title: STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett's adenocarcinomas.
abstract: Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC, n=49) and Barrett's adenocarcinomas (BAC, n=61) revealed similar STAT3 expression in ESCCs and BACs (P=0.109), but preferentially activated P-STAT3 in ESCCs (P=0.013). In vitro, strong STAT3 activation was seen by epidermal growth factor (EGF) stimulation in OE21 (ESCC) cells, whereas OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 (P=0.0148) and OE33 (P=0.0243) cells. Importantly, STAT3 knockdown reduced cell migration of OE33 cells by 2.5-fold in two types of migration assays (P=0.073, P=0.015), but not in OE21 cells (P=0.1079, P=0.386). Investigation of transcriptome analysis of STAT3 knockdown revealed a reduced STAT3 level associated with significant downregulation of cell cycle genes in both OE21 (P<0.0001) and OE33 (P=0.01) cells. In contrast, genes promoting cell migration (CTHRC1) were markedly upregulated in OE21 cells, whereas a gene linked to tight-junction stabilization and restricted cell motility (SHROOM2) was downregulated in OE21 but upregulated in OE33 cells. This study shows frequent, but distinct, patterns of STAT3 expression and activation in ESCCs and BACs. STAT3 knockdown reduces cell proliferation in ESCC and BAC cells, inhibits migration of BAC cells and may support cell migration of ESCC cells. Thereby, novel STAT3-regulated genes involved in ESCC and BAC cell proliferation and cell migration were identified. Thus, STAT3 may be further exploited as a potential novel therapeutic target, however, by careful distinction between the two histotypes of esophageal cancers.
authors.affiliation: Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Timme
authors.affiliation: Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ihde
authors.affiliation: 1] Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [2] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: C D
authors.initials: CD
authors.lastname: Fichter
authors.affiliation: Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Waehle
authors.affiliation: Institute of Medical Biometry and Medical Informatics, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bogatyreva
authors.affiliation: Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Atanasov
authors.affiliation: Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Kohler
authors.affiliation: Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schöpflin
authors.affiliation: Department of Pathology, St Vincentius Kliniken, Karlsruhe, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Geddert
authors.affiliation: Department of Pathology, St Vincentius Kliniken, Karlsruhe, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Faller
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Klimstra
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Tang
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany [3] Comprehensive Cancer Center Freiburg, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Reinheckel
authors.affiliation: Institute of Medical Biometry and Medical Informatics, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hauschke
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [2] German Cancer Consortium (DKTK), Heidelberg, Germany [3] German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Busch
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [2] German Cancer Consortium (DKTK), Heidelberg, Germany [3] German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Boerries
authors.affiliation: 1] Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [2] Comprehensive Cancer Center Freiburg, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany [4] German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Werner
authors.affiliation: 1] Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany [3] Comprehensive Cancer Center Freiburg, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [4] German Cancer Consortium (DKTK), Heidelberg, Germany [5] German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lassmann
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D055785:Gene Knockdown Techniques; D006801:Humans; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human