The
RNA-binding protein Tristetraprolin (
TTP, ZFP36) functions as a
tumor suppressor that impairs the development and disables the maintenance of MYC-driven
lymphoma. In addition, other human
cancers expressed reduced levels of
TTP, suggesting that it may function as a
tumor suppressor in several
malignancies. To identify genes that may be associated with
TTP tumor suppressor functions in human
cancer, we analyzed The
Cancer Genome Atlas (TCGA)
breast cancer,
lung adenocarcinoma, lung
squamous cell carcinoma, and
colon adenocarcinoma datasets. These analyses defined a signature of 50 genes differentially regulated between high and low
TTP-expressing
tumors. Notably, patients with low
TTP-expressing
breast cancer and
lung adenocarcinoma had decreased survival rates and more aggressive
tumors with increased
necrosis. In addition, analysis across non-TCGA
tumor gene expression databases identified a broad spectrum of human
cancers having similarities with the
TTP-low
tumor gene signature, including pancreatic, bladder, and
prostate cancer.
TTP has documented roles in regulating mRNAs encoding inflammatory
proteins, and pathway analysis identified several inflammatory pathways that are altered in
tumors with low
TTP expression. Surprisingly, the
TTP-low
tumor gene signature includes a core component of 20 under-expressed CREB target genes, suggesting that the regulation of CREB activity may be related to the
tumor suppressor function of
TTP. Thus, reduced levels of
TTP are a potential
biomarker for human
cancers with poor outcome, and targeting the CREB pathway may be a therapeutic route for treating aggressive
TTP-low
tumors.