Role of the Tripartite Motif Protein 27 in Cancer Development

Zoumpoulidou, Georgia; Broceño, Cristina; He, Li; Bird, Dennis K.; Thomas, George V.; Mittnacht, Sibylle

doi:10.1093/jnci/djs224

Cited by 36 publications

(36 citation statements)

References 48 publications

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Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that several members of the TRIM family play important roles in transcriptional regulation. [42][43][44] For instance, promyelocytic leukemia can regulate PPAR-δ expression in hematopoietic stem cells.45 Some other members travel between the cytosol and nucleus to exert their functions. 46,47 In this study, we have found that the expression of MG53 is markedly increased in several animal models with metabolic disorders, although the underlying mechanism remains elusive.…”

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confidence: 99%

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Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

et al. 2015

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Diabetes mellitus is an emerging global threat to human health. It is estimated that the total number of people experiencing diabetes mellitus will reach 366 million in 2030. 1 Although hypertension and coronary narrowing are major pathogenic factors of acquired cardiomyopathy, diabetes mellitus has been established as an independent risk factor since 1972.2 Diabetic cardiomyopathy, as a major complication, is the leading cause of morbidity and mortality for diabetic patients. Epidemiological studies have demonstrated that diabetic people have a 2-to 5-fold increase of risk in developing heart failure compared with age-matched healthy subjects after adjusting for age, blood pressure, weight, cholesterol level, and coronary artery disease. 3-7 Editorial see p 771 Clinical Perspective on p 804Rodent models are of particular value in study of diabetic cardiomyopathy because there is minimal confounding involvement of coronary atherosclerosis. It has been demonstrated that diabetic mice and rats fed with high-fat diet display cardiac remodeling and dysfunction. [8][9][10][11] Recently we and others have shown that mice overexpressing Mitsugumin 53 (MG53) Background-Diabetic cardiomyopathy, which contributes to >50% diabetic death, is featured by myocardial lipid accumulation, hypertrophy, fibrosis, and cardiac dysfunction. The mechanism underlying diabetic cardiomyopathy is poorly understood. Recent studies have shown that a striated muscle-specific E3 ligase Mitsugumin 53 (MG53, or TRIM72) constitutes a primary causal factor of systemic insulin resistance and metabolic disorders. Although it is most abundantly expressed in myocardium, the biological and pathological roles of MG53 in triggering cardiac metabolic disorders remain elusive. Methods and Results-Here we show that cardiac-specific transgenic expression of MG53 induces diabetic cardiomyopathy in mice. Specifically, MG53 transgenic mouse develops severe diabetic cardiomyopathy at 20 weeks of age, as manifested by insulin resistance, compromised glucose uptake, increased lipid accumulation, myocardial hypertrophy, fibrosis, and cardiac dysfunction. Overexpression of MG53 leads to insulin resistant via destabilizing insulin receptor and insulin receptor substrate 1. More importantly, we identified a novel role of MG53 in transcriptional upregulation of peroxisome proliferation-activated receptor alpha and its target genes, resulting in lipid accumulation and lipid toxicity, thereby contributing to diabetic cardiomyopathy. Conclusions-Our results suggest that overexpression of myocardial MG53 is sufficient to induce diabetic cardiomyopathy via dual mechanisms involving upregulation of peroxisome proliferation-activated receptor alpha and impairment of insulin signaling. These findings not only reveal a novel function of MG53 in regulating cardiac peroxisome proliferation-activated receptor alpha gene expression and lipid metabolism, but also underscore MG53 as an important therapeutic target for diabetes mellitus and associated cardiomyopathy. develop obes...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

et al. 2015

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“…Furthermore, high-level expression of TRIM27 correlates with the proliferation, migration and chemosensitivity of some tumor cells and could act as a potential prognostic indicator in some cancers. [9][10][11][12] The above results suggest that TRIM27 could be involved in the development and progression of tumor. However, its expression level and function in ovarian cancer remain unclear.…”

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confidence: 99%

Downregulation of TRIM27 expression inhibits the proliferation of ovarian cancer cells in vitro and in vivo

Wei

Bast

et al. 2016

Laboratory Investigation

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(tripartite motif-containing 27) was originally identified as a fusion partner with the RET (REarranged during transfection) proto-oncogene and is highly expressed in various tumor cells and tissues. However, the level of expression and function of TRIM27 in ovarian cancer remain unclear. Here we have measured the expression of TRIM27 in normal ovarian and fallopian tube epithelial cells and in ovarian serous carcinoma cells and correlated TRIM27 expression with clinical and pathological parameters. In addition, we detected the effect of TRIM27 knockdown on proliferation of ovarian cancer cells in cell culture and xenografts. The results demonstrated that TRIM27 was highly expressed in ovarian serous carcinoma cells, and TRIM27 expression was significantly correlated with metastasis and FIGO stage in ovarian serous carcinoma patients. Downregulation of TRIM27 expression suppressed the proliferation of ovarian cancer cells in cell culture and inhibited the growth of xenografts in nude mice. TRIM27 knockdown induced cell cycle arrest and apoptosis in ovarian cancer cells by upregulating the expression of p-P38 and downregulating the expression of p-AKT. Thus the present study suggests that TRIM27 could have important roles as an oncogene during the development of ovarian cancer and could serve as a diagnostic and therapeutic target.

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“…In a study that uses a cancer-profiling array containing tumour cRNA alongside cRNA from paired tissue, TRIM27 expression was found to be significantly increased in lung cancers versus normal tissue (Zoumpoulidou et al, 2012). TRIM27 expression is associated with poor prognosis of lung cancers with EGFR mutations suggesting that TRIM27 status might be associated with response to anticancer therapy in EGFRmutated lung cancers (Iwakoshi et al, 2012).…”

Section: Lung Cancermentioning

confidence: 99%

“…Trim27 expression peaks in early mouse cancer development (Zoumpoulidou et al, 2012). Moreover, mice with TRIM27 deletion are resistant to development of chemically induced SSC (Zoumpoulidou et al, 2012). Zoumpoulidou G, Mittnacht S Atlas Genet Cytogenet Oncol Haematol.…”

Section: Murine Squamous Carcinoma Of the Skinmentioning

confidence: 99%

TRIM27 (tripartite motif containing 27)

Zoumpoulidou¹,

Mittnacht²

2015

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Role of the Tripartite Motif Protein 27 in Cancer Development

Abstract: TRIM27 expression is a modifier of disease incidence and progression relevant to the development of common human cancers and is a potential target for intervention in cancer.

Cited by 36 publications

References 48 publications

Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

Downregulation of TRIM27 expression inhibits the proliferation of ovarian cancer cells in vitro and in vivo

TRIM27 (tripartite motif containing 27)

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