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STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett’s adenocarcinomas

Oncogene volume 33, pages 3256–3266 (2014)Cite this article

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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.

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Acknowledgements

We thank Martina Gansz for assistance with Cathepsin analyses. We acknowledge the support of the study by the Deutsche Forschungsgemeinschaft (SFB850 project C5 to SL, MW; SFB850 project B7 to TR; Gerok stipend of SFB850 project Z1 to ST). Preliminary work for this study has been supported by the Mushett Family Foundation, Chester, NJ, USA (grant to SL, MW, LT, DK). TR and SL are member and associate members of BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany. This study was supported by DFG SFB850 C5 (MW, SL); DFG SFB850 B7 (TR); DFG SFB850 Z1 (Gerok position to ST); and Mushett Family Foundation, Chester, NJ (DK, LT, MW, SL).

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Author notes

  1. S Timme, S Ihde and C D Fichter: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany

    S Timme, S Ihde, C D Fichter, V Waehle, K Atanasov, I Kohler, A Schöpflin, M Werner & S Lassmann

  2. Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany

    C D Fichter

  3. Institute of Medical Biometry and Medical Informatics, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany

    L Bogatyreva & D Hauschke

  4. Department of Pathology, St Vincentius Kliniken, Karlsruhe, Germany

    H Geddert & G Faller

  5. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    D Klimstra & L Tang

  6. Institute of Molecular Medicine and Cell Research, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany

    T Reinheckel, H Busch & M Boerries

  7. BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany

    T Reinheckel & S Lassmann

  8. Comprehensive Cancer Center Freiburg, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany

    T Reinheckel, M Werner & S Lassmann

  9. German Cancer Consortium (DKTK), Heidelberg, Germany

    H Busch, M Boerries, M Werner & S Lassmann

  10. German Cancer Research Center (DKFZ), Heidelberg, Germany

    H Busch, M Boerries, M Werner & S Lassmann

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  1. S Timme
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Timme, S., Ihde, S., Fichter, C. et al. STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett’s adenocarcinomas. Oncogene 33, 3256–3266 (2014). https://doi.org/10.1038/onc.2013.298

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