Abstract 125: A novel OSM inhibition of cancer metastasis and epithelial-mesenchymal transition in lung adenocarcinoma through STAT1-mediated suppression of Slug

Abstract

Abstract We previously reported that mesenchymal stem cells (MSCs) secrete a multifunctional cytokine - Oncostatin M (OSM) which effectively inhibited the metastasis and growth of LAC cells, and induced the mesenchymal epithelial transition (MET) pathway, as evidenced by the reduction of several epithelial-mesenchymal transition related markers, including SLUG. However, the underlying mechanism of how OSM mediates the suppression of SLUG is still unknown. To dissect the downstream effectors of OSM-dependent suppression of SLUG, we individually knocked down STAT1 (STAT1-KD) and STAT3 (STAT3-KD), the two well-known downstream transcription factors activated by OSM, in A549 and CL1-5 cells using lentiviral expressed short hairpin RNAs (shRNA). We demonstrated that knockdown of STAT1, but not STAT3, reversed the OSM suppressed SLUG level and resulted in a higher SLUG mRNA and protein in comparison to scrambled shRNA control. Consistently, knockdown of STAT1 in LAC cells rescued the OSM-mediated inhibition of cell migration, invasion, and proliferation, indicating that STAT1 is the effector of OSM-dependent induction of MET and suppression of cell motility. Moreover, we constructed SLUG promoter-driven luciferase expression reporters and test the effect of OSM and STAT1 on SLUG promoter activity. We observed that STAT1-KD cells had increased SLUG promoter activity than control cells, while OSM treatment augments this difference. A mutation in the putative STAT1 binding sequence (gamma activated sequence) mapped at -599 bp upstream of STAT1 transcriptional start site diminished the SLUG promoter activity in STAT1-KD cells. We also showed STAT1 binding to SLUG promoter region after OSM treatment by using a chromatin immunoprecipitation assay. These data indicated that the OSM-dependent inhibition of SLUG and elevation of MET signaling is mediated, at least in part, by a STAT1-dependent pathway through a transcriptional control. Our findings revealed a novel paracrine effect of OSM and the underlying mechanism on cancer metastasis and MET in LAC. Citation Format: Chih-Ming Pan, Mong-Lien Wang, Cheng-Wen Wu. A novel OSM inhibition of cancer metastasis and epithelial-mesenchymal transition in lung adenocarcinoma through STAT1-mediated suppression of Slug. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 125. doi:10.1158/1538-7445.AM2014-125