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Transcriptomic analysis by RNA-seq reveals AP-1 pathway as key regulator that green tea may rely on to inhibit lung tumorigenesis. Mol Carcinog 2014 Jan;53(1):19-29 PMID: 24343902

Pubmed ID

24343902

DOI

10.1002/mc.21941

Abstract

Green tea is a promising chemopreventive agent for lung cancer. Multiple signaling events have been reported, however, the relative importance of these mechanisms in mediating the chemopreventive function of green tea is unclear. In the present study, to examine the involvement of AP-1 in green tea polyphenols induced tumor inhibition, human NSCLC cell line H1299 and mouse SPON 10 cells were identified as AP-1 dependent, as these two lines exhibit high constitutive AP-1 activity, and when TAM67 expression was induced with doxycycline, cell growth was inhibited and correlated with suppressed AP-1 activity. RNA-seq was used to determine the global transcriptional effects of AP-1 inhibition and also uncover the possible involvement of AP-1 in tea polyphenols induced chemoprevention. TAM67 mediated changes in gene expression were identified, and within down-regulated genes, AP-1 was identified as a key transcription regulator. RNA-seq analysis revealed that Polyphenon E-treated cells shared 293 commonly down-regulated genes within TAM67 expressing H1299 cells, and by analysis of limited Chip-seq data, over 10% of the down-regulated genes contain a direct AP-1 binding site, indicating that Polyphenon E elicits chemopreventive activity by regulating AP-1 target genes. Conditional TAM67 expressing transgenic mice and NSCLC cell lines were used to further confirm that the chemopreventive activity of green tea is AP-1 dependent. Polyphenon E lost its chempreventive function both in vitro and in vivo when AP-1 was inhibited, indicating that AP-1 inhibition is a major pathway through which green tea exhibits chemopreventive effects.

Author List

Pan J, Zhang Q, Xiong D, Vedell P, Yan Y, Jiang H, Cui P, Ding F, Tichelaar JW, Wang Y, Lubet RA, You M

Authors

Jing Pan PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Yian Wang MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Qi Zhang PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Carcinogenesis
Cell Line, Tumor
Cell Proliferation
Cluster Analysis
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Lung Neoplasms
Mice
Peptide Fragments
Promoter Regions, Genetic
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-jun
Signal Transduction
Tea
Transcription Factor AP-1
Transcriptome
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e