• Checkpoint inhibitor
• Colorectal cancer
• Cytokine
• Immunotherapy

The expression of ZFP36 in previous study was reduced in prostate cancer (PCa) tissues as compared to benign prostate tissues, indicating the potential of ZFP36 as an auxiliary marker for PCa. Further evaluation was conducted in clinical samples for in vitro and in vivo experiments, to prove the potential possibility that ZFP36 dysregulation participated in the malignant phenotype of PCa, to determine its potential mechanism for tumor regulation, and to provide a new theoretical basis for gene therapy of PCa.

First, the expression of ZFP36 in prostate tissue and PCa tissue was explored, and the relationship between ZFP36 and clinical features of PCa patients was illustrated. Subsequently, the impact of ZFP36 on the biology of PCa cells and relevant downstream pathways of ZFP36's biological impact on PCa were elucidated. Finally, whether oxidative stress mediated the regulation of ZFP36 in PCa was verified by the determination of oxidative stress-related indicators and bioinformatics analysis.

The downregulation of ZFP36 in PCa tissue had a positive correlation with high Gleason scores, advanced pathological stage, and biochemical recurrence. ZFP36 was identified as an independent prognostic factor for PCa patients' BCR-free survival (P = 0.022) by survival analysis. Following a subsequent experiment of function gain and loss, ZFP36 inhibited the proliferation, invasion, and migration in DU145 and 22RV1 cells and inhibits tumor growth in the mouse model. Additionally, high-throughput sequencing screened out CDK6 as the downstream target gene of ZFP36. Western blot/Q-PCR demonstrated that overexpression of ZFP36 could reduce the expression of CDK6 at both cellular and animal levels, and the dual-luciferase experiment and RIP experiment proved that CDK6 was the downstream target of ZFP36, indicating that CDK6 was a downstream target of ZFP36, which mediated tumor cell growth by blocking cell cycle at the G1 stage. Furthermore, ZFP36 inhibited oxidative stress in PCa cells.

In PCa, ZFP36 might be a tumor suppressor that regulated growth, invasion, and migration of PCa cells. The lately discovered ZFP36-CDK6 axis demonstrated the molecular mechanism of PCa progression to a certain extent which might act as a new possible therapeutic target of PCa therapy.

• NF κB
• Nrf2
• STAT3
• Src
• chemoprevention
• inflammation

CD47 is expressed in all human cancer cells, including head and neck cancer, and initiates a signaling cascade to inhibit macrophage phagocytosis. However, the mechanism 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.

• RNA-binding proteins
• cancer
• lncRNA
• microRNA
• posttranscriptional regulation

• Alternative Splicing/genetics
• Carcinogenesis/metabolism
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• RNA-Binding Proteins/metabolism
• Tumor Suppressor Proteins/metabolism

Metabolic syndrome (MetS) is a common disorder characterized as a low-grade chronic inflammatory state. The association of tristetraprolin (TTP), a novel anti-inflammatory protein, and MetS remains to be explored. We evaluated circulating TTP in a group of adult males and females with and without MetS. Serum levels of TTP were higher in the MetS group than in controls. In all subjects, serum TTP was also correlated with MetS components (e.g., glucose, lipids, and obesity indices). These findings suggest that TTP may be a promising biomarker for MetS.

Tristetraprolin (TTP) is an mRNA binding protein suggested to have a substantial role in regulating the mRNA expression of numerous inflammatory factors, but data on TTP and its association with metabolic syndrome (MetS), a chronic low-grade inflammatory disorder, are scarce. We hypothesize that TTP may modulate MetS and its components. A total of 200 Saudi adults (aged 38.6 ± 8.3 years) were included in this cross-sectional study. Anthropometrics data were collected and fasting blood glucose taken for the assessment of glycemic, lipids and inflammatory markers using commercially available assays. The National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) criteria were used to define MetS. Results showed significantly higher levels of TTP in the MetS group than in controls [288.1 pg/mL vs. 150.9 pg/mL, p < 0.001]. Circulating TTP was significantly associated with tumor necrosis factor alpha [TNF-α, R = 0.30, p < 0.05], interleukin 1β [IL-1β, R = 0.41, p < 0.01] and C-reactive protein [CRP, R = 0.36, p < 0.01], adiponectin [R = 0.36, p < 0.05], insulin [R = 0.37, p < 0.05], and insulin resistance [HOMA-IR, R = 0.40, p < 0.05]. Receiver operating characteristics (ROC) suggest a potential use of TTP as diagnostic biomarker for MetS [AUC = 0.819, p < 0.001]. The findings suggest that TTP is associated with inflammation and glycemia, which may influence MetS. TTP is a promising diagnostic biomarker for MetS which can be confirmed in larger cohorts.

• Saudi
• inflammatory markers
• insulin
• metabolic syndrome
• tristetraprolin

Stress granules (SGs) represent important non-membrane cytoplasmic compartments, involved in cellular adaptation to various stressful conditions (e.g., hypoxia, nutrient deprivation, oxidative stress). These granules contain several scaffold proteins and RNA-binding proteins, which bind to mRNAs and keep them translationally silent while protecting them from harmful conditions. Although the role of SGs in cancer development is still poorly known and vary between cancer types, increasing evidence indicate that the expression and/or the activity of several key SGs components are deregulated in colorectal tumors but also in pre-neoplastic conditions (e.g., inflammatory bowel disease), thus suggesting a potential role in the onset of colorectal cancer (CRC). It is therefore believed that SGs formation importantly contributes to various steps of colorectal tumorigenesis but also in chemoresistance. As CRC is the third most frequent cancer and one of the leading causes of cancer mortality worldwide, development of new therapeutic targets is needed to offset the development of chemoresistance and formation of metastasis. Abolishing SGs assembly may therefore represent an appealing therapeutic strategy to re-sensitize colon cancer cells to anti-cancer chemotherapies. In this review, we summarize the current knowledge on SGs in colorectal cancer and the potential therapeutic strategies that could be employed to target them.

• Stress-Granules
• Colorectal cancer
• Adenylate-Uridylate-rich element-binding proteins
• Post-transcriptional regulation
• Oncogenes
• Tumor suppressors

• Colonic Neoplasms
• Colorectal Neoplasms/drug therapy
• Cytoplasmic Granules
• Humans
• RNA, Messenger
• RNA-Binding Proteins
• Stress, Physiological

• DSS
• IL-17
• RNA-binding protein
• TH17
• colitis
• mRNA decay
• tristetraprolin

• Animals
• Anti-Inflammatory Agents/pharmacology
• Antibodies, Neutralizing/pharmacology
• Colitis/chemically induced
• Colitis/immunology
• Colitis/metabolism
• Colitis/prevention & control
• Colon/drug effects
• Colon/immunology
• Colon/metabolism
• Colon/pathology
• Dermatitis/immunology
• Dermatitis/metabolism
• Dextran Sulfate
• Disease Models, Animal
• Humans
• Interleukin-17/blood
• Interleukin-17/genetics
• Jurkat Cells
• Mice, Inbred C57BL
• Mice, Knockout
• RNA Stability
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Signal Transduction
• Th17 Cells/drug effects
• Th17 Cells/immunology
• Th17 Cells/metabolism
• Tristetraprolin/deficiency
• Tristetraprolin/genetics
• Tristetraprolin/metabolism

• UL1 TR002345 NCATS NIH HHS
• R01 CA163808 NCI NIH HHS

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

• RNA-binding proteins
• ZFP36
• post-transcriptional regulation
• tristetraprolin
• tumor suppressor

• IL-13/STAT6 pathway
• Nephrotic syndrome
• doxorubicin
• tristetraprolin

• Biologics
• IL-17
• IL-23
• Protein-protein interactions
• Small molecules

• RBPs
• colorectal cancer
• oncogene
• post-transcriptional regulation
• tumor suppressor

Tristetraprolin (TTP), a well-characterized AU-rich element (ARE) binding protein, functions as a tumor suppressor gene. The purpose of this study was to investigate whether a bioactive substance derived from a natural medicinal plant affects the induction of TTP and to elucidate its mechanism. We examined the effects of natural bioactive materials including Resveratrol (RSV), thymoquinone (TQ) and curcumin on the expression of TTP in cancer cell. TQ derived from a natural plant Nigella sativa increased the expression levels of TTP mRNA and proteins in a dose-dependent manner in gastric and breast cancer cells. TQ-induced TTP increased the instability of MUC4 mRNA by direct binding of TTP to ARE in the 3′UTR of MUC4 mRNA. The induction of TTP by TQ also reduced the proliferation, migration and invasion of cancer cells. The expression of the epithelial-mesenchymal (EMT)-related genes, which were target genes of TTP, was also decreased by the TQ treatment. In the in vivo experiments using mouse melanoma cells, TQ-induced TTP inhibited metastasis of tumor cells. We have found that TQ-induced TTP might inhibit metastasis by reducing tumor cell migration and invasion through destabilization of MUC4 mRNA, which suggest the MUC4 as a novel target to TTP.

• ARE
• MUC4
• TQ
• TTP
• binding protein
• bioactive substance

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Benzoquinones/pharmacology
• Benzoquinones/therapeutic use
• Cell Line
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred C57BL
• Mucin-4/genetics
• Mucin-4/metabolism
• Neoplasms, Experimental/drug therapy
• RNA Stability
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Tristetraprolin/metabolism

Tristetraprolin (TTP) is an RNA binding protein that plays a critical role in regulating proinflammatory immune responses by destabilizing target mRNAs via binding to their AU-rich elements (AREs) in the 3′-UTRs of mRNAs. A recent CLIP-seq study revealed that TTP-binding sites are enriched in the intronic regions of RNA. TTP is also a nuclear protein that exhibits putative DNA-binding activity. These features suggested that TTP might regulate gene transcription and/or alternative splicing of pre-mRNAs in the absence of stimulation.

To elucidate the regulatory pattern of TTP, we cloned and overexpressed the human TTP-encoding gene, ZFP36, in HeLa cells in the absence of inflammatory stimuli. The transcriptomes of the control and ZFP36-overexpressing cells were sequenced and subjected to analysis and validation. Upon ZFP36 overexpression, the expression of genes associated with innate immunity, including those in the type I interferon signaling pathway and viral response, were specifically upregulated, implying a transcriptional regulatory mechanism associated with the predicted DNA binding activity of TTP. TTP preferentially regulated the alternative splicing of genes involved in the positive regulation of the I-κB/NF-κB cascade and the TRIF-dependent toll-like receptor, MAPK, TNF, and T cell receptor signaling pathways.

Our findings indicated that TTP may regulate the immune response via the regulation of alternative splicing and potentially transcription, which greatly expands the current understanding of the mechanisms of TTP-mediated gene regulation.

The online version of this article (10.1186/s12865-019-0292-1) contains supplementary material, which is available to authorized users.

• Alternative splicing
• Gene expression
• Overexpression
• RNA-seq
• ZFP36

Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a group of RNA-binding proteins called “Adenylate-Uridylate-rich elements binding proteins” (AUBPs) control mRNA stability or translation through their binding to AU-rich elements enriched in the 3’UTRs of inflammation- and cancer-associated mRNA transcripts. AUBPs play a central role in the recruitment of target mRNAs into small cytoplasmic foci called Processing-bodies and stress granules (also known as P-body/SG). Alterations in the expression and activities of AUBPs and P-body/SG assembly have been observed to occur with colorectal cancer (CRC) progression, indicating the significant role AUBP-dependent post-transcriptional regulation plays in controlling gene expression during CRC tumorigenesis. Accordingly, these alterations contribute to the pathological expression of many early-response genes involved in prostaglandin biosynthesis and inflammation, along with key oncogenic pathways. In this review, we summarize the current role of these proteins in CRC development. CRC remains a major cause of cancer mortality worldwide and, therefore, targeting these AUBPs to restore efficient post-transcriptional regulation of gene expression may represent an appealing therapeutic strategy.

• Colorectal cancer
• Adenylate-Uridylate-rich element-binding proteins
• Oncogenes
• Tumor suppressors
• Post-transcriptional regulation

• RNA-binding protein
• gastrointestinal cancer
• posttranscriptional gene regulation

• Butyrate
• Dietary fiber
• Proinflammatory cytokines
• Signaling pathways
• T-regulatory cells

• TTP
• cytoskeleton
• meiosis
• oocyte
• reproduction

• ARE
• GRE
• cancer
• cytokine signaling
• cytokines
• immune responses
• mRNA decay
• mRNA stability
• post-transcriptional regulation

• K24 AI096925 NIAID NIH HHS
• R01 AI072068 NIAID NIH HHS
• R56 AI057484 NIAID NIH HHS
• T32 AI083196 NIAID NIH HHS

• ARE
• Cancer
• Cytokine and growth factor signaling
• GRE
• Post-transcriptional gene regulation
• mRNA stability

• 3' Untranslated Regions
• Animals
• Apoptosis
• Cytokines/genetics
• Cytokines/metabolism
• Gene Expression Regulation
• Humans
• Intercellular Signaling Peptides and Proteins/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• Mice
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/physiopathology
• Protein Processing, Post-Translational/physiology
• RNA Stability
• Receptors, Cytokine/genetics
• Receptors, Cytokine/metabolism
• Signal Transduction

• K02 AI052170 NIAID NIH HHS
• K24 AI096925 NIAID NIH HHS
• R01 AI049494 NIAID NIH HHS
• R01 AI072068 NIAID NIH HHS

Tristetraprolin (TTP) is an adenine/uridine (AU)-rich element (ARE)-binding protein that can induce degradation of mRNAs. In this study, we report that TTP suppresses the expression of interleukin-33 (IL-33), a tumor-promoting inflammatory cytokine, and thereby inhibits the progression of gastric cancer (GC). Overexpression of TTP decreased the level of IL-33, whereas knockdown of TTP increased IL-33 levels. We also discovered that TTP inhibited the proliferation, migration, and invasion of GC cell lines through regulation of IL-33. Furthermore, TTP RNA and protein levels were remarkably reduced in GC and inversely correlated with IL-33 level, and they were also closely associated with depth of invasion, lymph node metastasis, advanced TNM stage, as well as survival rate. Taken together, these findings identified TTP as a downregulator of IL-33, and further suggest that TTP can serve as a novel biomarker for the diagnosis of GC and as a potential therapeutic target for GC treatment.

• Animals
• Computer Simulation
• Humans
• Interleukins/antagonists & inhibitors
• Interleukins/metabolism
• Mathematical Concepts
• Mice
• Models, Immunological
• Neoplasms, Experimental/immunology
• Neoplasms, Experimental/therapy
• Tumor Microenvironment/immunology

• Aged
• Albuminuria/blood
• Albuminuria/etiology
• Biomarkers
• Creatinine/urine
• DNA, Complementary/genetics
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/genetics
• Diabetes Mellitus, Type 2/urine
• Diabetic Nephropathies/blood
• Diabetic Nephropathies/genetics
• Diabetic Nephropathies/urine
• Disease Progression
• Female
• Gene Expression Regulation
• Humans
• Inflammation
• Interleukin-18/biosynthesis
• Interleukin-18/genetics
• Interleukin-18/urine
• Interleukin-6/biosynthesis
• Interleukin-6/genetics
• Interleukin-6/urine
• Kidney Glomerulus/physiopathology
• Male
• Middle Aged
• Proteinuria/blood
• Proteinuria/etiology
• RNA, Messenger/blood
• RNA, Messenger/genetics
• RNA, Messenger/urine
• Tristetraprolin/blood
• Tristetraprolin/genetics
• Tristetraprolin/physiology
• Tristetraprolin/urine

Aim of the study was to evaluate the potential role of regulatory and proinflammatory cytokines IL-23 and IL-17 as Th17 lymphocyte activity markers in relation to invasiveness in laryngeal cancer.

The immunological analysis was conducted in 50 patients treated for squamous cell laryngeal carcinoma and 30 healthy volunteers as controls. The levels of IL-23 and IL-17 in supernatants of purified peripheral blood mononuclear cell cultures were determined by using the enzyme-linked immunosorbent assay (ELISA). The clinicomorphological criteria included pTNM, stage, G, and the total tumour front grading (TFG) score.

Our data demonstrated higher concentrations of IL-23 in patients as compared to controls (p = 0.0001). No statistical difference for IL-17 in these groups was observed. Our study revealed significant dependences in IL-23 expression on pT (p = 0.04), histological differentiation (p = 0.04), and TFG total score (p = 0.02). Advanced tumours (pT3–pT4) with higher grade (G2–G3) and higher invasiveness (> 14 TFG points) were characterised by elevated IL-23 levels in PBMC supernatants. Our data did not indicate a relationship between cytokine levels and three- and five-year survival. However, a tendency towards lower content of IL-23 in PBMC cultures in patients who lived longer than five years after treatment was noted. The relationships between IL-17 level in PBMC cultures and clinicomorphological and prognostic parameters have not been disclosed.

The results of this study suggest the importance of regulatory cytokine IL-23 in determining the aggressive potential of laryngeal carcinomas.

• IL-17
• IL-23
• laryngeal carcinoma
• tumour front grading

• TTP
• glioma
• uPA
• uPAR

• 3' Untranslated Regions
• Antineoplastic Agents/pharmacology
• Brain Neoplasms/genetics
• Brain Neoplasms/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Down-Regulation
• Gene Expression Regulation, Neoplastic/drug effects
• Glioblastoma/genetics
• Glioblastoma/pathology
• Humans
• Receptors, Urokinase Plasminogen Activator/genetics
• Tristetraprolin/pharmacology
• Urokinase-Type Plasminogen Activator/genetics

• AU-rich element (ARE)
• CNOT1
• CNOT7/hCAF1
• ICAM-1
• IL-8
• Tristetraprolin (TTP)

• Atherosclerosis
• Endothelial Dysfunction
• NADPH Oxidase
• Reactive Nitrogen Species
• Reactive Oxygen Species (ROS)
• Tumor Necrosis Factor (TNF)

• Animals
• Aorta/metabolism
• Aorta/pathology
• Atherosclerosis/genetics
• Atherosclerosis/immunology
• Atherosclerosis/metabolism
• Cholesterol/metabolism
• Chronic Disease
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Female
• Male
• Membrane Glycoproteins/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidases/metabolism
• Organ Culture Techniques
• Oxidative Stress/physiology
• RNA Stability/physiology
• Reactive Nitrogen Species/metabolism
• Reactive Oxygen Species/metabolism
• Tristetraprolin/genetics
• Tristetraprolin/metabolism
• Tumor Necrosis Factor-alpha/genetics
• Tumor Necrosis Factor-alpha/metabolism
• Vasculitis/genetics
• Vasculitis/immunology
• Vasculitis/metabolism