STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

Cancer Res. 2016 Jul 1;76(13):3872-83. doi: 10.1158/0008-5472.CAN-14-1306. Epub 2016 May 23.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology*
  • Etoposide / pharmacology*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Interferon Regulatory Factor-1 / metabolism*
  • Neoplasm Staging
  • Precancerous Conditions / drug therapy*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Prognosis
  • STAT3 Transcription Factor / metabolism*
  • Tumor Cells, Cultured
  • Uterine Cervical Dysplasia / drug therapy*
  • Uterine Cervical Dysplasia / metabolism
  • Uterine Cervical Dysplasia / pathology
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology


  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Biomarkers, Tumor
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Etoposide
  • Cisplatin