Universität zu Köln

Walch-Rueckheim, Barbara, Pahne-Zeppenfeld, Jennifer, Fischbach, Jil, Wickenhauser, Claudia, Horn, Lars Christian, Tharun, Lars, Buettner, Reinhard, Mallmann, Peter, Stern, Peter, Kim, Yoo-Jin, Bohle, Rainer Maria, Ruebe, Christian, Stroeder, Russalina, Juhasz-Boess, Ingolf, Solomayer, Erich-Franz and Smola, Sigrun (2016). STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs. Cancer Res., 76 (13). S. 3872 - 3884. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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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 neo-adjuvant 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. (C) 2016 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Walch-Rueckheim, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Pahne-Zeppenfeld, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischbach, Jil UNSPECIFIED UNSPECIFIED UNSPECIFIED Wickenhauser, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Horn, Lars Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Tharun, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Mallmann, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Stern, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Yoo-Jin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bohle, Rainer Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruebe, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroeder, Russalina UNSPECIFIED UNSPECIFIED UNSPECIFIED Juhasz-Boess, Ingolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Solomayer, Erich-Franz UNSPECIFIED UNSPECIFIED UNSPECIFIED Smola, Sigrun UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-270624
DOI:	10.1158/0008-5472.CAN-14-1306
Journal or Publication Title:	Cancer Res.
Volume:	76
Number:	13
Page Range:	S. 3872 - 3884
Date:	2016
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BREAST-CANCER; IN-VIVO; IRF-1 EXPRESSION; LEUKEMIA-CELLS; INTERLEUKIN-6; GENE; CARCINOMA; GROWTH; TRANSCRIPTION; RESISTANCE Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27062