Abstract A25: Dysregulation of MYC via STAT1 promotes tumor progression in serous papillary endometrial cancer

• Published in: Molecular cancer research 2015-10, Vol.13 (10_Supplement), p.A25-A25
• Main Authors: Kharma, Budiman, Baba, Tsukasa, Matsumura, Noriomi, Murakami, Ryusuke, Yamaguchi, Ken, Hamanishi, Junzo, Mandai, Masaki, Konishi, Ikuo
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1557-3125.MYC15-A25

Serous papillary endometrial cancers (SPEC) harboring several genetic alterations, such as TP53 mutation, are known highly progressive with worse prognosis compared with endometrioid counter-part, but it still remains unclear which molecular pathway is responsible for their unfavorable features. 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, and was involved in maintaining basal expression of tumor pro-survival STAT3 target genes, such as MYC, with unclear mechanism in some cancers. A previous report of the cancer genome atlas (TCGA) indicated MYC amplification in some SPECs; as MYC is known to be maintained also by STAT1, we investigate the role of STAT1-MYC axis in the malignant features of SPECs. Gene expression microarray was conducted for 63 endometrial cancer samples and SPEC cell line, SPAC-1L. Immunohistochemical staining were conducted using endometrial cancer samples under protocols approved by the Institutional Review Board to investigate SPEC-specific pathways (Kyoto cohort: n=91, Vancouver cohort: n=462). Using SPAC-1L cell line, several functional assay in vitro such as cellular proliferation, migration, invasion and apoptosis under treatment of cisplatin, doxorubicin, and paclitaxel were assessed with or without suppressing target genes. In vivo tumorigenesis was performed in mouse model and some computational analysis were done in silico. Gene expression microarray analysis revealed STAT1 pathway was commonly activated in SPECs both in our dataset and TCGA dataset as a key molecule of ‘SPEC signature’. In two independent cohorts, STAT1 expression was confirmed significantly higher in SPECs (p