Tribbles Homolog Research Articles

TRIB3 overexpression predicts malignant progression and poor prognosis in human solid tumors: bioinformatics validation and clinical significance

ABSTRACT Introduction Overexpression of tribbles homolog 3 (TRIB3) has been reported in various cancers, yet its clinical significance remains contentious. This study aims to elucidate the association between TRIB3 overexpression and the progression and prognosis of solid tumors. Methods A comprehensive analysis was conducted using data from published studies and The Cancer Genome Atlas (TCGA) up to May 2023. We evaluated the impact of high TRIB3 expression on tumor malignancy and survival outcomes across different cancer types. Results Seventeen studies met the inclusion criteria. Our findings revealed that TRIB3 overexpression is significantly associated with increased distant metastasis (OR = 4.01, 95% CI: 2.36–6.74, p < 0.001) and advanced histological stage (OR = 2.68, 95% CI: 1.50–4.78, p < 0.001). Additionally, high TRIB3 expression significantly elevated the risk of reduced overall survival (OS) in cancer patients (HR = 1.52, 95% CI: 1.05–2.20, p < 0.001), indicating a poor prognosis. Analyses of TCGA data among various prognostic indicators corroborated these findings. Conclusions TRIB3 overexpression is significantly linked to malignant progression and unfavorable prognosis in diverse solid tumors. These results suggest that TRIB3 holds promise as a biomarker and therapeutic target in human cancers.

Cell-permeated peptide P-T3H2 inhibits malignancy on hepatocellular carcinoma through stabilizing HNF4α protein

ObjectivesHepatocyte nuclear factor 4α (HNF4α) is a key regulator of hepatocyte function and has a strong therapeutic effect on hepatocellular carcinoma (HCC) by inducing the differentiation of hepatoma cell into hepatocytes. Our previous study showed that Tribbles homolog 3 (TRIB3) directly interacts with and promotes the degradation of HNF4α in non-alcoholic fatty liver disease (NAFLD). Disrupting the TRIB3–HNF4α interaction by a cell-permeating peptide, called P-T3H2, stabilized HNF4α protein. This study aimed to assess the anti-tumor impact of P-T3H2 in HCC.MethodsThe expression of TRIB3 and HNF4α was evaluated using western blot and immunohistochemistry (IHC). Hepatic functions and cellular senescence of HCC cells were evaluated through periodic acid-Schiff (PAS) staining, acetylated low-density lipoprotein (ac-LDL) uptake and senescence-associated β-galactosidase (SA-β-gal) activity staining, respectively. RNA-Seq analysis was performed to identify differentially expressed genes in Huh7 cells treated with P-T3H2. The impact of P-T3H2 on HCC malignancy was assessed in vitro and in vivo.ResultsTRIB3 exhibited a negative correlation with HNF4α in both human and mouse HCC tissues. The administration of P-T3H2 significantly inhibited the malignancy of HCC cells. Additionally, P-T3H2 stabilized HNF4α protein and facilitated the restoration of hepatic functions and the cellular senescence in HCC cells. RNA-Seq analysis demonstrated that P-T3H2 enhanced the transcriptional activity of HNF4α in HCC. Furthermore, P-T3H2 effectively suppressed the carcinogenesis and progression of HCC in mice.ConclusionP-T3H2 suppressed HCC progression through the stabilization of HNF4α protein and may be a promising therapeutic candidate for clinical application in the treatment of HCC.

Rapid increase of C/EBPα p42 induces growth arrest of acute myeloid leukemia (AML) cells by Cop1 deletion in Trib1-expressing AML.

Cop1 encodes a ubiquitin E3 ligase that has been well preserved during evolution in both plants and metazoans. In metazoans, the C/EBP family transcription factors are targets for degradation by Cop1, and this process is regulated by the Tribbles pseudokinase family. Over-expression of Tribbles homolog 1 (Trib1) induces acute myeloid leukemia (AML) via Cop1-dependent degradation of the C/EBPα p42 isoform. Here, we induced rapid growth arrest and granulocytic differentiation of Trib1-expressing AML cells using a Cop1 conditional knockout (KO), which is associated with a transient increase in the C/EBPα p42 isoform. The growth-suppressive effect of Cop1 KO was canceled by silencing of Cebpa and reinforced by exogenous expression of the p42 isoform. Moreover, Cop1 KO improved the survival of recipients transplanted with Trib1-expressing AML cells. We further identified a marked increase in Trib1 protein expression in Cop1 KO, indicating that Trib1 is self-degraded by the Cop1 degradosome. COP1 downregulation also inhibits the proliferation of human AML cells in a TRIB1-dependent manner. Taken together, our results provide new insights into the role of Trib1/Cop1 machinery in the C/EBPα p42-dependent leukemogenic activity, and a novel idea to develop new therapeutics.

Liraglutide ameliorates high glucose-induced vascular endothelial injury through TRIB3/NF-κB signaling pathway.

As one of the most commonly used antidiabetic medications clinically, liraglutide is involved in the protection of vascular endothelium, and whether it can relieve high glucose-induced vascular endothelial damage was unknown. This study aims to address the response of liraglutide (LIRA) on human umbilical vein endothelial cells, as well as to elucidate its possible underlying mechanism. We established a vascular endothelial cell injury model by exposing human umbilical vein endothelial cells (HUVECs) to high glucose, and used LIRA pretreatment before HG treatment to address the endothelial protective effect of LIRA. Our results suggest that LIRA prevented HG-induced HUVEC apoptosis, oxidative stress, inflammasome activation, and pyroptosis. Furthermore, silencing of tribbles homolog 3 (TRIB3) could markedly reduce HG-induced HUVEC apoptosis, ROS level, the expressions of TXNIP, cleaved caspase3, NLRP3, and caspase1, indicating TRIB3 inhibition protected HUVECs against HG-induced vascular endothelial injury. In addition, LIRA restrained NF-κB/IκB-α signaling pathway activation in HUVECs. Thus, LIRA appears to mitigate HG-induced apoptosis, oxidative stress, inflammasome activation, and pyroptosis in HUVECs via regulating the TRIB3/NF-κB/IκB-α signaling pathway. Our study provides new insight into the mechanisms underlying the protective activity of LIRA against the vascular endothelial injury in diabetic vascular complication.

Diverse functions of Tribbles homolog 3 in cancers and its potential as a therapeutic target.

Currently, cancer is the second leading cause of death worldwide, and potential targeted drugs and molecular pathways for cancer development and progression have been a hot research topic worldwide. In recent years, the importance of the kinase superfamily in diseases has been well demonstrated by studies on various molecular mechanisms of kinases and the successful application of their inhibitors in diseases. Pseudokinases are members of the kinase superfamily, which have been increasingly documented to play a crucial role in cancers year after year. As a member of pseudokinases, tribbles homolog 3 (TRIB3) also exerts diverse functions in different cancers through different interacting proteins and molecular pathways, especially in tumor immunity, stemness, drug resistance, metabolism, and autophagy. In addition, peptide drugs targeting TRIB3 have high specificity in preclinical studies, which shows great promise for TRIB3 application in diseases including cancers. In this review, we dissect diverse functions played by TRIB3 in different cancers, describing the underlying mechanisms in detail. Notably, inhibitors and agonists currently available for TRIB3 are discussed, indicating the potential for TRIB3 as a therapeutic target.

Tyrosine-phosphorylated DNER sensitizes insulin signaling in hepatic gluconeogenesis by inducing proteasomal degradation of TRB3

ObjectiveHepatic insulin resistance, which leads to increased hepatic gluconeogenesis, is a major contributor to fasting hyperglycemia in type 2 diabetes mellitus (T2DM). However, the mechanism of impaired insulin-dependent suppression of hepatic gluconeogenesis remains elusive. Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER), firstly described as a neuron-specific Notch ligand, has been recently identified as a susceptibility gene for T2DM through genome-wide association studies. We herein investigated whether DNER regulates hepatic gluconeogenesis and whether this is mediated by enhanced insulin signaling. MethodsThe association between DNER, tribbles homolog 3 (TRB3) and Akt signaling was evaluated in C57BL/6J, ob/ob and db/db mice by western blot analysis. DNER loss-of-function and gain-of-function in hepatic gluconeogenesis were analyzed by western blot analysis, quantitative real-time PCR, glucose uptake and output assay in AML-12 cells and partially validated in primary mouse hepatocytes. Hepatic DNER knockdown mice were generated by tail vein injection of adenovirus to confirm the effects of DNER in vivo. The interaction between DNER and TRB3 was investigated by rescue experiments, cycloheximide chase analysis, co-immunoprecipitation and immunofluorescence. The potential insulin-stimulated phosphorylation sites of DNER were determined by co-immunoprecipitation, LC-MS/MS analysis and site-specific mutagenesis. ResultsHere we show that DNER enhanced hepatic insulin signaling in gluconeogenesis by inhibiting TRB3, an endogenous Akt inhibitor, through the ubiquitin-proteasome degradation pathway. In AML-12 hepatocytes, insulin-stimulated activation of Akt and suppression of gluconeogenesis are attenuated by DNER knockdown, but potentiated by DNER over-expression. In C57BL/6J mice, hepatic DNER knockdown is accompanied by impaired glucose and pyruvate tolerance. Furthermore, the in vitro effects of DNER knockdown or over-expression on both Akt activity and hepatic gluconeogenesis can be rescued by TRB3 knockdown or over-expression, respectively. In response to insulin stimulation, DNER interacted directly with insulin receptor and was phosphorylated at Tyr677. This site-specific phosphorylation is essential for DNER to upregulate Akt activity and then downregulate G6Pase and PEPCK expression, by interacting with TRB3 directly and inducing TRB3 proteasome-dependent degradation. ConclusionsTaken together, the crosstalk between insulin-Akt and DNER-TRB3 pathways represents a previously unrecognized mechanism by which insulin regulates hepatic gluconeogenesis.

Chronic intermittent hypoxia-induced oxidative stress activates TRB3 and phosphorylated JNK to mediate insulin resistance and cell apoptosis in the pancreas.

This study explores the potential mechanisms of obstructive sleep apnoea (OSA) complicates type 2 diabetes mellitus (T2DM) by which chronic intermittent hypoxia (CIH) induces insulin resistance and cell apoptosis in the pancreas through oxidative stress. Four- and eight-week CIH rat models were established, and Tempol (100 mg/kg/d), was used as an oxidative stress inhibitor. This study included five groups: 4-week CIH, 4-week CIH-Tempol, 8-week CIH, 8-week CIH-Tempol and normal control (NC) groups. Fasting blood glucose and insulin levels were measured in the serum. The expression levels of 8-hidroxy-2-deoxyguanosine (8-OHdG), tribbles homologue 3 (TRB3), c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), insulin receptor substrate-1 (IRS-1), phosphorylated IRS-1 (Ser307) (p-IRS-1ser307 ), protein kinase B (AKT), phosphorylated AKT (Ser473) (p-AKTser473 ), B cell lymphoma protein-2 (Bcl-2), cleaved-caspase-3 (Cl-caspase-3), and the islet cell apoptosis were detected in the pancreas. CIH induced oxidative stress in the pancreas. Compared with that in the NC group and CIH-Tempol groups individually, the homeostasis model assessment of insulin resistance (HOMA-IR) and apoptosis of islet cells was increased in the CIH groups. CIH-induced oxidative stress increased the expression of p-IRS-1Ser307 and decreased the expression of p-AKTSer473 . The expression levels of TRB3 and p-JNK were higher in the CIH groups than in both the CIH-Tempol and NC groups. Meanwhile, the expressions of Cl-caspase-3 and Bcl-2 were upregulated and downregulated, respectively, in the CIH groups. Hence, the present study demonstrated that CIH-induced oxidative stress might not only induce insulin resistance but also islet cell apoptosis in the pancreas through TRB3 and p-JNK.

The pleiotropic approach to coronavirus disease-19 pathogenesis: The impact of liver diseases associated host genetic variants.

Coronavirus disease-2019 (COVID-19) is a novel multisystemic viral disease caused pandemic. The disease impact involves liver and associated systems. Undoubtedly, host genetic background influences the predisposition and prediction of infection. Variants among human populations might increase susceptibility or protect against severe outcomes. In this manner, rs738409 variant of patatin-like phospholipase domain-containing protein 3 gene appears to be protective in some populations in spite of its aggravating effect on non-alcoholic fatty liver diseases (NAFLDs) and steatohepatitis. DRB1*15:01 allele of human leukocyte antigen is associated with protective effect in European and Japanese populations. DRB1*03:01 contrarily increases the susceptibility of severe COVID-19 infection in European populations. rs1260326 in glucokinase regulatory protein gene, rs112875651 in tribbles homolog 1 gene, rs429358 in apolipoprotein 1, and rs58542926 in transmembrane 6 superfamily 2 alleles are found related with NAFLD and obesity; thus, hypercoagulability and severe COVID-19 outcomes. In chronic or acute liver diseases, comorbid syndromes are the key factors to explain increased severity. There might not be a direct association between the variant and severe COVID-19 infection. As it is concluded, there are genes and variants known and unknown yet to be studied to reveal the association with disease severity.

Evaluation of sestrin 2 and tribbles homolog 3 levels in obese and nonobese women with polycystic ovary syndrome.

This study was designed to evaluate the relationship of two new biomarkers [tribbles homolog 3 (TRB3) and sestrin 2 levels], which were previously associated with obesity, with metabolic parameters in obese and nonobese women with polycystic ovary syndrome (PCOS). This cross-sectional case control study was conducted between September 2017 and August 2019 in the gynecology department of a tertiary referral hospital. The values of the plasma sestrin 2, TRB3, insulin, fasting plasma glucose, lipid profile, and homeostasis model assessment of insulin resistance (HOMA-IR) were compared in 90 obese women with PCOS (BMI > 30), 90 women with nonobese PCOS (BMI < 30), and 90 control patients (BMI < 30). The mean age of the study group consisting of all PCOS patients (26.11 ± 4.64 years) and the mean age of the control group (26.3 ± 4.4 years) were statistically similar (p = 0.239). The serum sestrin 2 values of the obese PCOS group were found to be statistically significantly lower than the control and non-obese PCOS groups (p = 0.001, p = 0.0001), while the sestrin 2 values of the nonobese PCOS group were found to be statistically significantly lower than the control group (p = 0.0001). The TRB3 values of the control group were found to be statistically significantly lower than the obese and nonobese PCOS groups (p = 0.0001), while the TRB3 values of the nonobese PCOS group were found to be statistically significantly lower than the obese PCOS group (p = 0.0001). A negative correlation was observed between the sestrin 2 level and BMI (r = -0.272 p = 0.0001), insulin (r = -0.261 p = 0.0001), and HOMA-IR levels (r = -0.250 p = 0.0001). A positive correlation was observed between the TRB3 values and TG (r = 0.248 p = 0.0001), and LDL-C values (r = 0.235 p = 0.0001). According to the findings in this study, low sestrin 2 and high TRB3 levels may be related to impaired metabolic status in the obese PCOS group. Thus, it may be promising for the development of treatment of PCOS and associated metabolic disorder in the future.

Emodin suppresses adipogenesis of bone marrow derived mesenchymal stem cells from aplastic anemia via increasing TRIB3 expression

BackgroundIncreasing evidence indicate that enhanced adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) could contribute to the adiposity alteration in marrow microenvironment of aplastic anemia (AA). Identifying small molecule drugs with role in inhibiting adipogenesis of BM-MSCs may represent a novel direction in AA therapy by improving BM-MSCs mediated marrow microenvironment. MethodsFor the purpose, we isolated AA BM-MSCs through whole bone marrow cell culture, evaluated a series of small molecule drugs using the in vitro adipogenic differentiation model of BM-MSCs, and finally focused on emodin, a natural anthraquinone derivative. Subsequently, we systematically investigated the molecular mechanism of emodin in attenuating adipogenic process by means of microarray profiling, bioinformatics analysis and lentivirus-mediated functional studies and rescue assay. ResultsWe found that emodin presented significantly suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Further mechanistic investigation revealed that emodin could increase the expression of Tribbles homolog 3 (TRIB3) which exhibited remarkably decreased expression in AA BM-MSCs compared with the normal counterparts and was subsequently demonstrated as a negative regulator in adipogenesis of AA BM-MSCs. Besides, TRIB3 depletion alleviated the suppressive effect of emodin on the adipogenic differentiation of AA BM-MSCs. ConclusionOur findings propose that emodin mediated TRIB3 up-regulation alleviates the adipogenic capacity of AA BM-MSCs, and emodin could serve as a potential therapeutic regimen for AA therapy.

Interfering TRIB3 protects the blood brain barrier through PI3K/Akt pathway to alleviate cerebral ischemia-reperfusion injury in diabetes mellitus mice

This study aimed to treat diabetic cerebral ischemia-reperfusion injury (CI/RI) by affecting blood brain barrier (BBB) permeability and integrity. The CI/RI model in DM mice and a high glucose (HG) treated oxygen and glucose deprivation/reoxygenation (OGD/R) brain endothelial cell model were established for the study. Evans blue (EB) staining was used to evaluate the permeability of BBB in vivo. TTC staining was used to analyze cerebral infarction. The location and expression of tribbles homolog 3 (TRIB3) in endothelial cells were detected by immunofluorescence. Western blotting was used to detect the protein expressions of TRIB3, tight junction molecules, adhesion molecules, phosphorylated protein kinase B (p-AKT) and AKT. The levels of pro-inflammatory cytokines were detected by qRT-PCR. Trans-epithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran were used to measure vascular permeability in vitro. TRIB3 ubiquitination and acetylation levels were detected. Acetyltransferase bound to TRIB3 were identified by immunoprecipitation. TRIB3 was localized in cerebral endothelial cells and was highly expressed in diabetic CI/R mice. The BBB permeability in diabetic CI/R mice and HG-treated OGD/R cells was increased, while the junction integrity was decreased. Interference with TRIB3 in vitro reduces BBB permeability and increases junction integrity. In vivo interfering with TRIB3 reduced cerebral infarction volume, BBB permeability and inflammation levels, and upregulated p-AKT levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin reversed the effects of TRIB3-interfering plasmid. In vitro HG treatment induced TRIB3 acetylation through acetyltransferase p300, which in turn reduced ubiquitination and stabilized TRIB3. Interfering TRIB3 protects BBB by activating PI3K/AKT pathway and alleviates brain injury, which provides a new target for diabetic CI/RI.

Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.

TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response

Robust regenerative response post liver injuries facilitates the architectural and functional recovery of the liver. Intrahepatic redox homeostasis plays a key role in liver regeneration. In the present study, we investigated the contributory role of Tribbles homolog 1 (Trib1), a pseudokinase, in liver regeneration and the underlying mechanism. We report that Trib1 expression was transiently down-regulated in animal and cell models of liver regeneration. Further analysis revealed that hepatocyte growth factor (HGF) repressed Trib1 transcription by evicting liver X receptor (LXRα) from the Trib1 promoter. Knockdown of Trib1 enhanced whereas over-expression of Trib1 suppressed liver regeneration after partial hepatectomy in mice. Of interest, regulation of liver regenerative response by Trib1 coincided with alterations of intracellular ROS levels, GSH levels, and antioxidant genes. Transcriptional assays suggested that Trib1 influenced cellular redox status by attenuating nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Mechanistically, Trib1 interacted with the C-terminus of Nrf2 thus masking a potential nuclear localization signal (NLS) and blocking nuclear accumulation of Nrf2. Finally, correlation between Trib1 expression, Nrf2 nuclear localization, and cell proliferation was identified in liver specimens taken from patients with acute liver failure. In conclusion, our data unveil a novel pathway that depicts Trib1 as a critical link between intracellular redox homeostasis and cell proliferation in liver regeneration.

The role of tribbles homolog 2 in vascular smooth muscle cell proliferation.

Tribbles homolog 2 (TRIB2) functions as an adapter protein that regulates signal transductions involved in a variety of cellular functions, including tumorigenesis. However, the role of TRIB2 in the proliferation of vascular smooth muscle cells (VSMCs) and the underlying expression mechanisms remain unclear. The present study investigated the role of TRIB2 in VSMC proliferation and revealed that TRIB2 expression increases following vascular injury and platelet-derived growth factor (PDGF)-BB-stimulated VSMCs. We found that pretreatment with diphenyleneiodonium (a nicotinamide adenine dinucleotide phosphate oxidase inhibitor), U0126 (an inhibitor of mitogen-activated protein kinase kinase 1 [MEK1]), or siRNA targeting the gene encoding early growth response 1 (EGR-1) significantly inhibits PDGF-BB-induced TRIB2 expression in VSMCs. Furthermore, TRIB2 knockdown significantly inhibits PDGF-BB-induced proliferation of VSMCs but does not affect the phosphorylation of AKT. However, phosphorylation of ERK1 and expression of proliferating cell nuclear antibody are significantly suppressed in VSMCs by PDGF-BB stimulation. Thus, PDGF-BB-induced TRIB2 expression is mediated by ROS/ERK/EGR-1 pathways and plays a critical role in VSMC proliferation via modulation of ERK activity. We propose TRIB2 as a promising therapeutic target for the prevention of neointima formation and vascular disease.

Effect of TRIB1 Variant on Lipid Profile and Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Emerging evidence indicates tribbles homolog 1 (Trib1) protein may be involved in lipid metabolism regulation and coronary artery disease (CAD) pathogenesis. However, whether TRIB1 gene variants affect lipid levels and CAD remains elusive, this study is aimed at clarifying the effect of TRIB1 variants on lipid profile and CAD. By searching PubMed and Cochrane databases for studies published before December 18, 2022, a total of 108,831 individuals were included for the analysis. The outcomes of the analysis on all individuals showed that the A allele carriers of rs17321515 and rs2954029 variants had higher low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels than the noncarriers. Consistently, a higher CAD risk was observed in the A allele carriers. Subgroup analysis indicated that increased LDL-C, TC, and CAD risk were observed in Asian population. Variants of TRIB1 (i.e., rs17321515 and rs2954029) may serve as causal genetic markers for dyslipidemia and CAD in Asian population.

The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer.

Currently, cancer ranks as the second leading cause of death worldwide, and at the same time, the burden of cancer continues to increase. The underlying molecular pathways involved in the initiation and development of cancer are the subject of considerable research worldwide. Further understanding of these pathways may lead to new cancer treatments. Growing data suggest that Tribble's homolog 3 (TRIB3) is essential in oncogenesis in many types of cancer. The mammalian tribbles family's proteins regulate various cellular and physiological functions, such as the cell cycle, stress response, signal transduction, propagation, development, differentiation, immunity, inflammatory processes, and metabolism. To exert their activities, Tribbles proteins must alter key signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. Recent evidence supports that TRIB3 dysregulation has been linked to various diseases, including tumor development and chemoresistance. It has been speculated that TRIB3 may either promote or inhibit the onset and development of cancer. However, it is still unclear how TRIB3 performs this dual function in cancer. In this review, we present and discuss the most recent data on the role of TRIB3 in cancer pathophysiology and chemoresistance. Furthermore, we describe in detail the molecular mechanism TRIB3 regulates in cancer.

Comparing Tribbles Homolog 3 (TRIB3) Protein Expression Levels with Clinicopathological Characteristics and Survival Among Neuroblastoma Patients.

Tribbles Homolog 3 (TRIB3) is a member of the pseudokinase family of tribbles and acts as an adaptor protein to regulate different cellular processes. Upregulation of TRIB3 expression was shown either as a favorable or an adverse prognostic factor in various adult malignancies. However, TRIB3 expression has not been examined in pediatric cancers. Neuroblastoma is the most common malignant solid tumor of childhood, which affects mostly children under 5 years old. Risk stratification of patients defined by International Neuroblastoma Risk Group was used to determine prognosis and treatment of the disease. This study aimed to examine the relationship between TRIB3 protein expression levels and clinicopathological features and survival of patients. TRIB3 protein expression was analyzed using immunohistochemical staining on formalin-fixed paraffin-embedded tissue samples of neuroblastoma patients (n = 56). Survival analyses were performed with Kaplan-Meier method and log-rank tests. Association between TRIB3 expression and clinicopathological characteristics were analyzed with Spearman's correlation. Of the patients, 32.1% were in the low-risk group, 21.4% in the medium-risk group, and 46.4% in the high-risk group. Survival analysis was performed in the entire neuroblastoma patient group and sub-risk groups of neuroblastoma patients. In the entire patient group, there was no significant difference in overall survival (P = .202) and event-free survival (P = .172) between TRIB3-positive and -negative patients. However, when survival analyses were performed in each risk group, TRIB3 expression was significantly associated with higher overall survival (P = .034) and event-free survival (P = .032) in low-risk group neuroblastoma patients. Nevertheless, no association was found between TRIB3 expression and overall survival (P = .799) and event-free survival (P = .448) in high-risk neuroblastoma patients. Furthermore, a significant correlation was identified between 1p36 loss-of-heterozygosity and TRIB3 expression (P = .030). However, TRIB3 expression did not correlate with other clinicopathological features. TRIB3 expression is a potential predictive biomarker for low-risk neuroblastoma patients.

The molecular characteristic analysis of TRIB2 gene and its expressional patterns in Bos grunniens tissue and granulosa cells

Tribbles homolog 2 (TRIB2) plays an important role in the follicular development of female mammals. However, its expression and function in the yak (Bos grunniens) are still unclear. In this study, we predicted the molecular characteristics of TRIB2, and revealed its expression pattern in yak (Bos grunniens) tissues and ovarian granulosa cells. We cloned the full length of the yak TRIB2 gene obtained by RT-PCR was 1368 bp and the coding sequence (CDS) was 624 bp, encoding 207 amino acids (AA). Homology analysis showed that the yak TRIB2 is highly conserved among species. TRIB2 was detected to be extensively expressed in seven tissues of the yak liver, spleen, lung, kidney, ovary, oviduct and uterus by qPCR. The expression of TRIB2 mRNA in the ovary during gestation was significantly lower than that in the non-pregnant (p < 0.05). At each stage of follicle development, the TRIB2 mRNA in granulosa cells showed a significant upward trend with the development of follicles. The expression of TRIB2 gradually decreased with the increase of the culture time of the granulosa cells in vitro. In conclusion, these results suggest that TRIB2 may play an important role in the follicular development of yaks.

Exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) enhances the docetaxel resistance of prostate cancer via the microRNA-136-5p/tribbles homolog 1 pathway.

Exosomal circular RNA was found to mediate cancer chemoresistance. However, whether exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) was involved in the chemoresistance of prostate cancer (PCa) remains unclear. The docetaxel (DTX) resistance of PCa cells was analyzed by Cell Counting Kit 8 assay. Quantitative real-time PCR was used to measure circSFMBT2, microRNA (miR)-136-5p and tribbles homolog 1 (TRIB1) expression. Cell proliferation, apoptosis, migration and invasion were analyzed by 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, wound-healing assay and transwell assay. RNA interaction was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Protein expression was measured by western blot analysis. Exosomes-extracted from cells were identified by transmission electron microscope, nanoparticles tracking analysis and western blot. Xenograft mice models were constructed to analyze the effect of exosomal circSFMBT2 on the DTX sensitivity of PCa tumors in vivo. CircSFMBT2 was upregulated in DTX-resistant PCa cells, and its knockdown enhanced the DTX sensitivity of DTX-resistant PCa cells by suppressing cell proliferation, migration, invasion and enhancing apoptosis. CircSFMBT2 severed as miR-136-5p sponge to positively regulate TRIB1. The regulation of circSFMBT2 knockdown on the DTX sensitivity of DTX-resistant PCa cells could be reversed by miR-136-5p inhibitor or TRIB1 overexpression. Exosomal circSFMBT2 from DTX-resistant PCa could increase the DTX resistance of normal PCa cells. In addition, exosomal circSFMBT2 also enhanced the DTX resistance of PCa tumors in vivo, and it was highly expressed in the serum of DTX-resistance PCa patients. Exosomal circSFMBT2 enhanced the DTX resistance of PCa by miR-136-5p/TRIB1 axis, indicating that circSFMBT2 might be a potential target for the treatment of PCa chemoresistance.

Local anesthetic lidocaine-inducible gene, growth differentiation factor-15 suppresses the growth of cancer cell lines

Administration of local anesthetics, such as lidocaine, in the perioperative period improves outcomes of cancer patients. However, its precise mechanism is still unresolved. The growth of human cancer cell lines, including HeLa cells, are suppressed by lidocaine treatment. We identified that growth differentiation factor-15 (GDF-15) was commonly upregulated in lidocaine-treated cancer cell lines. GDF-15 is a divergent member of the transforming growth factor-β (TGF-β) superfamily and it is produced as an unprocessed pro-protein form and then cleaved to generate a mature form. In lidocaine-treated HeLa cells, increased production of GDF-15 in the endoplasmic reticulum (ER) was observed and unprocessed pro-protein form of GDF-15 was secreted extracellularly. Further, lidocaine induced apoptosis and apoptosis-inducible Tribbles homologue 3 (TRIB3) was also commonly upregulated in lidocaine-treated cancer cell lines. In addition, transcription factor C/EBP homologous protein (CHOP), which is a positive regulator of not only GDF-15 but TRIB3 was also induced by lidocaine. Lidocaine-induced growth suppression and apoptosis was suppressed by knockdown of GDF-15 or TRIB3 expression by small interference RNA (siRNA). These observations suggest that lidocaine suppresses the growth of cancer cells through increasing GDF-15 and TRIB3 expression, suggesting its potential application as cancer therapy.