TY - JOUR
T1 - Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers
AU - Ji, Zhe
AU - He, Lizhi
AU - Regev, Aviv
AU - Struhl, Kevin
N1 - Funding Information:
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.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/5/7
Y1 - 2019/5/7
N2 - 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.
AB - 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.
KW - Cancer
KW - Epignetic switch
KW - Gene regulatory network
KW - Inflammation
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U2 - 10.1073/pnas.1821068116
DO - 10.1073/pnas.1821068116
M3 - Article
C2 - 30910960
AN - SCOPUS:85065617207
SN - 0027-8424
VL - 116
SP - 9453
EP - 9462
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -