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A Requirement of STAT3 DNA Binding Precludes Th-1 Immunostimulatory Gene Expression by NF-κB in Tumors
- Source :
- Cancer Research. 71:3772-3780
- Publication Year :
- 2011
- Publisher :
- American Association for Cancer Research (AACR), 2011.
-
Abstract
- Both STAT3 and NF-κB are persistently activated in diverse cancers and promote tumor cell proliferation, survival, angiogenesis, and metastasis through transcriptional activation of multiple common genes. Paradoxically, STAT3 also suppresses many NF-κB–inducible genes involved in innate and adaptive antitumor immunity in spite of elevated levels of NF-κB in tumors. In this study, we show that expression of many NF-κB downstream target genes in tumors depends on STAT3 DNA binding. When STAT3 is elevated in tumor cells and tumor-infiltrating immune cells, persistently activated NF-κB interacts with STAT3 and preferentially binds to genes with STAT3-binding site(s) in promoters. A large number of NF-κB downstream genes associated with oncogenesis and chronic inflammation contain STAT3 DNA-binding site(s). However, in contrast, many genes frequently associated with antitumor immunity lack STAT3 DNA-binding site(s) and can only be activated by NF-κB when STAT3 is inhibited in tumors. The introduction of STAT3 DNA-binding sequences by site-specific mutagenesis in an immunostimulatory gene promoter allows its transcriptional activation by NF-κB in tumor cells. Furthermore, STAT3 facilitates NF-κB binding to genes that are important for tumor growth while inhibiting its binding to Th-1 immunostimulatory genes in growing tumors, including in tumor-infiltrating immune cells. The results of this study provide insight into how some of the oncogenic/inflammatory and Th-1 immunostimulatory genes are differentially regulated in cancer. Cancer Res; 71(11); 3772–80. ©2011 AACR.
- Subjects :
- STAT3 Transcription Factor
Transcriptional Activation
Chromatin Immunoprecipitation
Cancer Research
Transcription, Genetic
Cell Growth Processes
Biology
medicine.disease_cause
Article
Mice
Immune system
Cell Line, Tumor
Gene expression
medicine
Animals
Humans
Promoter Regions, Genetic
Melanoma
Gene
Regulation of gene expression
Binding Sites
NF-kappa B
Promoter
DNA, Neoplasm
Th1 Cells
Suicide gene
Gene Expression Regulation, Neoplastic
Oncology
Cancer research
Carcinogenesis
Chromatin immunoprecipitation
Signal Transduction
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 71
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....be066bcc20b403ad5132377478443047