Ncsis.2013.17 2013 Macmillan Publishers Limited All rights reserved 2157-9024/13 nature/oncsisORIGINAL ARTICLEPeriostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironmentGS Wong1,two,three, J-S Lee4, Y-Y Park4, AJ Klein-Szanto5, TJ Waldron1,2,three, E Cukierman5, M Herlyn6, P Gimotty3,7, H Nakagawa1,two,three and AK Rustgi1,2,3,8 Periostin (POSTN), a matricellular protein, has been reported to be critical in supporting tumor cell dissemination. Having said that, the molecular mechanisms underlying POSTN function inside the tumor microenvironment are poorly understood. In this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that POSTN cooperates with a conformational missense p53 mutation to improve invasion. Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53R175H mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix. Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the significance of STAT1 in promoting invasion. Furthermore, we discover that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors. All round, these benefits highlight the novel molecular mechanisms supporting the capacity of POSTN in mediating tumor invasion throughout ESCC development and have implications of therapeutic approaches targeting the tumor microenvironment. Oncogenesis (2013) 2, e59; doi:ten.1038/oncsis.2013.17; published on-line five August 2013 Subject Categories: Molecular oncology Keywords and phrases: tumor microenvironment; periostin; mutant p53; STAT1; invasionINTRODUCTION Esophageal cancer comprises two subtypes: esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC). ESCC is an aggressive gastrointestinal cancer that’s the predominant subtype accounting for the majority of cases in a lot of countries in Asia and Africa.1,two Because of a lack of early symptoms, individuals with ESCC are typically diagnosed at Calcium Channel Inhibitor web sophisticated stages with the disease, and clinical outcomes remain dismal. Widespread danger components associated with ESCC are smoking tobacco, excessive alcohol use, aromatic hydrocarbons in smoked foods and particular nutritional deficiencies.1 The improvement of ESCC is often a multi-step procedure, and selective genetic alterations happen to be identified. One example is, aberrant expression of epidermal development issue receptor (EGFR) and Insulin Receptor list cyclin D1, activation of human telomerase, inactivation of p16Ink4a and p120 catenin and somatic mutations within the DNA-binding domain (DBD) from the p53 tumor-suppressor gene all have been discovered to be involved in the initiation and progression of ESCC.3 EGFR and cyclin D1 overexpression correlate with squamous dysplasia or neoplastic lesions, which are early events in tumor initiation,four whereas inactivation of p16Ink4a and p120 catenin and mutations in p53 have been associated with later stages of ESCC progression.The majority of human cancers harbor missense mutations in TP53, which not just result in loss of wild-type p53 transcriptional activity but additionally an accumulation of mutant p53 protein with gainof-function activities.5 These missense muta.