Tristetraprolin, a Potential Safeguard Against Carcinoma: Role in the Tumor Microenvironment

Zhang, Diwen; Zhou, Zhigang; Yang, Runhua; Zhang, Sujun; Zhang, Bin; Tan, Yanxuan; Chen, Lingyao; Li, Tao; Tu, Jian

doi:10.3389/fonc.2021.632189

Cited by 6 publications

(6 citation statements)

References 107 publications

(120 reference statements)

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“…TTP has previously been described as a 'prospective' cancer tumor suppressor (18,29,30).Here, we establish the role of TTP as a tumor suppressor in PCa and determine NF-κB activation contributes to the deleterious effects of TTP loss within tumor cells. Given the finding that TTP loss occurs early in PCa development, we used genetically engineered mouse models (GEMMs) to investigate the impact of TTP loss in combination with PTEN loss on prostate epithelial cell transformation to cancer.…”

Section: Introductionmentioning

confidence: 69%

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Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Morel

Hamid

Falcón

et al. 2022

Preprint

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Phenotypic plasticity is a hallmark of cancer and an increasingly realized as a mechanism of resistance in prostate tumors progressing on second generation AR targeted therapy. With the advent of treating prostate cancer (PCa) patients upfront with these agents, it is critical to identify mechanisms and actionable targets that drive phenotypic plasticity and prevent emergence of resistance. Here, we report that loss of tristetraprolin (TTP, gene ZFP36), an RNA binding protein that regulates mRNA stability increases NF-κB activation and is associated with higher rates of aggressive disease and early recurrence in primary PCa. Given ZFP36 loss occurs in early PCa we sought to examine the clinical and biological impact of ZFP36 loss combined with PTEN loss, a known driver of PCa. Analysis of independent primary PCa cohorts demonstrated that combined loss of PTEN and ZFP36 expression coincided with increased risk of recurrence. Engineering ZFP36 deletion specific to prostate luminal epithelial cells in vivo induced high-grade prostatic intraepithelial neoplasia (HG-PIN), and when combined with PTEN deletion resulted in rapid progression to invasive adenocarcinoma associated with increased proliferation and development of micro-metastases. Combined loss of ZFP36 and PTEN in mice significantly reduced overall survival as well as time to progression when mice were surgically castrated. Gene expression analysis revealed that loss of ZFP36 expression alters the cell state that is driven by PTEN loss, demonstrated by positive enrichment of gene sets including EMT, Inflammation, TNFα/NF-κB, IL6-JAK/STAT3. In addition, our work revealed the unique finding that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor, dimethylaminoparthenolide (DMAPT) induced significant therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed resistance to castration. This work identifies a novel molecular mechanism which drives resistance to castration through loss of ZFP36 expression driving the induction of phenotypic plasticity, that can be reversed by inhibition of NF-κB activity using DMAPT.

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Section: Introductionmentioning

confidence: 69%

“…TTP has previously been described as a ‘prospective’ cancer tumor suppressor (18, 29, 30). Here, we establish the role of TTP as a tumor suppressor in PCa and determine NF-κB activation contributes to the deleterious effects of TTP loss within tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Morel

Hamid

Falcón

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…ZFP36 (ZFP36 ring finger protein) is a well-known mRNA binding protein. In the tumor microenvironment, ZFP36 might reduce the growth and invasion of glioma cells by targeting IL-13 mRNA to inhibit the role of PI3K/Akt/mTOR pathways [ 73 - 75 ] . CP (ceruloplasmin) serves as a prognostic biomarker in many cancers, including bile duct cancer, bladder cancer, breast cancer, etc .…”

Section: Discussionmentioning

confidence: 99%

Multicellular biomarkers of drug resistance as promising targets for glioma precision medicine and predictors of patient survival

Shao

2022

Cancer Drug Resist

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Aim: This study aimed to translate a known drug-resistance mechanism of long-term CSF1R inhibition into multicellular biomarkers that can serve as potential therapeutic targets as well as predictive markers for the survival of glioma patients. Methods: Using existing data from a published mouse study of drug resistance in immunotherapy for glioma, we identified multicellular differentially expressed genes (DEGs) between drug-sensitive and drug-resistant mice and translated the DEGs in mouse genome to human homolog. We constructed correlation gene networks for drug resistance in mice and glioma patients and selected candidate genes via concordance analysis of human with mouse gene networks. Markers of drug resistance and an associated predictive signature for patient survival were developed using regularized Cox models with data of glioma patients from The Cancer Genome Atlas (TCGA) database. Predictive performance of the identified predictive signature was evaluated using an independent human dataset from the Chinese Glioma Genome Atlas (CGGA) database. Results: Fourteen genes (CCL22, ADCY2, PDK1, ZFP36, CP, CD2, PLAUR, ACAP1, COL5A1, FAM83D, PBK, FANCA, ANXA7, and TACC3) were identified as genetic biomarkers that were all associated with pathways in glioma progression and drug resistance. Five of the 14 genes (CCL22, ADCY2, PDK1, CD2, and COL5A1) were used to construct a signature that is predictive of patient survival in the proneural subtype GBM patients with an AUC under the time-dependent receiver operating characteristic (ROC) of 2-year survival equal to 0.89. This signature also shows promising predictive accuracy for the survival of LGG patients but not for non-proneural type GBMs. Conclusion: Our translational approach can utilize gene correlation networks from multiple types of cells in the tumor microenvironment of animals. The identified biomarkers of drug resistance have good power to predict patient survival in some major subtypes of gliomas (the proneural subtype of GBM and LGG). The expression levels of the biomarkers of drug resistance may be modified for the development of personalized immunotherapies to prolong survival for a large portion of glioma patients.

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“…Because of its ability to bind and target ARE-containing mRNAs for rapid degradation, numerous studies have shown that TTP exhibits as tumor-suppressor. Thus, loss of TTP expression or function is closely associated with tumor progression or poor outcome in malignant tumors ( 13 , 14 ). It was known that some tumor-associated genes with ARE sequences can be subject to TTP-mediated mRNA degradation.…”

Section: Introductionmentioning

confidence: 99%

Tristetraprolin regulates phagocytosis through interaction with CD47 in head and neck cancer

Lee

Kim

et al. 2022

Exp Ther Med

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CD47 is expressed in all human cancer cells, including head and neck cancer, and initiates a signaling cascade to inhibit macrophage phagocytosis. However, the mecha nism underlying CD47 overexpression has not been elucidated in radioresistant head and neck cancer. The present study demonstrated that decreased Tristetraprolin (TTP) expression induced a sustained overexpression of CD47 using reverse transcription-quantitative PCR and western blotting, and that CD47 overexpression prevented phagocytosis using a phagocytosis assay in a radioresistant HN31R cell line. Subsequently, using TTP transfection, RNA interference, duel-luciferase assay and EMSA, it was revealed that TTP transfection enhanced phagocytosis through degradation of CD47 mRNA by directly binding to CD47 AREs within the CD47 3'UTR. Based on our previous study, methylation-specific PCR and western blotting revealed that DNMT1 was overexpressed in radioresistant HN31R cell line and TTP expression was decreased epigenetically by DMNT1 associated DNA methylation. Overall, these findings provided novel insight into the role of TTP as a biomarker of CD47-positive head and neck cancer patients.

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Tristetraprolin, a Potential Safeguard Against Carcinoma: Role in the Tumor Microenvironment

Cited by 6 publications

References 107 publications

Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Multicellular biomarkers of drug resistance as promising targets for glioma precision medicine and predictors of patient survival

Tristetraprolin regulates phagocytosis through interaction with CD47 in head and neck cancer

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