OPCML, a systems regulator of receptor tyrosine kinases in ovarian and other cancers

Experts Meeting on Gynecologic Oncology

May 19-21, 2016 San Antonio, USA

Hani Gabra

Imperial College London, UK

Posters & Accepted Abstracts: J Cancer Sci Ther

Abstract :

OPCML, a GPI anchored tumor suppressor gene is inactivated by somatic methylation in multiple cancers. We demonstrated inactivation by LOH and somatic methylation in 80% of ovarian cancers. We showed that OPCML is a strong in-vivo tumor suppressor in SKOV-3 and PEO1 ovarian cancer cell lines with no expression of OPCML. We demonstrated that OPCML negatively regulates a specific repertoire of receptor tyrosine kinases (RTKs) including EPHA2, FGFR1, HER2 and AXL with no effect on other RTKs e.g., VEGFR1 and VEGFR3. shRNA knockdown of OPCML accelerates the growth of normal ovarian surface epithelial cells in vitro. Immunoprecipitation revealed that OPCML binds to EphA2, FGFR1, HER2 and AXL extracellular domains with no such interaction to EGFR, thus OPCML binds directly to RTKS that it negatively regulates. We demonstrated that OPCML is located exclusively in the raft membrane fraction and sequesters RTKs that it binds to the raft fraction. We demonstrate that OPCML abrogates EGF and Gas 6 mediated phosphorylation of FGFR1, HER2 and AXL and the downstream phosphosignaling of pErk and pAKT. A recombinant modified OPCML-like protein without a GPI anchor caused inhibition of wound healing assay and tumorigenicity in skov3. In summary, the OPCML tumor suppressor mediates its suppressor function on the external leaflet of the plasma membrane by systems level negative regulation of at least 5 RTKs, and a recombinant modified derivative biotherapy is a potent tumor suppressor protein therapeutic in-vitro and in-vivo that recapitulates the in-vitro mechanism.

Biography :

Email: h.gabra@imperial.ac.uk