Vely, as observed in vitro, these findings imply that POSTN indirectly cooperates with mutant p53 to mediate STAT1 activation in vivo. DISCUSSION Current findings have provided mounting evidence for the value of POSTN in tumor invasion, tumor cell dissemination also as building a supportive environment for metastatic colonization.268 However, the molecular mechanisms engaged by POSTN to foster invasion within the tumor microenvironment remain poorly understood. In this study, we demonstrate that POSTN cooperates with mutant p53 in immortalized key esophageal cells to promote invasion in to the underlying ECM. Our discovering that the propensity for POSTN to invade is mediated by mutant p53R175H, a p53 DBD conformational mutant identified in2013 Macmillan Publishers Limitedapproximately 6 of human cancers,29 prompted us to test irrespective of whether this phenotype is recapitulated with other p53 missense mutations. Intriguingly, we observe that POSTN drives invasion to a greater extent when expressed in context of a p53 DBD conformational mutant compared using a p53 DNA-contact mutant, raising the possibility that the dominant-negative capacity of p53 conformational mutants to suppress wild-type p53 activities influences the degree of invasion mediated by POSTN. On account of the higher prevalence of p53 mutations in human cancers, there has been an accelerated interest towards development of therapeutics focused on restoration of wild-type p53 function in tumors.30 Tiny molecule screens have identified promising tiny molecule compounds that selectively target and stabilize the core DBD of mutant p53 in tumor cells and restores wild-type p53 activities including apoptosis and proliferation in vitro.24,31,32 Interestingly, a current study demonstrated the therapeutic efficacy of restoring wild-type p53 in p53R172H mice, which corresponds to human p53R175H, suggesting that the removal of mutant p53 dominant-negative impact on functional wild-type p53 can halt tumor growth and subsequent tumor invasion.33 Working with a combination of genetic and pharmacological approaches to restore wild-type p53 activities in invasive cells overexpressing mutant p53, our results of decreased cell motility and invasion are novel. It also establishes for the first time, to our knowledge, thatOncogenesis (2013), 1 Periostin and tumor invasion GS Wong et alhTERTRelative mRNA expression10 8 six 4STAT1 IFI6 DuoxA2 IDO1 IL-12 SerpinA3 CXCL* * ** 0 hTERT-p53R175hneo hTERT-p53R175hPOSTNFigure four. Esophageal cells with mutant p53R175H and POSTN reveal activation with the STAT1 signaling pathway. (a) Venn diagram displaying the amount of genes with significant differential expression amongst the compared groups. Gene expression data had been generated with RNA isolated from dissected epithelia of EPC-hTERT-p53R175H-POSTN cells grown in organotypic culture (n three) compared with EPC-hTERTp53R175H-neo cells (n three) as well as parental non-invading EPC-hTERT cells (n three).Gemfibrozil The blue circle (gene lists hTERT and p53R175H) represents genes differentially expressed amongst EPC-hTERT and EPC-hTERT-p53R175H-neo (3121).Erythrosine B The red circle (gene lists p53R175H and POSTN) represents genes differentially expressed involving EPC-hTERT-p53R175H-neo and EPC-hTERT-p53R175H-POSTN (1808).PMID:24455443 (Po0.001). (b) Heatmap of gene expression data presented in Venn diagram. Expression is depending on a log2 scale where red represents upregulation and green represents downregulation. Expression patterns of POSTN not hTERT or p53R175H (779) are particular to ex.