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

Zhe Ji, Lizhi He, Aviv Regev, Kevin Struhl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9453-9462
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number19
DOIs
StatePublished - May 7 2019

Funding

ACKNOWLEDGMENTS. This work was supported by the Searle Leadership Fund in the Life Sciences from Northwestern University (to Z.J.), National Cancer Institute K99 CA 207865 (to Z.J.), and National Institutes of Health Research Grant CA 107486 (to K.S.). A.R. is a Howard Hughes Investigator.

Keywords

  • Cancer
  • Epignetic switch
  • Gene regulatory network
  • Inflammation

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers'. Together they form a unique fingerprint.

Cite this