scholarly journals Down-Regulated MAC30 Suppresses Lung Cancer Invasion and EMT by Inhibiting Wnt/β-Catenin Signaling Pathway

2021 ◽  
Author(s):  
jingzhu zhou ◽  
xiuhai ji ◽  
ruhua chen ◽  
yan fen ◽  
Hui ding
Keyword(s):  
Lung Cancer ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Cancer Invasion ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Related Proteins ◽  
Proliferation And Invasion ◽  
Worse Prognosis

Abstract Backgrounds：Over-expressed meningioma-associated protein (MAC30) was proved to be a biomarker for worse prognosis in non–small cell lung cancer (NSCLC). However, the regulated mechanism of MAC30 in epithelial–mesenchymal transition (EMT) and lung cancer invasion is unknown. Methods：Transformed growth factor (TGF-β) was used to induce EMT in A549 cells in vitro. MAC30 siRNA was transfected into cells to silence the gene expression. Real-Time PCR was prepared to assess the levels of MAC30 mRNA. Methyl thiazolyl tetrazolium (MTT) and Transwell invasion assays were performed to study the proliferation and invasion of A549 cells. Expression of MAC30, EMT-related proteins, Wnt/β-catenin signal and its downstream factors were explored by ELISA. Results: We found enhanced MAC30 expression in A549 cells. MAC30 Knockdown inhibited TGF-β-induced lung cell proliferation and invasion. Furthermore, elevated levels of mesenchymal markers (N-cadherin, vimentin) and decreased levels of epithelial markers E-cadherin in A549 cells with TGF-β incubation were reversed by MAC30 siRNA. Finally, MAC30 knockdown significantly suppressed TGF-β-upregulated protein levels of Wnt/ β-catenin signaling and its downstream genes (surviving, c-myc and cyclin D1). Conclusions: We firstly confirm that MAC30 knockdown limits lung cancer growth and EMT through inhibiting the activation of Wnt/β-catenin pathway.

scholarly journals miR-185 Inhibits the Proliferation and Invasion of Non-Small Cell Lung Cancer by Targeting KLF7

2019 ◽  
Vol 27 (9) ◽  
pp. 1015-1023 ◽  
Author(s):  
Lili Zhao ◽  
Yao Zhang ◽  
Jiaoxia Liu ◽  
Wei Yin ◽  
Dan Jin ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Cancer Types ◽  
Proliferation And Invasion

MicroRNAs (miRNAs) are short endogenous noncoding RNAs that frequently play vital roles in many cancer types. Herein we demonstrated that miR-185 was remarkably downregulated in NSCLC tissues compared with adjacent normal tissues. A lower level of miR-185 was associated with lymph node metastasis. Functional assays showed that upregulation of miR-185 inhibited the proliferation, colony formation, and invasion capacities of NSCLC cells in vitro. Furthermore, we found that miR-185 suppressed the epithelial‐mesenchymal transition (EMT) process. Bioinformatics analysis and luciferase reporter gene assays revealed that Kruppel-like factor 7 (KLF7) was the target of miR-185. Overexpression of miR-185 reduced the expression of KLF7 in NSCLC cells. Upregulation of KLF7 partly neutralized the inhibitory effects of miR-185 on the proliferation and invasion of NSCLC. Additionally, we confirmed that miR-185 suppressed the tumor growth of NSCLC A549 cells in vivo. Taken together, these results demonstrate that miR-185 acts as a suppressor by targeting KLF7 in NSCLC.

YAP1 Overexpression Is Associated with Kidney Dysfunction in Lupus Nephritis

Pathobiology ◽  
2021 ◽  
pp. 1-12
Author(s):  
Ying Xie ◽  
Yuanyuan Ruan ◽  
Huimei Zou ◽  
Yixin Wang ◽  
Xin Wu ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Tissue ◽  
Mouse Kidney ◽  
Experimental Comparison ◽  
Control Group ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Protein Levels

<b><i>Objective:</i></b> The goal of the present study was to determine the expression of yes-associated protein 1 (YAP1) in renal tissues of mice with lupus nephritis (LN) and elucidate its role in the progression of renal fibrosis. <b><i>Methods:</i></b> C57BL/6 mice and MRL/lpr mice were selected for experimental comparison. Mouse kidney tissues were removed and sectioned for hematoxylin and eosin staining, Masson’s trichome staining, Sirius staining, and immunohistochemistry. The mRNA and protein levels of YAP1 in mouse kidney tissues were detected, and the correlation between YAP1 and fibronectin (FN) mRNA levels was analyzed. Mouse renal epithelial cells were used for in vitro experiments. After transfection and stimulation, the cells were divided into 4 groups, namely the C57BL/6 serum group (group 1), the MRL/lpr serum group (group 2), the MRL/lpr serum + siRNA-negative control group (group 3), and the MRL/lpr serum + siRNA-YAP1 group (group 4). Epithelial-mesenchymal transition (EMT) markers in each group were detected by Western blotting and immunofluorescence staining. Serum creatinine, blood urea nitrogen, and urinary protein levels were detected and assessed for their correlation with YAP1 mRNA levels by Spearman’s analysis. <b><i>Results:</i></b> Compared to C57BL/6 mice, MRL/lpr mice exhibited obvious changes in fibrosis in renal tissues. In addition, YAP1 expression was significantly higher in the renal tissues of MRL/lpr mice than in those of C57BL/6 mice, and YAP1 mRNA levels were positively correlated with those of FN. YAP1 silencing in lupus serum-stimulated cells could effectively relieve serum-induced EMT. Finally, we observed that YAP1 mRNA levels in mouse kidney tissue were significantly and positively correlated with the degree of renal function injury. <b><i>Conclusion:</i></b> YAP1 expression in the kidney tissues of LN mice was higher than that observed in normal mice, indicating that YAP1 may play an important role in the occurrence and development of LN.

scholarly journals EXTH-51. ANTI-INVASIVE EFFICACY AND SURVIVAL BENEFIT OF THE YAP-TEAD INHIBITOR VERTEPORFIN IN PRECLINICAL GLIOBLASTOMA MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii98-ii98
Author(s):  
Anne Marie Barrette ◽  
Alexandros Bouras ◽  
German Nudelman ◽  
Zarmeen Mussa ◽  
Elena Zaslavsky ◽  
...  
Keyword(s):  
Survival Benefit ◽  
De Novo ◽  
Epithelial Mesenchymal Transition ◽  
Intraperitoneal Administration ◽  
Standard Of Care ◽  
Tumor Burden ◽  
Mesenchymal Transition ◽  
Protein Levels

Abstract Glioblastoma (GBM) remains an incurable disease, in large part due to its malignant infiltrative spread, and current clinical therapy fails to target the invasive nature of tumor cells in disease progression and recurrence. Here, we use the YAP-TEAD inhibitor Verteporfin to target a convergence point for regulating tumor invasion/metastasis and establish the robust anti-invasive therapeutic efficacy of this FDA-approved drug and its survival benefit across several preclinical glioma models. Using patient-derived GBM cells and orthotopic xenograft models (PDX), we show that Verteporfin treatment disrupts YAP/TAZ-TEAD activity and processes related to cell adhesion, migration and epithelial-mesenchymal transition. In-vitro, Verteporfin impairs tumor migration, invasion and motility dynamics. In-vivo, intraperitoneal administration of Verteporfin in mice with orthotopic PDX tumors shows consistent drug accumulation within the brain and decreased infiltrative tumor burden, across three independent experiments. Interestingly, PDX tumors with impaired invasion after Verteporfin treatment downregulate CDH2 and ITGB1 adhesion protein levels within the tumor microenvironment. Finally, Verteporfin treatment confers survival benefit in two independent PDX models: as monotherapy in de-novo GBM and in combination with standard-of-care chemoradiation in recurrent GBM. These findings indicate potential therapeutic value of this FDA-approved drug if repurposed for GBM patients.

scholarly journals Propofol Inhibits Lung Cancer A549 Cell Growth and Epithelial‐Mesenchymal Transition Process by Upregulation of MicroRNA-1284

2018 ◽  
Vol 27 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Wei-Zhen Liu ◽  
Nian Liu
Keyword(s):  
Lung Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
A549 Cell ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Foxm1 Expression

Propofol has been widely used in lung cancer resections. Some studies have demonstrated that the effects of propofol might be mediated by microRNAs (miRNAs). This study aimed to investigate the effects and mechanisms of propofol on lung cancer cells by regulation of miR-1284. A549 cells were treated with different concentrations of propofol, while transfected with miR-1284 inhibitor, si-FOXM1, and their negative controls. Cell viability, migration, and invasion, and the expression of miR-1284, FOXM1, and epithelial‐mesenchymal transition (EMT) factors were detected by CCK-8, Transwell, qRT-PCR, and Western blot assays, respectively. In addition, the regulatory and binding relationships among propofol, miR-1284, and FOXM1 were assessed, respectively. Results showed that propofol suppressed A549 cell viability, migration, and invasion, upregulated E-cadherin, and downregulated N-cadherin, vimentin, and Snail expressions. Moreover, propofol significantly promoted the expression of miR-1284. miR-1284 suppression abolished propofol-induced decreases of cell viability, migration, and invasion, and increased FOXM1 expression and the luciferase activity of FOXM1-wt. Further, miR-1284 negatively regulated FOXM1 expression. FOXM1 knockdown reduced cell viability, migration, and invasion by propofol treatment plus miR-1284 suppression. In conclusion, our study indicated that propofol could inhibit cell viability, migration, invasion, and the EMT process in lung cancer cells by regulation of miR-1284.

scholarly journals Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2021 ◽  
Author(s):  
Chi-Chung Wang ◽  
Yuan-Ling Hsu ◽  
Chi-Jen Chang ◽  
Chia-Jen Wang ◽  
Tzu-Hung Hsiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Binding ◽  
Lung Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Inhibitor Of Dna Binding ◽  
E Cadherin

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research team discovered that the expression of the inhibitor of DNA binding 4 (Id4) was inversely related to cell invasiveness in LADC cells by cDNA microarray screening. However, the functional role of Id4 and its mechanism of action in lung cancer metastasis remain unclear. In this study, we report that the expression of Id4 could attenuate cell migration and invasion in vitro and cancer metastasis in vivo. Detailed analyses indicated that Id4 could promote E-cadherin expression through the binding of Slug, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Moreover, the examination of the gene expression database (GSE31210) also revealed that high-level expression of Id4/E-cadherin and low-level expression of Slug were associated with a better clinical outcome in LADC patients. In summary, Id4 may act as a metastatic suppressor, which could not only be used as an independent predictor but also serve as a potential therapeutic for LADC treatment.

scholarly journals PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells

2020 ◽  
Vol 295 (40) ◽  
pp. 13798-13811 ◽  
Author(s):  
Yueli Shi ◽  
Xinyu Wang ◽  
Zhiyong Xu ◽  
Ying He ◽  
Chunyi Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Effector Proteins ◽  
Scaffolding Protein ◽  
Migration And Invasion ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Smad3 Protein

Transforming growth factor β (TGFβ) signaling plays an important role in regulating tumor malignancy, including in non–small cell lung cancer (NSCLC). The major biological responses of TGFβ signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFβ–SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGFβ signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasion in vitro and lung metastasis in vivo. In addition, TGFβ signaling and TGFβ-induced epithelial–mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGFβ-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGFβ signaling and NSCLC progression.

scholarly journals Mapping lung cancer epithelial-mesenchymal transition states and trajectories with single-cell resolution

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Loukia G. Karacosta ◽  
Benedict Anchang ◽  
Nikolaos Ignatiadis ◽  
Samuel C. Kimmey ◽  
Jalen A. Benson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Single Cell ◽  
Cancer Progression ◽  
Time Course ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Samples ◽  
Neural Net ◽  
Mesenchymal Transition ◽  
Phenotypic Profile

AbstractElucidating the spectrum of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in clinical samples promises insights on cancer progression and drug resistance. Using mass cytometry time-course analysis, we resolve lung cancer EMT states through TGFβ-treatment and identify, through TGFβ-withdrawal, a distinct MET state. We demonstrate significant differences between EMT and MET trajectories using a computational tool (TRACER) for reconstructing trajectories between cell states. In addition, we construct a lung cancer reference map of EMT and MET states referred to as the EMT-MET PHENOtypic STAte MaP (PHENOSTAMP). Using a neural net algorithm, we project clinical samples onto the EMT-MET PHENOSTAMP to characterize their phenotypic profile with single-cell resolution in terms of our in vitro EMT-MET analysis. In summary, we provide a framework to phenotypically characterize clinical samples in the context of in vitro EMT-MET findings which could help assess clinical relevance of EMT in cancer in future studies.

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