STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett's adenocarcinomas Journal Article
| Authors: | Timme, S.; Ihde, S.; Fichter, C. D.; Waehle, V.; Bogatyreva, L.; Atanasov, K.; Kohler, I.; Schöpflin, A.; Geddert, H.; Faller, G.; Klimstra, D.; Tang, L.; Reinheckel, T.; Hauschke, D.; Busch, H.; Boerries, M.; Werner, M.; Lassmann, S. |
| Article 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. © 2014 Macmillan Publishers Limited. |
| Keywords: | immunohistochemistry; signal transduction; epidermal growth factor; controlled study; human tissue; protein expression; protein phosphorylation; human cell; major clinical study; protein function; cell proliferation; gene; cell function; stat1 protein; stat3 protein; gene expression; tyrosine; transcription regulation; cancer cell; cell migration; cellular distribution; down regulation; upregulation; esophageal adenocarcinoma; stat5 protein; transcriptome; cell motility; esophageal cancer; esophageal squamous cell carcinoma; inhibition; stat3; barrett esophagus; human; priority journal; article; cthrc1 gene; shroom2 gene |
| Journal Title: | Oncogene |
| Volume: | 33 |
| Issue: | 25 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-06-19 |
| Start Page: | 3256 |
| End Page: | 3266 |
| Language: | English |
| DOI: | 10.1038/onc.2013.298 |
| PROVIDER: | scopus |
| PUBMED: | 23912451 |
| DOI/URL: | |
| Notes: | Export Date: 1 August 2014 -- CODEN: ONCNE -- Source: Scopus |
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