title: Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment.
abstract: Periostin (POSTN), a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, 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 p53(R175H) 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 importance of STAT1 in promoting invasion. Furthermore, 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 during ESCC development and have implications of therapeutic strategies targeting the tumor microenvironment.
authors.affiliation: 1] Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [2] Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [3] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Wong
authors.forename: J-S
authors.initials: JS
authors.lastname: Lee
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Park
authors.forename: A J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: T J
authors.initials: TJ
authors.lastname: Waldron
authors.forename: E
authors.initials: E
authors.lastname: Cukierman
authors.forename: M
authors.initials: M
authors.lastname: Herlyn
authors.forename: P
authors.initials: P
authors.lastname: Gimotty
authors.forename: H
authors.initials: H
authors.lastname: Nakagawa
authors.forename: A K
authors.initials: AK
authors.lastname: Rustgi
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