MTBP Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Enhancing the MDM2-Mediated Degradation of E-Cadherin

Lü, Shan; Zhou, Wei; Wei, Haiyun; Zhou, MengChu; Li, Liang

doi:10.1007/s10620-015-3824-4

Cited by 12 publications

(14 citation statements)

References 32 publications

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“…For example, Bi et al 17 reported the suppressive metastasis function of MTBP in HCC. In marked contrast, Lu et al 22 reported that MTBP promoted invasion and metastasis in HCC cells through the enhancement of MDM2-mediated degradation of E-cadherin. Considering the uncertainty about the role of MTBP in tumor metastasis, it is clearly necessary to define its function in stage I lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 88%

MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial–mesenchymal transition in lung cancer cells

Pan¹,

Han

et al. 2018

OTT

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BackgroundIt is clearly necessary to discover prognostic biomarkers to identify stage I patients at risk of recurrence and give them timely postoperative treatment.Materials and methodsData of stage I lung adenocarcinoma were retrieved from four gene series in Gene Expression Omnibus (GEO) database (GSE50081, GSE30219, GSE37745, and GSE13213). Partek Genomics Suite software was used to identify survival-related genes for finding candidate indicators for early-stage patients at risk of recurrence. Differential expression of MTBP (MDM2 binding protein) in early-stage lung adenocarcinoma tissues was determined by immunohistochemical staining. The effects of MTBP interference expression and overexpression on viability, migration, and invasion capacity of lung cells were evaluated using Cell Counting Kit-8, wound healing, and Transwell assays. The tumor growth and lung metastasis in vivo were observed in chick embryo chorioallantoic membrane model. Human Exon 2.0 ST Array was used to analyze downstream regulation genes of MTBP in lung cancer cells. Involvement of ZEB2 and epithelial–mesenchymal transition (EMT) markers was investigated by Western blot.ResultsBy mining GEO database, we identified MTBP as a poor prognostic indicator of stage I lung adenocarcinomas. In addition, increased expression of MTBP was also associated with poor survival in our early-stage lung adenocarcinoma cohort. Further experiment suggested that knockdown of MTBP suppressed the migration and invasion of A549 and H1975 cells in vitro and in vivo, whereas overexpression of MTBP in HCC827 and PC9 cells promoted the migration and invasion in vitro and in vivo. Furthermore, ZEB2 upregulation directly activated EMT to mediate the downstream effects of MTBP involved in lung cancer cells metastasis.ConclusionMTBP is an independent indicator for poor prognosis in stage I lung adenocarcinomas and might promote the aggressive phenotype of non-small-cell lung cancer by inducing the EMT process through upregulating ZEB2 expression.

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Section: Discussionmentioning

confidence: 88%

MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial–mesenchymal transition in lung cancer cells

Pan¹,

Han

et al. 2018

OTT

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“…Through MDM2 stabilization and p53 degradation, MTBP inhibits the expression of the p53 effectors of apoptosis and cell cycle arrest/cell senescence, upregulates the expression of c-myc oncoprotein, and promotes tumor growth and treatment resistance. Although the role of MTBP in the invasion of tumor cells is still controversial 33, 34, its pro-proliferative effect via interaction with c-myc has been reported in several human malignancies, including breast cancers 35, B-cell lymphomas 36 and lung cancers 9. In B-cell lymphoma, MTBP expression is induced by c-myc, suggesting that MTBP might be a transcriptional target of c-myc 36.…”

Section: Discussionmentioning

confidence: 99%

MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas

et al. 2019

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Background: Glioblastoma (GBM) is highly proliferative and resistant to radio-chemotherapy. Loss of tumor suppressor gene TP53 function frequently occurs at protein level in GBMs. This inhibition is often mediated by other components within the p53 signaling axis, including MDM2, whose binding protein (MTBP) plays an important role in the regulation of MDM2 and p53 activity. We investigated the role of MTBP in the biology of TP53-wildtype (TP53wt) GBMs.Methods: MTBP expression was examined in TCGA and REMBRANDT datasets. MTBP was silenced or overexpressed in TP53wt GBM cells and glioma stem cells (GSCs). The effects on cell viability, apoptosis, and clonogenicity were assessed. The transcriptional regulation of MTBP was investigated.Results: Upregulation of MTBP was correlated with the Classical molecular subtype, and it predicted poor survival. In TP53wt GBM cells, the protein levels of MTBP were positively associated with those of MDM2 but negatively correlated with those of p53. MTBP knockdown promoted apoptosis and inhibited clonogenicity, while overexpression of this protein enhanced tumorigenicity in vitro and in vivo. The pro-survival effect of MTBP depended on the activity of MDM2 and p53. MTBP was transcriptionally regulated by c-myc, thereby forming a positive regulatory loop. Finally, MTBP silencing increased the sensitivity of TP53wt GSCs to radiation and TMZ treatment in vitro and in vivo.Conclusion: MTBP regulates the cell survival and treatment sensitivity of TP53wt GBMs through MDM2-dependent post-translational modification of p53. MTBP-targeting treatments are potentially useful in increasing patients' survival.

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“…[ 119 – 121 ] In another study on human HCC, increased MTBP expression is shown to be associated with increase in MDM2 levels and metastasis, as well as poor survival of HCC patients, which is contrary to previously published studies. [ 122 ] Thus, the roles of MTBP in cancer metastasis, the underlying mechanisms, and functional association between MDM2 and MTBP need to be further clarified in the future.…”

Section: Metastasis Suppressorsmentioning

confidence: 99%

Murine double minute 2, a potential p53-independent regulator of liver cancer metastasis

Ranjan

Bera

Iwakuma

2016

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Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the mechanisms underlying HCC progression remain unclear. Unlike other cancers, systematic chemotherapy is not effective for HCC patients, while surgical resection and liver transplantation are the most viable treatment options. Thus, identifying factors or pathways that suppress HCC progression would be crucial for advancing treatment strategies for HCC. The murine double minute 2 (MDM2)-p53 pathway is impaired in most of the cancer types, including HCC, and MDM2 is overexpressed in approximately 30% of HCC. Overexpression of MDM2 is reported to be well correlated with metastasis, drug resistance, and poor prognosis of multiple cancer types, including HCC. Importantly, these correlations are observed even when p53 is mutated. Indeed, p53-independent functions of overexpressed MDM2 in cancer progression have been suitably demonstrated. In this review article, we summarize potential effectors of MDM2 that promote or suppress cancer metastasis and discuss the p53-independent roles of MDM2 in liver cancer metastasis from clinical as well as biological perspectives.

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MTBP Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Enhancing the MDM2-Mediated Degradation of E-Cadherin

Abstract: Our data show that MTBP aggravates the invasion and metastasis of HCC by promoting the MDM2-mediated degradation of E-cadherin.

Cited by 12 publications

References 32 publications

MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial–mesenchymal transition in lung cancer cells

MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial–mesenchymal transition in lung cancer cells

MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas

Murine double minute 2, a potential p53-independent regulator of liver cancer metastasis

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MTBP Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Enhancing the MDM2-Mediated Degradation of E-Cadherin

Abstract: Our data show that MTBP aggravates the invasion and metastasis of HCC by promoting the MDM2-mediated degradation of E-cadherin.

Cited by 12 publications

References 32 publications

MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial&ndash;mesenchymal transition in lung cancer cells

MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial&ndash;mesenchymal transition in lung cancer cells

MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas

Murine double minute 2, a potential p53-independent regulator of liver cancer metastasis

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MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial–mesenchymal transition in lung cancer cells

MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial–mesenchymal transition in lung cancer cells