Tripartite Motif-containing 28 Research Articles

Research progress of TRIM14 in malignant tumors

Tripartite motif-containing 14 (TRIM14) is a member of tripartite motif family. Regulating innate immune response and affecting cell differentiation are the main physiological functions of TRIM14. It is reported TRIM14 expresses in various tumors such as non-small cell lung cancer, breast cancer, hepatocellular carcinoma, osteosarcoma and oral squamous cell carcinoma. The proliferation, invasion, metastasis, drug resistance of malignant tumors and the prognosis of patients with cancer can be affected via different mechanisms of TRIM14. Key words: Neoplasms; Cell proliferation; Neoplasms metastasis; Tripartite motif-containing 14

The two TRIM25 isoforms were differentially induced in Larimichthys crocea post poly (I:C) stimulation

In this study, we identified and characterized a tripartite motif containing 25 (TRIM25) gene homologue, LcTRIM25, from large yellow croaker (Larimichthys crocea). Two isoforms of LcTRIM25, which were generated via alternative splicing, were identified via a molecular analysis of cDNA clones. The long isoform of LcTRIM25 (termed as LcTRIM25-L) contained the full open reading frame of the gene, encoded a protein of 698 amino acid residues, and possessed 11 exons. The short isoform of LcTRIM25 (termed as LcTRIM25-S) contained 9 exons and encoded a protein of 665 amino acid residues. The two LcTRIM25 isoforms contained a conserved Really Interesting New Gene (RING) domain, a B-box2 domain, a Coiled-coil domain (CCD), and variable C-terminal PRY/SPRY domains. Phylogenetic analysis showed that the two LcTRIM25 isoforms of the large yellow croaker was clustered together with their counterparts from other teleost fish. The Real-time PCR analysis showed that the LcTRIM25-L and LcTRIM25-S isoforms were both ubiquitously expressed in nine examined tissues in the large yellow croaker, with predominant expressions in the liver. The expression levels of the two isoforms of LcTRIM25 were rapidly and significantly upregulated in vivo after poly (I:C) stimulation in peripheral blood, head kidney, spleen and liver. Moreover, LcTRIM25-L and LcTRIM25-S showed differential expression post poly(I:C) stimulation. LcTRIM25 may have a dual role in innate immunity via alternative gene splicing. These results indicated that LcTRIM25 is likely to be involved in antiviral immune responses.

TRIM14 promotes colorectal cancer cell migration and invasion through the SPHK1/STAT3 pathway

BackgroundColorectal cancer (CRC) is one of the most lethal malignancies. Tripartite Motif Containing 14 (TRIM14) is a member of TRIM family proteins, which are involved in the pathogenesis of various cancers. This study aimed to investigate TRIM14 expression in CRC tissues, and its effects on the migration and invasion of CRC cell lines.MethodsTRIM14 mRNA expression was detected by real-time PCR analysis. Cell migration and invasion were measured by Transwell assays. Protein expression was assessed by western blot analysis.ResultsThe expression of TRIM14 was significantly higher in CRC tissues than in matched non-cancerous tissues. TRIM14 knockdown by specific short hairpin RNA (shRNA) attenuated CRC cell migration and invasion, whereas TRIM14 overexpression caused reverse effect. Moreover, TRIM14 positively regulated the protein levels of sphingosine kinase 1 (SPHK1) and phosphorylated STAT3 (p-STAT3), as well as the mRNA and protein expression of matrix metalloproteinase 2, MMP9 and vascular endothelial growth factor, which are transcriptional targets of the STAT3 signaling pathway. Importantly, the blockage of the SPHK1/STAT3 signaling pathway by SKI-II or AG490 could reverse the TRIM14-promoted CRC cell migration and invasion.ConclusionsOur results reveal a critical role for TRIM14 in promoting migration and invasion of CRC cells, and suggest TRIM14 may serve as a potential molecular target to prevent CRC metastasis.

Elevated TRIM23 expression predicts poor prognosis in Chinese gastric cancer

The gene TRIM23 (tripartite motif containing 23) is a member of the tripartite motif (TRIM) family whose expression putatively participates in many pathophysiological processes. Nonetheless, the role of TRIM23 in gastric cancer (GC) remains uncertain. Our study evaluated the expression of TRIM23 in GC tissues and cell lines, and investigated an association between TRIM23 and survival. In the present study, our results demonstrated that TRIM23 mRNA and protein were frequently over-expressed in GC cell lines and GC tissues. High level of TRIM23 protein correlated with tumor size, tumor-node-metastasis (TNM) stage, depth of invasion, lymph node metastasis (LNM), tumor differentiation, and nerve invasion. Compared with the low TRIM23 protein group, the high TRIM23 protein group was significantly associated with worse prognosis of GC patients. Consistently, the KM-plot database suggested that high TRIM23 mRNA expression was also linked to a poor prognosis in GC patients both in positive and negative subgroups of human epidermal growth factor receptor 2 (HER2). But in the HER2 positive subgroup, the advantages of the low TRIM23 expression on overall survival were much more statistically significant. The univariate analysis indicated that TRIM23 expression correlated with overall survival. The multivariate analysis showed that independent factors of prognosis in GC were lymph node metastasis, vascular invasion, and depth of invasion. In summary, TRIM23 may be associated with progression of GC, and may be considered a therapeutic target for GC patients.

TRIM28 is overexpressed in glioma and associated with tumor progression.

BackgroundTripartite motif containing 28 (TRIM28) is a transcriptional co-factor targeting many genes with pleiotropic biological activities, but the study on the role of TRIM28 in glioma is rare.MethodsTo explore the function of TRIM28 in glioma, we first detected the expression levels of TRIM28 in glioma tissues and analyzed the correlations of TRIM28 expression with clinicopathological variables of patients in 85 cases of glioma. Meanwhile, we used shRNA to knockdown TRIM28 in glioma cell lines to detect the biological functions of TRIM28 in cell and animal experiments.ResultsWe found that TRIM28 was expressed at significantly higher level in glioma tissues than in non-tumor brain, and TRIM28 expression correlated significantly with tumor malignancy. Furthermore, TRIM28 higher expression was also correlated with poor survival of glioma patients (P<0.01). Functionally, knockdown of TRIM28 could significantly inhibit cell proliferation and migration in glioma cells. Additionally, we found that TRIM28 could inhibit the expression of E-cadherin significantly by reducing its mRNA stability at the post-transcriptional level.ConclusionOur results suggest that TRIM28 overexpression is correlated with glioma malignant progression and patients’ poor survival, so targeting TRIM28 could be an efficacious strategy in glioma.

The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPAR\u03b3

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that regulates adipocyte differentiation and glucose homeostasis. The transcriptional activity of PPARγ is regulated not only by ligands but also by post-translational modifications (PTMs). In this study, we demonstrate that a novel E3 ligase of PPARγ, tripartite motif-containing 25 (TRIM25), directly induced the ubiquitination of PPARγ, leading to its proteasome-dependent degradation. During adipocyte differentiation, both TRIM25 mRNA and protein expression significantly decreased and negatively correlated with the expression of PPARγ. The stable expression of TRIM25 reduced PPARγ protein levels and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, the specific knockdown of TRIM25 increased PPARγ protein levels and stimulated adipocyte differentiation. Furthermore, TRIM25-knockout mouse embryonic fibroblasts (MEFs) exhibited an increased adipocyte differentiation capability compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPARγ and that TRIM25 is a novel target for PPARγ-associated metabolic diseases.

TRIM14 promotes the migration and invasion of gastric cancer by regulating epithelial‑to‑mesenchymal transition via activation of AKT signaling regulated by miR‑195‑5p.

Tripartite motif-containing 14 (TRIM14) is a member of the TRIM protein family which has been implicated in several critical processes and is dysregulated in human cancers in a cancer-specific trend. However, its expression and function in human gastric cancer (GC) are still largely unknown. In this study, we confirmed for the first time that TRIM14 mRNA and protein were upregulated in GC tissues and cell lines as determined by qRT-PCR and western blot analysis. Clinical data disclosed that high TRIM14 expression was significantly associated with aggressive prognostic features, including advanced TNM stage and lymph node metastasis. In regards to 5-year survival, TRIM14 served as a potential prognostic marker for GC. Notably, TRIM14 promoted migration, invasion as measured by Transwell and epithelial-to-mesenchymal transition (EMT) as determined by western blot analysis and immunofluorescence (IF) in vitro and in vivo. Moreover, TRIM14 induced protein kinase B (AKT) pathway activation, and inhibition of AKT reversed the TRIM14-induced promotive effects on cell migration, invasion and EMT progression. Furthermore, we demonstrated that TRIM14 expression was regulated by miR-195-5p. miR-195-5p exerted an inhibitory role in GC migration and invasion. Finally, we confirmed that alteration of TRIM14 expression abolished the effects of miR-195-5p on GC cells. Conclusively, our results demonstrated that TRIM14 functions as an oncogene in regulating EMT and metastasis of GC via activating AKT signaling, which was regulated by miR-195-5p, supporting its potential utility as a therapeutic target for GC.

Abstract 787: Cytosolic TRIM24 characterizes an aggressive subset of ER- PR- and TP53 mutant breast cancer

Abstract Introduction: Tripartite Motif Containing 24 (TRIM24) is a PhD/Bromodomain containing steroid receptor co-activator that targets p53 for proteosomal degradation, transforms human mammary epithelial cells, and promotes treatment resistance in preclinical models. While bromodomain inhibitors and proteolysis targeting chimeras have been developed against TRIM24, the disease subtype it is most relevant to remains under explored. In this study, we characterize a uniquely annotated cohort of invasive ductal carcinomas for tumor expression of TRIM24 protein by immunohistochemistry (IHC) to assess its relationship with molecular and clinicopathological features. Methods: Tissue microarrays (TMAs) representing 198 tumors with 6 cores/tumor were obtained from the Tayside Biospecimen Repository and stained by IHC for TRIM24. TMAs were scored for nuclear and cytosolic intensity and the proportion of tumor cells with staining. These values were combined into Histo-scores (H-Scores) and averaged as a semi-quantitative metric for tumor TRIM24 expression. Statistical associations between TRIM24 H-Scores, clinicopathological annotations, and existing molecular profiles generated from the same TMA were determined using SciPy and SPSS. Results: TRIM24 has four distinct expression patterns in the 170 tumors with scorable cores on the TMA: nuclear (55), cytosolic (38), nuclear and cytosolic (35), and negative (42). Non-parametric analysis revealed associations between TRIM24 expression pattern and ER (χ2=21.3, p=0.000), PR (χ2=14.8, p=0.002), invasive grade (χ2=14.9, p=0.021), and TP53 mutation (χ2=9.55, p=0.023). No significant association was found with HER2 (χ2=1.51, p=0.68). Higher nuclear H-scores are observed in ER+ (p=0.0008) and PR+ (p=0.001) tumors. Higher cytosolic but not nuclear H-scores are observed in Grade 3 (p=0.003), triple negative (TNBC, p=0.004), and TP53 mutant (p=0.0289) cases. Kaplan-Meier analysis revealed high cytosolic (p=0.037) but not nuclear (p=0.601) H-scores associated with poor survival in ER- patients. No significant survival difference was found in ER+ patients stratified by nuclear (p=0.781) or cytosolic (p=0.683) H-scores. Similar analysis of TNBC was underpowered. TP53 mutant (p=0.142) but not TP53 wild type (p=0.378) disease with high cytosolic H-scores trend toward diminished survival. No such trend is observed in cases stratified by nuclear H-scores and TP53 status. Conclusions: TRIM24 is overexpressed in most human breast cancers. Nuclear expression is more common in ER+/PR+ tumors but does not stratify outcome. Cytosolic expression occurs in Grade 3, ER-, and TP53 mutant tumors and associates with poor clinical outcome in ER- disease. This suggests TRIM24 may be a more relevant drug target in ER-/PR- than luminal breast cancer and emphasizes the need for studies investigating the cytosolic functions of TRIM24 in ER-/PR- and TP53-mutant breast cancer. Citation Format: Lalit R. Patel, Jurgen Mitsch, Grazziela P. Figueredo, Philip Quinlan, Lee B. Jordan, Colin A. Purdie, Savitri Krishnamurthy, Michelle C. Barton, Alastair M. Thompson. Cytosolic TRIM24 characterizes an aggressive subset of ER- PR- and TP53 mutant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 787.

Abstract 2540: TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma

Abstract Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac)-binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Our findings uncover a pathway in which TRIM24 functions as a signal relay for oncogenic EGFR signaling and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation. Citation Format: Deguan Lv, Yanxin Li, Weiwei Zhang, Angel A. Alvarez, Jianming Tang, Bo Hu, Shi-Yuan Cheng, Haizhong Feng. TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2540.

TRIM22 knockdown suppresses chronic myeloid leukemia via inhibiting PI3K/Akt/mTOR signaling pathway.

Tripartite motif-containing 22 (TRIM22) is reported to participate in numerous cellular activities. Recent studies confirm that TRIM22 is a target gene for P53, and inhibits clonogenic growth of leukemic U-937 cells. The current study aims to discover the effect of TRIM22 in progression of human chronic myeloid leukemia (CML) and explore the related mechanism. TRIM22 was knocked down by siRNA transfection in CML cell K562. We observed that TRIM22 knockdown decreased proliferation and invasion in K562 cells. TRIM22 knockdown significantly induced cell cycle arrest by regulating the level of CDK4, Cyclin D1, P70S6K, and P53 in K562 cell. Moreover, loss of TRIM22 also promoted apoptosis through modulation of Bcl-2, Bax and active Caspase 3 in K562 cell. Furthermore, we demonstrated that TRIM22 knockdown inhibited the activation of PI3K/Akt/mTOR pathway by decreasing the level of the phosphorylated form p-Akt and p-mTOR in K562 cell. In conclusion, loss of TRIM22 suppresses the progression and invasion of CML through regulation of PI3K/Akt/mTOR pathway, suggesting that TRIM22 might be as a potential target for the treatment strategy of CML.

TRIM14 promotes chemoresistance in gliomas by activating Wnt/β-catenin signaling via stabilizing Dvl2.

Gliomas are a lethal class of brain cancer, with a median survival below 15 months in spite of therapeutic advances. The poor prognosis of this disease is largely attributed to acquired chemotherapy resistance, and new strategies are urgently needed to target resistant glioma cells. Herein, our study demonstrated that tripartite motif-containing 14 (TRIM14) overexpressed in glioma specimens (including tissues and cell lines), and that high level of TRIM14 predicted poor outcome of glioma patients. Furthermore, we found that upregulation of TRIM14 in glioma cells conferred chemoresistance to temozolomide in vitro and in vivo; conversely, silencing TRIM14 sensitized glioma cells to temozolomide. These findings demonstrated that TRIM14 stabilized dishevelled (Dvl2) and subsequently activated the canonical Wnt signaling and promoted chemoresistance. Moreover, inhibition of Dvl2 reversed the oncogenic effect of TRIM14 on chemoresistance. Importantly, consistent with the abovementioned results, we found that TRIM14 expression was significantly associated with hyperactivation of canonical Wnt pathway in clinical glioma specimens. Collectively, the study reveals a new molecular mechanism driving chemotherapy resistance in gliomas, and suggests an opportunity to develop novel therapeutic interventions against gliomas.

TRIM27 functions as an oncogene by activating epithelial-mesenchymal transition and p-AKT in colorectal cancer.

Tripartite motif-containing 27 (TRIM27) belongs to the tripartite motif (TRIM) protein family and is involved in various malignant tumor processes. However, the function and mechanism of TRIM27 in colorectal cancer (CRC) remains to be elucidated. In the present study, the expression of TRIM27 was analyzed in CRC tissues and adjacent normal tissues by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. LoVo and HCT116 cell lines were then selected to further investigate the function of TRIM27 in the proliferation, invasion and metastasis of CRC in vitro and in vivo. Finally, the potential mechanism underlying the effects of TRIM27 in CRC was examined by western blotting. The results showed that TRIM27 was upregulated in CRC tissues, and the expression level of TRIM27 was significantly associated with tumor invasion, metastasis and prognosis. Following TRIM27 inhibition and overexpression in CRC cells, it was found that TRIM27 promoted cell proliferation, possibly via the inhibition of apoptosis and cell cycle regulation. TRIM27 also facilitated invasion and metastasis. Finally, it was observed that TRIM27 promoted epithelial-mesenchymal transition and activated phosphorylated AKT serine/threonine kinase in CRC cells. These results suggested that TRIM27 is an oncogenic protein in the progression of CRC, and may represent a novel target for CRC detection and therapy.

TRIM24 siRNA induced cell apoptosis and reduced cell viability in human nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is a common cancer occurring primarily in East Asia and Africa. The high rate of recurrence and metastasis of NPC continuously endangers the health of patients. The present study aimed to identify the underlying mechanisms involved in the progression of NPC and provide experimental basis to develop a novel and efficient agent against NPC. The present study measured the expression level of tripartite motif containing24 (TRIM24) in tumor tissues from NPC patients using reverse transcription quantitative polymerase chain reaction. Subsequently, Cell Counting kit‑8 and flow cytometry were used to detect the cell proliferation and apoptosis of NPC cell lines HONE1 and CNE1 cells where the TRIM24 gene was knocked‑down with small interfering RNA (siRNA). Further, caspase kits and western blot analysis were used to detect the expression of apoptosis and angiogenesis‑associated proteins. The present study detected a higher expression level of TRIM24 in tumor tissues and NPC cell lines and lower cell viability and higher apoptotic rate were observed when TRIM24 was silenced. Meanwhile, upregulated caspase‑3 and caspase‑9 indicated induced cell apoptosis in HONE1 and CNE1 cells following the treatment with TRIM24 siRNA. Additionally, the downregulated expression level of vascular endothelial growth factor (VEGF) and VEGF receptor 2 suggested inhibited angiogenesis of NPC cells. Additionally, the reduced levels of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) indicated a blocked JAK2/STAT3 signaling pathway. However, there was no direct evidence that inactivation of the JAK2/STAT3 signaling pathway was involved in regulation of siTRIM24, these results suggested that TRIM24 has an important role in the growth of NPC. Additionally, silenced TRIM24 may lead to inhibited cell proliferation and induced cell apoptosis in NPC cells. The limitation of this study was that HONE1, CNE1 and CNE2 cells may have been contaminated with other cells. Further experiments with validated NPC cells may be needed.

TRIM59 induces epithelial-to-mesenchymal transition and promotes migration and invasion by PI3K/AKT signaling pathway in medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children. Despite remarkable advances over previous decades, the long-term survival of patients with medulloblastoma remains poor due to the frequent metastatic nature of this malignancy. The aim of the present study was to examine the role of tripartite motif containing 59 (TRIM59) in cell metastasis in medulloblastoma. It was initially demonstrated that TRIM59 expression was significantly increased in clinical medulloblastoma tissues compared with adjacent non-cancerous tissues and differentially expressed in a series of medulloblastoma cell lines. The knockdown of TRIM59 in D283 cells resulted in epithelial-to-mesenchymal transition (EMT), and decreased cell migratory and invasive capacities. By contrast, the overexpression of TRIM59 in Daoy cells was able to inhibit the EMT process and increase migratory and invasive capacities of the cells. Notably, the knockdown of TRIM59 was able to decrease the protein level of matrix metalloproteinase (MMP)-2 without altering the levels of MMP-9, and conversely the overexpression of TRIM59 was able to increase the protein level of MMP-2. Importantly, the downregulation of TRIM59 in D283 cells was able to inhibit the levels of phosphorylated (p)-AKT (Ser473), glycogen synthase kinase 3 β(GSK3β; Ser9) and phosphoinositide 3-kinase (PI3K) p85 (Tyr458) without altering the levels of total protein. The data from the present study suggest that TRIM59 induces epithelial-to-mesenchymal transition and promotes migration and invasion by PI3K/AKT signaling pathway in medulloblastoma. This data may provide novel insight into tumor metastasis and pave the way for the development of therapeutic strategies for the treatment of medulloblastoma in the clinic.

Prognostic value of tripartite motif containing 29 expression in patients with gastric cancer following surgical resection.

Tripartite motif containing 29 (TRIM29) dysregulation serves an important function in the progression of numerous types of cancer, but its function in the prognosis of patients with gastric cancer remains unknown. The present study assessed the prognostic value of TRIM29 in patients with gastric cancer following surgical resection. A total of 243 fresh gastric adenocarcinoma and adjacent normal tissues were continuously retrieved from patients who underwent curative surgery for gastric cancer at the Cancer Hospital of Henan Province (Zhengzhou, China) between January 2005 and December 2011. The reverse transcription-quantitative polymerase chain reaction was performed to assess TRIM29 expression. The association between TRIM29 expression and clinicopathological features and prognosis was subsequently evaluated. The results of the present study revealed that the expression of TRIM29 was increased in the gastric cancer tissues compared with the normal adjacent tissues, and that upregulated expression of TRIM29 was associated with tumor cell differentiation, tumor stage, lymph node metastasis, and tumor-node-metastasis (TNM) stage. In the training and validation data, high TRIM29 expression was associated with poor overall survival in patients with gastric cancer. Furthermore, multivariate analysis identified that TRIM29 expression was an independent prognostic factor for overall survival, in addition to TNM stage and Lauren classification. Combining TRIM29 expression with the TNM staging system generated a novel predictive model that exhibited improved prognostic accuracy for overall survival in patients with gastric cancer. The present study revealed that TRIM29 was an independent adverse prognostic factor in patients with gastric cancer. Incorporating TRIM29 expression level into the TNM staging system may improve risk stratification and render prognosis more accurate in patients with gastric cancer.

High Levels of TRIM14 Are Associated with Poor Prognosis in Hepatocellular Carcinoma

Background: Tripartite motif containing 14 (TRIM14) has been reported to play a critical role in tumor development. However, little is known about TRIM14 expression and its clinical significance in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the expression and prognostic value of TRIM14 in patients with HCC. Materials and Methods: The mRNA and protein levels of TRIM14 in HCC were evaluated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The association of TRIM14 expression with clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS) was analyzed. Results: TRIM14 expression was significantly upregulated in HCC-related tissues. High TRIM14 expression correlated with C-reactive protein (p = 0.01), alanine aminotransferase (p = 0.02), tumor size (p = 0.005), lesion number (p = 0.023), vascular invasion (p = 0.041), tumor/node/metastasis (TNM) stage (p = 0.001), and Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.003). In addition, high TRIM14 expression was associated with poor OS and RFS (both p < 0.001). Cox regression analysis revealed that high TRIM14 expression was an independent prognostic factor for both OS (hazard ratio (HR) 1.657, 95% confidence interval (CI) 1.031-2.687; p = 0.018) and RFS (HR 2.297, 95% CI 1.184-2.312; p = 0.007). Conclusion: TRIM14 is a potential prognostic predictor for OS and RFS in patients with HCC.

Overexpression of TRIM24 Stimulates Proliferation and Glucose Metabolism of Head and Neck Squamous Cell Carcinoma.

TRIM24 (Tripartite Motif Containing 24) is a recently identified oncogene overexpressed in various cancers. However, the molecular mechanism of TRIM24 in the progression of head and neck squamous cell carcinoma (HNSCC) remains ambiguous. In the present study, we analyzed the expression pattern of TRIM24 in 100 HNSCC tissues and found that TRIM24 was overexpressed in 43/100 HNSCC cases. Significant association was found between TRIM24 overexpression and tumor-node-metastasis (TNM) stage (p = 0.0034) and T stage (p = 0.0048). Furthermore, we overexpressed and knocked down TRIM24 in Detroit 562 and FaDu cell lines, respectively. TRIM24 overexpression promoted proliferation, colony formation, and invasion, while TRIM24 depletion inhibited proliferation, colony formation, and invasion. Further studies showed that TRIM24 facilitated cell cycle transition and upregulated cyclin D1 and p-Rb. In addition, we found that GLUT3, a key protein involved in regulating glucose metabolism, was altered in HNSCC cells overexpressing TRIM24. We demonstrated that TRIM24 overexpression increased glucose uptake ATP production. Overexpression of TRIM24 increases cell sensitivity to glucose deprivation in Detroit cells. Depleting TRIM24 in FaDu cells demonstrated the opposite results. We also showed that TRIM24 could bind to the promoter region of cyclin D1. In conclusion, TRIM24 is upregulated in HNSCC and promotes HNSCC cell growth and invasion through modulation of cell cycle, glucose metabolism, and GLUT3, making TRIM24 a potential oncoprotein in HNSCC.

Identification of key genes implicated in the suppressive function of human FOXP3+CD25+CD4+ regulatory T cells through the analysis of time‑series data.

Human forkhead box P3 (FOXP3)+ cluster of differentiation (CD)25+CD4+ regulatory T cells (Tregs) are a type of T cell that express CD4, CD25 and FOXP3, which are critical for maintaining immune homeostasis. The present study aimed to determine the mechanisms underlying Treg function. The GSE11292 dataset was downloaded from the Gene Expression Omnibus, which included data from Treg cells at 19 time points (0–360 min) with an equal interval of 20 min, and corresponding repeated samples. However, data for Treg cells at time point 120 min were missing. Using the Mfuzz package, the key genes were identified by clustering analysis. Subsequently, regulatory networks and protein-protein interaction (PPI) networks were constructed and merged into integrated networks using Cytoscape software. Using Database for Annotation, Visualization and Integrated Discover software, enrichment analyses were performed for the genes involved in the PPI networks. Cluster 1 (including 292 genes), cluster 2 (including 111 genes), cluster 3 (including 194 genes) and cluster 4 (including 103 genes) were obtained from the clustering analysis. GAPDH (degree, 40) in cluster 1, Janus kinase 2 (JAK2) (degree, 10) and signal transducer and activator of transcription 5A (STAT5A) (degree, 9) in cluster 3, and tumor necrosis factor (TNF) (degree, 26) and interleukin 2 (IL2) (degree, 22) in cluster 4 had higher degrees in the PPI networks. In addition, it was indicated that several genes may have a role in Treg function by targeting other genes [e.g. microRNA (miR)-146b-3p→TNF, miR-146b-5p→TNF, miR-142-5p→TNF and tripartite motif containing 28 (TRIM28)→GAPDH]. Enrichment analyses indicated that IL2 and TNF were enriched in the immune response and T cell receptor signaling pathway. In conclusion, GAPDH targeted by TRIM28, TNF targeted by miR-146b-3p, miR-146b-5p and miR-142-5p, in addition to JAK2, IL2, and STAT5A may serve important roles in Treg function.

TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma

Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac)-binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Our findings uncover a pathway in which TRIM24 functions as a signal relay for oncogenic EGFR signaling and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation.

Tripartite motif-containing 3 (TRIM3) inhibits tumor growth and metastasis of liver cancer

BackgroundReduced expression of tripartite motif-containing 3 (TRIM3) has been reported to be involved in the pathogenesis of human glioblastoma. In our previous research, we found that TRIM3 expression was markedly reduced in human primary hepatocellular carcinoma (HCC) tissues and that low TRIM3 expression was associated with short survival of HCC patients. However, the role of TRIM3 in liver cancer remains unknown. This study aimed to investigate the function of TRIM3 in liver cancer cells.MethodsThe protein levels of TRIM3 in five liver cancer cell lines (SK-Hep1, Hep3B, Huh7, HepG2, Bel-7402) and one normal liver cell line (L02) were detected with Western blotting. HepG2 and Bel-7402 cells with low TRIM3 expression were infected with recombinant lentiviruses overexpressing TRIM3 (LV-TRIM3), whereas Huh7 and Hep3B cells with high TRIM3 expression were transfected with TRIM3-targeted small interfering RNA (siTRIM3). The functions of TRIM3 in the proliferation, colony formation, cell cycle, migration, invasion, and apoptosis of the above cell lines were examined. The effect of TRIM3 on tumor growth and metastases in nude mice was also investigated.ResultsTRIM3 was overexpressed in HepG2 and Bel-7402 cells with LV-TRIM3 infection, which further reduced proliferation, colony formation, migration, and invasion of both cell lines. Cell cycle analysis showed that TRIM3 overexpression induced G0/G1 phase arrest in HepG2 and Bel-7402 cells. Moreover, apoptosis was not increased in HepG2 or Bel-7402 cells overexpressing TRIM3. Contrarily, silencing TRIM3 expression in Huh7 and Hep3B cells by siTRIM3 led to significantly decreased percentages of both cells in the G0/G1 phase and promoted cell proliferation, colony formation, migration, and invasion. In vivo experiment results confirmed that TRIM3 overexpression suppressed tumor growth and metastasis.ConclusionsTRIM3 plays a tumor-suppressing role in the regulation of liver cancer development by reducing cell proliferation through cell cycle arrest at the G0/G1 phase.