Abstract 3996: ErbB4 is critical for tumor suppressive HPP1/STAT signaling in colon cancer.

Abstract

Abstract Background: HPP1 (also known as TMEFF2) encodes a cleavable transmembrane protein that is thought to be a tumor suppressive EGF-like ligand that activates STAT1 and 2-associated pathways. From phylogenetic analyses, it is postulated that HPP1 exerts its effects via erbB4. We sought to characterize the role of erbB4 in the context of the HPP1/STAT tumor suppressive signaling axis. Methods: Transient knockdown of erbB4 was achieved using siRNA in stable HPP1-overexpressing HCT116 transfectants. The impact of erbB4 manipulation on STAT signaling was assessed by expression and activation analyses using RT-PCR and Western blotting. Subsequent alterations in cell proliferation and anchorage-independent growth were evaluated by MTT and soft agar assays, respectively. Results: We have previously demonstrated that HPP1’s tumor suppressive effects are associated with activation of suppressive STAT1 and 2 and downregulation of oncogenic STAT3 and 5. Abrogation of erbB4 expression resulted in a reversal of this profile with a reduction in activated STAT1 and 2 and increased phosphorylation of STAT3 and 5. Moreover, inhibition of ErbB4 receptor in HPP1 over-expressing transfectants resulted in an attenuation of tumor suppressive behavior with increased cell proliferation (Optical Density: 0.12±0.11 vs. 0.35 ±0.040; p≤0.001) and colony formation in soft agar (385±25 vs. 66±30 colonies; p≤0.001) as compared to scrambled siRNA control transfectants. Conclusion: The EGF-like domain of HPP1 via erbB4 receptor signaling is essential for its tumor suppressive effects. Knockdown of erbB4 elicits a reversal of HPP1-mediated effects on cell behavior and STAT-family activation status. Therapeutic targeting of the erbB family of receptors is of great interest and our findings may lead to a greater understanding of the complex nature of their associated signaling pathways. Citation Format: Abul Elahi, Whalen Clark, Jonathan Hernandez, Leigh Ann Humphries, Jian Wang, Abidemi Ajidahun, David Shibata. ErbB4 is critical for tumor suppressive HPP1/STAT signaling in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3996. doi:10.1158/1538-7445.AM2013-3996