title: STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs.
abstract: Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from low-grade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. ©2016 AACR.
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Walch-Rückheim
authors.affiliation: Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pahne-Zeppenfeld
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Jil
authors.initials: J
authors.lastname: Fischbach
authors.affiliation: Institute of Pathology, University of Halle, Halle, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.affiliation: Institute of Pathology, University of Leipzig, Leipzig, Germany.
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Horn
authors.affiliation: Institute of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Tharun
authors.affiliation: Institute of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Department of Gynecology and Obstetrics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Mallmann
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Stern
authors.affiliation: Institute of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Institute of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Rainer Maria
authors.initials: RM
authors.lastname: Bohle
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Saarland University, Homburg/Saar, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rübe
authors.affiliation: Department of Gynecology and Obstetrics, Saarland University, Homburg/Saar, Germany.
authors.forename: Russalina
authors.initials: R
authors.lastname: Ströder
authors.affiliation: Department of Gynecology and Obstetrics, Saarland University, Homburg/Saar, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Juhasz-Böss
authors.affiliation: Department of Gynecology and Obstetrics, Saarland University, Homburg/Saar, Germany.
authors.forename: Erich-Franz
authors.initials: EF
authors.lastname: Solomayer
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany. sigrun.smola@uks.eu.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D005047:Etoposide; D002945:Cisplatin