PDF - 151K, Depletion of FN1 does not affect cancer cell proliferation and promoter activity of MMPs by TGFbeta-stimulated HPMCs. (A) HPMCs were transfected with control or FN1 siRNA, and 24 h later, cells were incubated with or without TGFbeta for 48 h. ES-2 and SKOV3 cells that constitutively expressed luciferase were seeded onto the HPMCs . Cells were lysed 24, 48, and 72 h after cell seeding, and luciferase activity was measured. (B) ES-2 and SKOV3 cells were transfected with pGL4, pGL4-MMP-2/promoter or pGL4-MMP-9/promoter together with pRLTK-luc, and 24 h later, the cells were seeded onto HPMCs treated as in (A). The cells were incubated for 24 h, and then, luciferase activity was measured.
ARTICLE ABSTRACT
The TGFβ-mediated alteration of the tumor microenvironment plays a crucial role in tumor progression. Mesothelial cells are the primary components of the tumor microenvironment for ovarian cancer cells; however, the exact role of TGFβ-stimulated mesothelial cells in ovarian cancer progression remains uncertain. In this report, we examined the effects of TGFβ-treated mesothelial cells on ovarian cancer progression. We show that TGFβ-stimulated human primary mesothelial cells (HPMC) are able to promote cancer cell attachment and proliferation and the activation of the promoter activities of MMP-2 and MMP-9, which are metalloproteinases necessary for tumor invasion. Expression of the miR200 family was downregulated in HPMCs by TGFβ stimulation, and restoration of the expression of miR200 family members in HPMCs suppressed cancer cell attachment and proliferation. Downregulation of the miR200 family by TGFβ induced fibronectin 1 production, which promoted cancer cell attachment to HPMCs. Finally, we demonstrated that the delivery of the miR200s to mesothelial cells in mice inhibited ovarian cancer cell implantation and dissemination. Our results suggest that alteration of the tumor microenvironment by the miR200 family could be a novel therapeutic strategy for ovarian cancer treatment. Mol Cancer Ther; 13(8); 2081–91. ©2014 AACR.
