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Proc Natl Acad Sci U S A. 2019 May 7;116(19):9453-9462. doi: 10.1073/pnas.1821068116. Epub 2019 Mar 25.

Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers.

Ji Z1,2, He L1, Regev A2,3,4,5, Struhl K6.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
2
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.
3
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 20140.
4
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 20140.
5
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 20140.
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; kevin@hms.harvard.edu.

Abstract

Using an inducible, inflammatory model of breast cellular transformation, we describe the transcriptional regulatory network mediated by STAT3, NF-κB, and AP-1 factors on a genomic scale. These proinflammatory regulators form transcriptional complexes that directly regulate the expression of hundreds of genes in oncogenic pathways via a positive feedback loop. This transcriptional feedback loop and associated network functions to various extents in many types of cancer cells and patient tumors, and it is the basis for a cancer inflammation index that defines cancer types by functional criteria. We identify a network of noninflammatory genes whose expression is well correlated with the cancer inflammatory index. Conversely, the cancer inflammation index is negatively correlated with the expression of genes involved in DNA metabolism, and transformation is associated with genome instability. We identify drugs whose efficacy in cell lines is correlated with the cancer inflammation index, suggesting the possibility of using this index for personalized cancer therapy. Inflammatory tumors are preferentially associated with infiltrating immune cells that might be recruited to the site of the tumor via inflammatory molecules produced by the cancer cells.

KEYWORDS:

cancer; epignetic switch; gene regulatory network; inflammation

PMID:
30910960
PMCID:
PMC6511065
[Available on 2019-09-25]
DOI:
10.1073/pnas.1821068116

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