Background: Ovarian cancer is the most lethal gynecological cancer. Tumor angiogenesis is essential for the progression and metastasis of ovarian cancer. Our data shows that STAT3, HIF-1α and VEGFA are the key regulators of tumor-specific angiogenesis. Our studies have provided evidence that VEGF is directly regulated by STAT3 in miR551b-3p expressing cells, which indicates that STAT3 is an important regulator of angiogenesis in a subset of ovarian cancers. Recently, we showed that miR551b-3p acts as an upstream regulator of STAT3 in ovarian cancer cells. We identified that anti-miR551b-3p inhibit the expression of miR551b-3p disrupt tumor-specific angiogenesis by preventing the expression of HIF-1α and VEGFA through direct inhibition of STAT3.

Methods: In this study, we explored the role of miR551b on angiogenesis in ovarian cancer cells by performing cell proliferation, western blot and qPCR of angiogenic markers, in vitro capillary tube formation, in vivo matrigel plug assay and ex-vivo aortic ring assays.

Results: We found that miR551b-3p upregulates STAT3, HIF-1α, VEGFR and VEGF in ovarian cancer cells and increases the abilities of cell proliferation, migration and tube formation of human umbilical vein endothelial (HUVEC) cells. In conjunction, knockdown of miR-551b decreased the level of STAT3, HIF-1α and VEGFR2 proteins as well as the angiogenic activity; also increased cellular apoptosis. Altogether, our data suggest critical roles of miR-551b on STAT-3–mediated angiogenesis in ovarian cancer cells. In complement to our in vitro results, the delivery of anti-miR551b inhibited angiogenesis in the matrigel plug injected in nude mice. Furthermore, the treatment of anti-miR551b reduced the angiogenic sprouting from rat thoracic aorta in our ex vivo culture. Taken together, our findings provide the first evidence that miR-551b is a pivotal regulator of tumor angiogenesis and inhibiting miR551b could be used to inhibit tumor-specific angiogenesis in ovarian cancer.

Conclusions: miR551b markedly augmented the pro-angiogenic effects in vitro, in vivo and ex-vivo models. Our data suggest that miR551b is an actionable target to disrupt tumor-specific angiogenesis in ovarian cancer. In our pre-clinical model, we are using anti-miR551b encapsulated in nanoliposomes for in vivo delivery to inhibit and sensitize anti- angiogenic therapy and chemotherapy. We expect that the completion of our studies will identify novel mechanisms regulate tumor-specific angiogenesis and novel targets to treat ovarian cancer patients.

Citation Format: Deepak Parashar, Anjali Geethadevi, Jasmine George, Gopakumar Gopinathan Nair, Changliang Chen, Sunila Pradeep, Pradeep Chaluvally-Raghavan. miR551b-mediated tumor-specific angiogenesis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 206.