Targeting Dlk1-Cd44 Signaling Axis for Resistant Ovarian Cancer

Ovarian cancer is a gynecological cancer with poor prognosis and high mortality rate. The incidence of ovarian cancer continues to escalate worldwide in recent years, underscoring the demand of developing novel diagnostic biomarkers and therapeutic approaches. 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/Pref-1 and tumorigenesis was also noted, including neuroendocrine tumor, hepatoma, and lung cancer. 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) Gene transfer studies were performed to elucidate the influence of cellular DLK1 level on the malignant behavior of ovarian cancer cells. Adenovirus-mediated DLK1 over-expression stimulated the ovarian cancer cells malignant behavior. 3) Conversely, DLK1 knockdown by RNA interference attenuating the malignant behavior in advanced ovarian cancer cells. 4) Both of tissue arrays and in vitro experiments results showed a correlation between DLK1 and EMT/CD44. 5) DLK1 over-expression was associated with increased tumor burden and stemness marker CD44 in xenograft model in nude mice. Moreover, DLK1 knockdown by RNA interference reduced tumor burden of mice. The above findings support that DLK1 plays an important role in ovarian carcinogenesis and possibly in responsiveness to cancer therapy. Thus, this 3-year project aims to delineate the potential of DLK1 as a novel diagnostic biomarker for ovarian cancer as well as an index to evaluate the responsiveness of chemotherapeutic treatment. The 3-year project is outlined as follows: The first year: To analyze the DLK1/CD44 signaling axis during the development of chemo-resistance (taxol and cisplatin) in ovarian cancer (in vitro and in vivo) The second year: To evaluate DLK1 secretion as a surrogate biomarker for resistant ovarian cancer by developing humanized DLK1 antibody and ELISA platform The third year: To investigate the potential of targeting DLK1 strategies (including DLK1 antibody, shRNA and DLK1-reducing dietary compounds) for chemo-resistant ovarian cancer (in vitro and in vivo) The results of this study would be helpful to clarify the role of DLK1 during development of chemo-resistance and responsiveness of chemotherapeutic treatment. Moreover, the humanized DLK1 antibody will assist the development of novel diagnosis and anti-neoplastic strategies for refractory ovarian cancer in the future.

Project ID:PC10607-0362
External Project ID:MOST106-2320-B182-019