Inhibition Of TGF-Beta-Induced Phenotype Alterations Through Epithelial-Mesenchymal Transition (EMT) In Lung Cancer By Gene Modulation Of Phosphorylation Sites In Tumor Suppressor Pten

2011 ◽  
Author(s):  
Daisuke Aoyama ◽  
Naozumi Hashimoto ◽  
Kazuyoshi Imaizumi ◽  
Takashi Kohnoh ◽  
Koji Sakamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Epithelial Mesenchymal Transition ◽  
Phosphorylation Sites ◽  
Tgf Beta ◽  
Gene Modulation ◽  
Mesenchymal Transition

DEAR1, a novel tumor suppressor, negative regulator of epithelial-mesenchymal transition, and prognostic factor in non-small cell lung cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10506-10506
Author(s):  
Alfonso Quintas-Cardama ◽  
Sean M. Post ◽  
Luisa Solis ◽  
Shunbin Xiong ◽  
Ignacio I. Wistuba ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Prognostic Factor ◽  
Tumor Suppressor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Mesenchymal Transition

10506 Background: DEAR1, also known as TRIM62, maps to 1p.35, a genomic interval within which loss of heterozygosity occurs at high frequency in carcinomas. DEAR1 has been proposed as a regulator of cell polarity in vitro. Methods: We genetically engineered mice lacking DEAR1 alleles at murine chromosome 4. To study the impact of DEAR1 loss in lung cancer, DEAR1 deficient mice were crossed to mice carrying the latent mutant K-rasG12D allele (K-rasLA1). Results: No survival difference was observed between DEAR1+/─ and DEAR1─/─ mice (729 vs 699 days, p=0.98) but they were markedly shorter than that of DEAR1 wild-type littermates (803 days, p=0.01). Over 90% of mice developed tumors, mainly adenocarcinomas, including invasive and/or metastatic lung cancer in 23% of cases. DEAR1-deficient K-rasLA1 mice had reduced life span compared with DEAR1+/+:K-ras+/LA1 littermates (184 vs 291 days, p<0.0001). The survival of DEAR1+/─:K-ras+/LA1 and DEAR1─/─:K-ras+/LA1 mice were similar (180 vs 153 days, p=0.38) and qPCR and IHC analyses suggested loss of the wild-type DEAR1 allele. The survival of DEAR1-deficient K-rasLA1 mice was also shorter than that of control p53+/─:K-ras+/LA1 mice (240 days; p=0.01). The metastasis incompetent K-rasLA1–positive LKR13 cell line after shRNA DEAR1 knock-down and cell lines derived from DEAR1-deficient K-rasLA1 tumors recapitulated an invasive phenotype in transwell migration and 3D culture assays and a metastatic phenotype on SC or IV injection into immunocompetent wild-type littermates. The latter was associated with epithelial-mesenchymal transition involving loss of E-cadherin and DEAR1 expression and upregulation of vimentin, Twist, and CD44. DEAR1 downregulation was very prevalent in a non-small cell lung cancer (NSCLC) tissue array with 214 samples. Patients with early stage NSCLC and loss of DEAR1 expression had a markedly shorter time to relapse compared to those retaining DEAR1 expression (5.1 vs 2.87 years, p=0.049) and worse 5-year relapse-free and overall survival rates. Conclusions: DEAR1 is a novel tumor suppressor that negatively regulates EMT and promotes lung cancer metastasis. DEAR1 loss is a poor prognostic factor in NSCLC.

scholarly journals αvβ3 Integrin induces partial EMT independent of TGF-β signaling

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yoshinobu Kariya ◽  
Midori Oyama ◽  
Takato Suzuki ◽  
Yukiko Kariya
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Αvβ3 Integrin ◽  
Poor Survival ◽  
Mesenchymal Transition ◽  
Intermediate States ◽  
Tgf Β1

AbstractEpithelial–mesenchymal transition (EMT) plays a pivotal role for tumor progression. Recent studies have revealed the existence of distinct intermediate states in EMT (partial EMT); however, the mechanisms underlying partial EMT are not fully understood. Here, we demonstrate that αvβ3 integrin induces partial EMT, which is characterized by acquiring mesenchymal phenotypes while retaining epithelial markers. We found αvβ3 integrin to be associated with poor survival in patients with lung adenocarcinoma. Moreover, αvβ3 integrin-induced partial EMT promoted migration, invasion, tumorigenesis, stemness, and metastasis of lung cancer cells in a TGF-β-independent fashion. Additionally, TGF-β1 promoted EMT progression synergistically with αvβ3 integrin, while a TGF-β signaling inhibitor showed no effect on αvβ3 integrin-induced partial EMT. Meanwhile, the microRNA-200 family abolished the αvβ3 integrin-induced partial EMT by suppressing αvβ3 integrin cell surface expression. These findings indicate that αvβ3 integrin is a key inducer of partial EMT, and highlight a new mechanism for cancer progression.

scholarly journals ID1 mediates resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer through epithelial–mesenchymal transition

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kejun Liu ◽  
Xianwen Chen ◽  
Ligang Wu ◽  
Shiyuan Chen ◽  
Nianxin Fang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Epithelial Mesenchymal Transition ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Egfr T790m ◽  
E Cadherin

Abstract Background ID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, the effect of ID1 expression on osimertinib resistance in EGFR T790M-positive NSCLC is not clear. Methods We established a drug-resistant cell line, H1975/OR, from the osimertinib-sensitive cell line H1975. Alterations in ID1 protein expression and Epithelial–mesenchymal transition (EMT)-related proteins were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA levels. ID1 silencing and overexpression were used to investigate the effects of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess the proliferation rate in cells with altered of ID1 expression. Transwell assay was used to evaluate the invasion ability of different cells. The effects on the cell cycle and apoptosis were also compared using flow cytometry. Results In our study, we found that in osimertinib-resistant NSCLC cells, the expression level of the EMT-related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin were higher than those of sensitive cells. ID1 expression levels was closely related to E-cadherin and vimentin in both osimertinib-sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression in H1975/OR cells could inhibit cell proliferation, reduce cell invasion, promote cell apoptosis and arrested the cell cycle in the G1/G0 stage phase. Our study suggests that ID1 may induce EMT in EGFR T790M-positive NSCLC, which mediates drug resistance of osimertinib. Conclusions Our study revealed the mechanism of ID1 mediated resistance to osimertinib in EGFR T790M-positive NSCLC through EMT, which may provide new ideas and methods for the treatment of EGFR mutated NSCLC after osimertinib resistance.

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