Wed. Jul 24th, 2024

Ncsis.2013.17 2013 Macmillan Publishers CETP supplier Limited All rights reserved 2157-9024/13 nature/oncsisORIGINAL ARTICLEPeriostin cooperates with mutant p53 to mediate invasion via the induction of STAT1 signaling in the esophageal tumor microenvironmentGS Wong1,two,three, J-S Lee4, Y-Y Park4, AJ Klein-Szanto5, TJ Waldron1,two,three, E Cukierman5, M Herlyn6, P Gimotty3,7, H Nakagawa1,2,3 and AK Rustgi1,two,3,8 Periostin (POSTN), a matricellular protein, has been reported to become crucial in supporting tumor cell dissemination. However, the molecular mechanisms underlying POSTN function within the tumor microenvironment are poorly understood. Within this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell ALDH2 web carcinoma (ESCC) tumor development in vivo and demonstrate that POSTN cooperates having a conformational missense p53 mutation to improve 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. Additionally, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors. General, 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) 2, e59; doi:ten.1038/oncsis.2013.17; published on the internet five August 2013 Topic Categories: Molecular oncology Search phrases: tumor microenvironment; periostin; mutant p53; STAT1; invasionINTRODUCTION Esophageal cancer comprises two subtypes: esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC). ESCC is definitely an aggressive gastrointestinal cancer that’s the predominant subtype accounting for the majority of instances in a lot of nations in Asia and Africa.1,two Because of a lack of early symptoms, patients with ESCC are generally diagnosed at sophisticated stages in the illness, and clinical outcomes stay dismal. Common threat aspects related with ESCC are smoking tobacco, excessive alcohol use, aromatic hydrocarbons in smoked foods and specific nutritional deficiencies.1 The development of ESCC is actually a multi-step process, and selective genetic alterations have been identified. As an example, aberrant expression of epidermal development aspect receptor (EGFR) and cyclin D1, activation of human telomerase, inactivation of p16Ink4a and p120 catenin and somatic mutations in the DNA-binding domain (DBD) on the p53 tumor-suppressor gene all happen to be discovered to be involved inside the initiation and progression of ESCC.3 EGFR and cyclin D1 overexpression correlate with squamous dysplasia or neoplastic lesions, that are early events in tumor initiation,four whereas inactivation of p16Ink4a and p120 catenin and mutations in p53 happen to be related 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 also an accumulation of mutant p53 protein with gainof-function activities.five These missense muta.