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

Abstract

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.

MTBP promoted the proliferation, migration and invasion of colon cancer cells by activating the expression of ZEB2

“…MTBP promoted the invasion and metastasis of hepatocellular carcinoma cells by enhancing the MDM2 induced degradation of E-cadherin (Lu et al 2015 ). MTBP promoted the migration and invasion of lung cancer cells by activating the ZEB2 induced EMT of these cells (Pan et al 2018 ). However, whether the expression of MTBP could regulate the migration and invasion of colon cancer cells by modulating the levels of ZEB2 in these cells is unclear.…”

MDM2 Binding Protein Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agents via Enhancing the Transcription Factor Activity of the Pregnane X Receptor

“…Recently, multiple points of evidence have indicated the pro-proliferative and oncogenic activation of MTBP. This activation has been carried out by multiple mechanisms: (1) MTBP is co-amplified with c-MYC and functions as c-Myc’s co-activator ( 50 ); (2) MTBP could enhance the activation of ZEB2 to induce the EMT process of cancerous cells ( 13 ); (3) MTBP inhibits the apoptosis of cancer cells via suppression of the MDM2/P53 axis ( 14 ); and (4) MTBP can enhance the metastasis of HCC cells via the MDM2-Mediated E-Cadherin Degradation ( 11 ).…”

“…The MDM2 binding protein (MTBP) has a molecular weight of 104 kDa and was originally found to interact with MDM2 (murine double minute 2) ( 11 , 12 ). Recently, MTBP has been regarded as an important regulator of human cancer cells’ proliferation or metastasis ( 13 , 14 ). MTBP could promote human cancer cells’ proliferation or metastasis by functioning as a co-activator of c-MYC (cellular-myelocytomatosis viral oncogene) or ZEB2 (Zinc Finger E-Box Binding Homeobox 2) ( 13 ).…”

“…Recently, MTBP has been regarded as an important regulator of human cancer cells’ proliferation or metastasis ( 13 , 14 ). MTBP could promote human cancer cells’ proliferation or metastasis by functioning as a co-activator of c-MYC (cellular-myelocytomatosis viral oncogene) or ZEB2 (Zinc Finger E-Box Binding Homeobox 2) ( 13 ). In this study, MTBP was found to function as a co-activator of PXR, further enhancing PXR’s downstream drug-resistance-related genes.…”

MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy

“…Similar to ZEB1, ZEB2 appears to play a crucial role in migration and invasion. In non-small cell lung cancer (NSCLC), MDM2 binding protein (MTBP) behaves as an oncogene to increase EMT through ZEB2 up-regulation [ 35 ]. This in turn enhanced the migration and metastasis of NSCLC tumor cells.…”