Estrogen plays a critical role in AAV2-mediated gene transfer in ovarian cancer1

Authors


  • 1

    Project supported by the National Natural Science Foundation of China (No 30772477) and a Young Investigator Award from the Alliance for Cancer Gene Therapy (ACGT) to JSB and grants from the National Institute of Health (R21 AI51388 and R01 AI51388), and the Ohio Division of the American Cancer Society to JSB.

Co-correspondence to Dr Wen-fang SHI and Prof Jeffrey S BARTLETT. Phn 86-21-2507-0836 Fax 86-21-3503-0677 E-mail shiwenfang1@gmail.comJeffrey.Bartlett@NationawideChildrens.org

Abstract

Aim: The aim of our study was to develop an effective gene delivery system for ovarian cancer gene therapy. Methods: The expression of heparin sulfate proteoglycan (HSPG) and integrins ανβ3 and ανβ5 were analyzed with flow cytometry on 2 human ovarian cancer cell lines (OVCAR-3 and SKOV-3ip). The gene transduction efficiencies were evaluated with recombinant adeno-associated viral vector (rAAV)2–green fluorescent protein or rAAV2–lactase Z followed by flow cytometry or cytohistochemistry staining. The effect of 17β-estradiol on ovarian cancer cell proliferation, HSPG, the expressions of integrins ανβ3 and ανβ5, and adeno-associated viral vector (AAV)2-mediated gene transduction were determined. Results: In the present study, we found: (1) a variation in HSPG and the expressions of integrins ανβ3 and ανβ5 between OVCAR-3 and SKOV-3ip; (2) that 17β-estradiol was shown to significantly stimulate cell proliferation and integrin β5 expression in certain ovarian cancer cell lines; and (3) integrin-targeted A520/N584RGD–rAAV2, which has alternative interactivity with integrins and abrogates the binding capacity HSPG, showed much higher gene transduction efficiency in ovarian cancer cells than rAAV2 in the presence/absence of 17β-estradiol. Moreover, this RGD-modified rAAV2 exerted more efficient transduction in ovarian cancer cells in response to 17β-estradiol. Conclusion: Our findings implied that A520/N584RGD-rAAV2 may offer great potential for ovarian cancer treatment in vivo.

Ancillary