Ncsis.2013.17 2013 Macmillan Publishers Limited All rights reserved 2157-9024/13 nature/oncsisORIGINAL ARTICLEPeriostin cooperates with mutant p53 to mediate Somatostatin Receptor Synonyms invasion by way of the induction of STAT1 signaling in the MAO-B review Esophageal tumor microenvironmentGS Wong1,2,3, J-S Lee4, Y-Y Park4, AJ Klein-Szanto5, TJ Waldron1,2,three, E Cukierman5, M Herlyn6, P Gimotty3,7, H Nakagawa1,two,3 and AK Rustgi1,2,3,8 Periostin (POSTN), a matricellular protein, has been reported to become critical in supporting tumor cell dissemination. Nonetheless, the molecular mechanisms underlying POSTN function within 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 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 in to the extracellular matrix. Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in advertising invasion. Additionally, we obtain 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 throughout ESCC development and have implications of therapeutic approaches targeting the tumor microenvironment. Oncogenesis (2013) two, e59; doi:ten.1038/oncsis.2013.17; published on the internet 5 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 instances in several countries in Asia and Africa.1,2 Resulting from a lack of early symptoms, sufferers with ESCC are frequently diagnosed at advanced stages with the disease, and clinical outcomes stay dismal. Typical threat factors connected with ESCC are smoking tobacco, excessive alcohol use, aromatic hydrocarbons in smoked foods and particular nutritional deficiencies.1 The development of ESCC is a multi-step method, and selective genetic alterations have been identified. By way of example, aberrant expression of epidermal growth element 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 have already been found to be involved within the initiation and progression of ESCC.three EGFR and cyclin D1 overexpression correlate with squamous dysplasia or neoplastic lesions, that are early events in tumor initiation,4 whereas inactivation of p16Ink4a and p120 catenin and mutations in p53 have been connected with later stages of ESCC progression.The majority of human cancers harbor missense mutations in TP53, which not merely result in loss of wild-type p53 transcriptional activity but additionally an accumulation of mutant p53 protein with gainof-function activities.five These missense muta.