Abstract LB-123: Novel function of STAT1 pathway as a modulator of tumor progression in serous papillary endometrial cancer

Abstract

Abstract Serous papillary endometrial cancers (SPEC) are highly progressive with poor prognosis, and its oncogenic profile is known different from endometrioid endometrial cancers. It, however, still remains unclear that which pathway promotes tumor progression. The IFN-γ transcription factor signal transducer and activator of transcription 1 (STAT1) has been considered as a tumor suppressor with transcription-dependent and transcription-independent mechanisms, but recent studies showed STAT1 was associated with poor prognosis in some cancers with unclear mechanisms. In this study, we performed a genome-wide analysis by microarray analysis of 63 human endometrial cancers which revealed STAT1 pathway was constitutively up-regulated in SPEC, and its expression was confirmed significantly higher in SPECs tissue cancer by immunohistochemical staining (p<0.001). Immunohistochemical staining also exhibited co-localization of ICAM-1 and PD-L1 at tumor frontier with CD8-T cells (p<0.001) as well as STAT1 expression in SPECs. Using a SPEC cell line, SPAC-1L, it was confirmed that IFN-γ induced STAT1 expression not only to promote cellular proliferation (p<0.05), adhesion (p<0.0001), and invasion (p=0.0002), but to induce expression of cMyc, ICAM-1 and PD-L1 (p<0.05). In contrast, suppression of STAT1 attenuated induction of these genes (p<0.05) and inhibited xenograft tumor growth on NOD-SCID mice (p<0.0001). These results indicate that STAT1 pathway modulates the micro-environment of SPECs in driving its downstream genes to promote tumor progression. Furthermore, it could be developed as a novel potential target for molecular therapy in SPEC. Citation Format: Budiman Kharma, Tsukasa Baba, Noriomi Matsumura, Hyun Sook Kang, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Masaki Mandai, Susan K Murphy, Ikuo Konishi. Novel function of STAT1 pathway as a modulator of tumor progression in serous papillary endometrial cancer. [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 LB-123. doi:10.1158/1538-7445.AM2014-LB-123