Ncsis.2013.17 2013 Macmillan Publishers Limited All rights reserved 2157-9024/13 nature/oncsisORIGINAL ARTICLEPeriostin cooperates with mutant p53 to mediate invasion by means of the induction of STAT1 signaling inside the esophageal tumor microenvironmentGS Wong1,two,3, J-S Lee4, Y-Y Park4, AJ Klein-Szanto5, TJ Waldron1,2,3, E Cukierman5, M Herlyn6, P Gimotty3,7, H Nakagawa1,two,3 and AK Rustgi1,2,3,eight Periostin (POSTN), a matricellular protein, has been reported to be essential in supporting tumor cell dissemination. However, the molecular mechanisms underlying POSTN Epoxide Hydrolase Inhibitor Formulation 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 development in vivo and demonstrate that POSTN cooperates using a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53R175H mutation show 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 value of STAT1 in promoting invasion. In addition, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors. Overall, these results highlight the novel molecular mechanisms supporting the capacity of POSTN in mediating tumor invasion in the course of ESCC development and have implications of therapeutic tactics targeting the tumor microenvironment. Oncogenesis (2013) 2, e59; doi:ten.1038/oncsis.2013.17; PROTACs Source published on the web five August 2013 Topic Categories: Molecular oncology Keywords: 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 is definitely the predominant subtype accounting for the majority of circumstances in quite a few countries in Asia and Africa.1,2 On account of a lack of early symptoms, individuals with ESCC are frequently diagnosed at sophisticated stages with the illness, and clinical outcomes stay dismal. Frequent danger variables related with ESCC are smoking tobacco, excessive alcohol use, aromatic hydrocarbons in smoked foods and certain nutritional deficiencies.1 The development of ESCC is really a multi-step procedure, and selective genetic alterations have already been identified. For example, aberrant expression of epidermal growth aspect receptor (EGFR) and cyclin D1, activation of human telomerase, inactivation of p16Ink4a and p120 catenin and somatic mutations within the DNA-binding domain (DBD) on the p53 tumor-suppressor gene all happen to be located to be involved in the initiation and progression of ESCC.three EGFR and cyclin D1 overexpression correlate with squamous dysplasia or neoplastic lesions, which are early events in tumor initiation,4 whereas inactivation of p16Ink4a and p120 catenin and mutations in p53 have already been related with later stages of ESCC progression.The majority of human cancers harbor missense mutations in TP53, which not just bring about loss of wild-type p53 transcriptional activity but additionally an accumulation of mutant p53 protein with gainof-function activities.5 These missense muta.