American Association for Cancer Research
00085472can141306-sup-130803_2_supp_3409389_448jym.png (126.3 kB)

Supplementary Figure S8 from STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

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posted on 2023-03-30, 23:50 authored by Barbara Walch-Rückheim, Jennifer Pahne-Zeppenfeld, Jil Fischbach, Claudia Wickenhauser, Lars Christian Horn, Lars Tharun, Reinhard Büttner, Peter Mallmann, Peter Stern, Yoo-Jin Kim, Rainer Maria Bohle, Christian Rübe, Russalina Ströder, Ingolf Juhasz-Böss, Erich-Franz Solomayer, Sigrun Smola

HeLa cells were transfected with 10 pmol/1.5 x 105 cells of human IRF1-specific siRNA (#8) or mock siRNA.


Deutsche Krebshilfe

Saarland Staatskanzlei



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.