Down-regulation of CMTM8 Induces Epithelial-to-Mesenchymal Transition-like Changes via c-MET/Extracellular Signal-regulated Kinase (ERK) Signaling

Zhang, Wenjuan; Mendoza, Michelle C.; Pei, Xiaolei; Ilter, Didem; Mahoney, Sarah J.; Zhang, Yingmei; Ma, Dalong; Blenis, John; Wang, Ying

doi:10.1074/jbc.m111.258236

Cited by 52 publications

(46 citation statements)

References 47 publications

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“…Previous studies have shown that phosphorylation of ERK-1/2 by MEK was elevated in PTCs from patients with DN and associated with EMT. Zuo, et al reported that EGFR activation induced a change with an EMT-like phenotype in scc10A cells [24]. Based on the EMT PCR Array analysis, we found that EGFR expression was up-regulated after GLIPR-2 overexpression.…”

Section: Discussionmentioning

confidence: 50%

GLIPR-2 Overexpression in HK-2 Cells Promotes Cell EMT and Migration through ERK1/2 Activation

et al. 2013

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The epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells in the adult kidney is one of the key events in renal interstitial fibrosis. Glioma pathogenesis related-2 (GLIPR-2) has been shown to be up-regulated in proximal tubular cells (PTCs) in the fibrotic kidney. However, the biological function of GLIPR-2 remains unknown. In this study, we found that GLIPR-2 expression is elevated in the kidney tissue samples of patients with diabetic nephropathy (DN). Human proximal renal tubular epithelial cells (HK-2 cells) were transfected with pcDNA3.0-GLIPR-2 and selected with G418. To identify the biological function of GLIPR-2, an epithelial-to-mesenchymal transition (EMT) PCR array analysis was performed, and genes that had statistically significantly altered expression levels with more than a two-fold difference compared with the pcDNA3.0-transfected HK-2 cells were considered. Key elements of the EMT process, such as E-cadherin and vimentin, were transcriptionally activated in the pcDNA3.0-GLIPR-2-transfected sublines. In addition, α-SMA gene expression, which is a marker of myofibroblasts, increased in the pcDNA3.0-GLIPR-2-transfected HK-2 cells. The cell migration assay demonstrated that the transfection of HK-2 with GLIPR-2 promoted cell migration following an EMT. Additionally, consistent with the effects of increased EGFR expression levels, we found that the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) was highly elevated in the pcDNA3.0-GLIPR-2-transfected group. Our study demonstrates that GLIPR-2 overexpression in HK-2 cells can potentiate EMT-like processes in this cell type through the ERK1/2 signaling pathway. GLIPR-2 may be responsible for the development of renal fibrosis by increasing the accumulation of interstitial fibroblasts.

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Section: Discussionmentioning

confidence: 50%

GLIPR-2 Overexpression in HK-2 Cells Promotes Cell EMT and Migration through ERK1/2 Activation

et al. 2013

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“…Together, these reports implicate Met as a potentially effective therapeutic target to reverse resistance to this important class of drugs in NSCLC. Moreover, the Met receptor promotes a complex biological program designated "invasion growth" that results from stimulation of cell motility, invasion and protection from apoptosis (Zhang et al, 2012;Luo et al, 2013). To better understand the up-stream pathways involved in NSCLC gefitinib resistance, we investigated the miRNA, miR130a, which can regulate Met expression.…”

Section: Discussionmentioning

confidence: 99%

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

Zhou

Liu²,

Sun³

2014

Asian Pacific Journal of Cancer Prevention

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is used for its treatment; however, drug resistance is a major obstacle. Expression of Met has been associated with both primary and acquired resistance to gefitinib, but the mechanisms regulating its expression are not fully understood. Recently, miRNAs such as miR-130a have been shown to play a role in gefitinib resistance, but importance in NSCLC and relationships with Met have not been fully explored. Here we show that miR-130a is over-expressed in gefitinibsensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Moreover, miR-130a expression was negatively correlated with that of Met. Further analysis revealed that over-expression of miR-130a increased cell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expression of miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in both gefitinib-sensitive and -resistant NSCLC cell lines, suggesting that miR-130a overcomes gefitinib resistance. We also demonstrated that miR-130a binds to the 3'-UTR of Met and significantly suppresses its expression. Finally, our results showed that over-expressing Met could "rescue" the functions of miR-130a regarding cell apoptosis and proliferation after cells are treated with gefitinib. These findings indicate that the miR-130a/Met axis plays an important role in gefitinib resistance in NSCLC. Thus, the miR-130a/Met axis may be an effective therapeutic target in gefitinib-resistant lung cancer patients.

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“…CMTM7 could promote epidermal growth factor receptor (EGFR) internalization, and further suppress Akt signaling pathway [31]. CMTM8 functions as a negative regulator of HGF/c-MET signaling to ERK [13]. CMTM3 might regulate MMP2 expression through the ERK1⁄2 signaling pathway [20].…”

Section: Discussionmentioning

confidence: 99%

“…Analyses carried out on DNA methylation patterns show that this process can be used as a biomarker for early diagnosis as well as for classification, prognosis, and therapy of human cancers [6]. Previous studies have identified the methylation of the promoter regions of over 40 tumor suppressor genes in oral squamous cell carcinoma and precancerous lesions, such as CDKN2A, MGMT, DAPK1, RUNX3, and p14 ARF [7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 98%

CMTM3 inhibits cell growth and migration and predicts favorable survival in oral squamous cell carcinoma

Zhang

et al. 2015

Tumor Biol.

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Downregulation of CKLF-like MARVEL transmembrane domain-containing member 3 (CMTM3) has been reported in a number of human tumors. However, the role of CMTM3 in oral squamous cell carcinoma (OSCC) remains largely unknown. In this study, we showed that the expression of CMTM3 was significantly reduced in OSCC cell lines and primary tumor specimens (P < 0.001). Methylation-specific PCR showed hypermethylation in CMTM3 promoter in a significant proportion of tumor tissues (61 %). The expression of CMTM3 was associated with T stage, lymph node metastasis, tumor node metastasis (TNM) stage, and recurrence of OSCC patients (P < 0.05, n = 201). More importantly, CMTM3 expression was associated with the prognosis of OSCC patients (P < 0.001) and was an independent prognostic factor (hazard ratio = 0.593, 95 % confidence interval, 0.272-1.292; P = 0.039). Overexpression of CMTM3 inhibited the growth and migration of OSCC cells. In vivo experiments also showed that the growth of OSCC xenografts in nude mice was significantly inhibited by CMTM3 overexpression. These findings indicate that downregulation of CMTM3 due to promoter hypermethylation contributed to the proliferation and migration of OSCC cells and suggest that CMTM3 is an independent prognostic factor for the evaluation of the survival of OSCC patients.

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Down-regulation of CMTM8 Induces Epithelial-to-Mesenchymal Transition-like Changes via c-MET/Extracellular Signal-regulated Kinase (ERK) Signaling

Cited by 52 publications

References 47 publications

GLIPR-2 Overexpression in HK-2 Cells Promotes Cell EMT and Migration through ERK1/2 Activation

GLIPR-2 Overexpression in HK-2 Cells Promotes Cell EMT and Migration through ERK1/2 Activation

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

CMTM3 inhibits cell growth and migration and predicts favorable survival in oral squamous cell carcinoma

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