Abstract:Deregulation of ubiquitin ligases contributes to the malignant progression of human cancers. Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and has been implicated in human diseases, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we showed that TRIM65 expression was increased in HCC tissues and associated with poor outcome in two independent cohorts containing 888 patients. In vitro and in vivo data demonstrated that overexpression of T… Show more
“…25,26 β-Catenin can also be triggered by TRIM65 via enhancement of the ubiquitination of Axin1 in the progression of hepatocellular carcinoma. 27 In the present study, we found that β-catenin was down-regulated by TRIM32 knockdown in SGC7901 and AGS cells and was up-regulated in MKN28 cells with TRIM32 overexpression. In the nuclear fraction, β-catenin expression was also remarkably enhanced in cells with TRIM32 overexpression and decreased in cells with silenced TRIM32.…”
Section: Trim32 Promotes Gastric Tumour Growth In Vivosupporting
The tripartite motif (TRIM) family comprises more than 70 members involved in the regulation of many cellular pathways. TRIM32 acts as an E3 ubiquitin ligase and has been reported to participate in many human cancers. Here, we aimed to investigate the role of TRIM32 in gastric cancer (GC) and the clinical implications. High expression of TRIM32 was observed in GC tissues and cell lines, and was significantly associated with poor prognosis. Knockdown TRIM32 expression remarkably suppressed the proliferation, migration, and invasion of GC cells in vitro and tumour growth in vivo, whereas overexpression of TRIM32 yielded the opposite results. Western blotting and quantitative reverse‐transcription PCR (qRT‐PCR) analyses revealed that up‐regulation of TRIM32 significantly enhanced expression of β‐catenin protein and of its downstream targets TCF1, cyclin D1, Axin2 and MMP7 mRNAs. Moreover, we found that the mechanism behind the TRIM32‐promoted GC progression was related to the β‐catenin signalling pathway. Collectively, these data suggest that TRIM32 promotes GC cell proliferation, migration, and invasion by activating the β‐catenin signalling pathway.
“…25,26 β-Catenin can also be triggered by TRIM65 via enhancement of the ubiquitination of Axin1 in the progression of hepatocellular carcinoma. 27 In the present study, we found that β-catenin was down-regulated by TRIM32 knockdown in SGC7901 and AGS cells and was up-regulated in MKN28 cells with TRIM32 overexpression. In the nuclear fraction, β-catenin expression was also remarkably enhanced in cells with TRIM32 overexpression and decreased in cells with silenced TRIM32.…”
Section: Trim32 Promotes Gastric Tumour Growth In Vivosupporting
The tripartite motif (TRIM) family comprises more than 70 members involved in the regulation of many cellular pathways. TRIM32 acts as an E3 ubiquitin ligase and has been reported to participate in many human cancers. Here, we aimed to investigate the role of TRIM32 in gastric cancer (GC) and the clinical implications. High expression of TRIM32 was observed in GC tissues and cell lines, and was significantly associated with poor prognosis. Knockdown TRIM32 expression remarkably suppressed the proliferation, migration, and invasion of GC cells in vitro and tumour growth in vivo, whereas overexpression of TRIM32 yielded the opposite results. Western blotting and quantitative reverse‐transcription PCR (qRT‐PCR) analyses revealed that up‐regulation of TRIM32 significantly enhanced expression of β‐catenin protein and of its downstream targets TCF1, cyclin D1, Axin2 and MMP7 mRNAs. Moreover, we found that the mechanism behind the TRIM32‐promoted GC progression was related to the β‐catenin signalling pathway. Collectively, these data suggest that TRIM32 promotes GC cell proliferation, migration, and invasion by activating the β‐catenin signalling pathway.
“…BCL9L (B-cell CLL/lymphoma 9 like) protein shares a conserved domain with BCL9, which is related to intestinal tumor progression. TRIM65 can trigger -catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma 11 .Figure 3Neoantigen comparison between LN-negative and LN-positive breast cancer. ( A ) The boxplot of the number of neoantigen peptides.…”
Lymph node metastasis is of major prognostic significance for breast cancer. Lymph node metastasis arises at a very early stage in some patients. Using the data downloaded from the TCGA database, we studied the differences between primary tumors with and without lymph node metastasis at the multi-omics level using bioinformatics approaches. Our study found that low mutation and neoantigen burdens correlated with lymph node metastazation of breast cancer. All three conserved domains in TP53 were mutated in lymph node-negative breast cancers, whereas only one domain was mutated in lymph node-positive samples. Mutations in microtubule-related proteins appear to help immune cells recognize tumors and inhibit their lymph node metastasis. Destroying microtubule-related proteins is a potential therapeutic strategy to inhibit lymph node metastasis of breast cancer. As the neoantigens specifically present in lymph node-positive breast cancers, MAPK10, BC9L, TRIM65, CD93, KITLG, CNPPD1, CPED1, CCDC146, TMEM185A, INO80D, and PSMD11 are potential targets for vaccine design. In the tumor microenvironment, reduced numbers of effector immune cells, especially activated memory CD4+ T cells and activated mast cells, facilitate breast cancer metastasis to the lymph nodes. According to transcriptome data, lymph node metastasis was mostly driven by gene mutation rather than by gene expression. Although differential gene expression analysis was based on lymph node metastasis status, many genes were shown to be differentially expressed based on estrogen receptor status.
“…To this end, it is tempting to conclude that TRIM65 is an important hub for signaling cross talk in general, which also implies that the functions of TRIM65 in a physiological or disease context should be considered. For example, in a study by Yang et al [16], HMGA1 seems to be an upstream transcription factor (TF) for TRIM65 regulation. We looked for a correlation between HMGA1 and TRIM65 in both the TCGA CRC data set and our cohort, and failed to see evidence for that finding.…”
Section: Discussionmentioning
confidence: 99%
“…Like other TRIM members that are involved in the immune response, TRIM65 also participates in the virus-induced innate immune response by ubiquitination of substrate proteins [13, 14]. In tumor malignancies, TRIM65 was first shown to harbor oncogenic activities in lung and liver cancers, and cancer-related TRIM65 substrates, including TP53 and AXIN1, had been reported [15, 16]. More recently, TRIM65 was reported to support bladder urothelial carcinoma cell progression by targeting ANXA2 for ubiquitination and degradation [17].…”
Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and a critical regulator of a variety of cellular processes as well as tumor progression. Therefore, more substrates must be identified in the physiology or disease context. Here, we found that TRIM65 is upregulated and associated with poor survival in colorectal cancer (CRC). More specifically, high expression of TRIM65 is associated with CRC metastasis and recurrence. Ectopic overexpression of TRIM65 in CRC cell lines enhanced proliferation, invasion, and migration, while knockdown of TRIM65 expression had the opposite effects. Furthermore, we identified a new substrate of TRIM65, namely ARHGAP35, a Rho GTPase-activating protein (GAP) that is involved in polarized cell migration. Phenotypically, forced expression of TRIM65 induces increased production of migration-related structures, focal adhesions, and/or filopodia and enhances CRC metastasis to the liver or the lung in a mouse model. Mechanistic studies revealed that TRIM65 mediates ubiquitination of ARHGAP35, whose degradation leads to elevated Rho GTPase activity. In addition, we identified several phosphorylation sites on TRIM65. In sum, we reveal a novel TRIM65–GAP–Rho regulatory axis that modulates the actin cytoskeleton and the migration behavior of CRC cells, and the TRIM65–ARHGAP35 interaction might be a valuable therapeutic target in CRC.
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