-037-MY3