scholarly journals MicroRNA-106a regulates autophagy-related cell death and EMT by targeting TP53INP1 in lung cancer with bone metastasis

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Lei Han ◽  
Zeyong Huang ◽  
Yan Liu ◽  
Lijuan Ye ◽  
Dongqi Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Lung Adenocarcinoma ◽  
Cancer Patients ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Lung Cancer Patients

AbstractBone metastasis is one of the most serious complications in lung cancer patients. MicroRNAs (miRNAs) play important roles in tumour development, progression and metastasis. A previous study showed that miR-106a is highly expressed in the tissues of lung adenocarcinoma with bone metastasis, but its mechanism remains unclear. In this study, we showed that miR-106a expression is dramatically increased in lung cancer patients with bone metastasis (BM) by immunohistochemical analysis. MiR-106a promoted A549 and SPC-A1 cell proliferation, migration and invasion in vitro. The results of bioluminescence imaging (BLI), micro-CT and X-ray demonstrated that miR-106a promoted bone metastasis of lung adenocarcinoma in vivo. Mechanistic investigations revealed that miR-106a upregulation promoted metastasis by targeting tumour protein 53-induced nuclear protein 1 (TP53INP1)-mediated metastatic progression, including cell migration, autophagy-dependent death and epithelial–mesenchymal transition (EMT). Notably, autophagy partially attenuated the effects of miR-106a on promoting bone metastasis in lung adenocarcinoma. These findings demonstrated that restoring the expression of TP53INP1 by silencing miR-106a may be a novel therapeutic strategy for bone metastatic in lung adenocarcinoma.

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 Phosphorylation of CAP1 regulates lung cancer proliferation, migration, and invasion

2021 ◽  
Author(s):  
Jie Zeng ◽  
Xuan Li ◽  
Long Liang ◽  
Hongxia Duan ◽  
Shuanshuan Xie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
A549 Cells ◽  
Migration And Invasion ◽  
Cancer Proliferation ◽  
Mesenchymal Transition ◽  
Lung Cancer Patients ◽  
Nsclc Patients

Abstract Purpose Cyclase-associated protein 1 (CAP1) is a ubiquitous protein which regulates actin dynamics. Previous studies have shown that S308 and S310 are the two major phosphorylated sites in human CAP1. In the present study, we aimed to investigate the role of CAP1 phosphorylation in lung cancer. Methods Massive bioinformatics analysis was applied to determine CAP1’s role in different cancers and especially in lung cancer. Lung cancer patients’ serum and tissue were collected and analyzed in consideration of clinical background. CAP1 shRNA-lentivirus and siRNA were applied to CAP1 gene knockdown, and plasmids were constructed for CAP1 phosphorylation and de-phosphorylation. Microarray analysis was used for CAP1-associated difference analysis. Both in vitro and in vivo experiments were performed to investigate the roles of CAP1 phosphorylation and de-phosphorylation in lung cancer A549 cells. Results CAP1 is a kind of cancer-related protein. Its mRNA was overexpressed in most types of cancer tissues when compared with normal tissues. CAP1 high expression correlated with poor prognosis. Our results showed that serum CAP1 protein concentrations were significantly upregulated in non-small cell lung cancer (NSCLC) patients when compared with the healthy control group, higher serum CAP1 protein concentration correlated with shorter overall survival (OS) in NSCLC patients, and higher pCAP1 and CAP1 protein level were observed in lung cancer patients’ tumor tissue compared with adjacent normal tissue. Knockdown CAP1 in A549 cells can inhibit proliferation and migration, and the effect is validated in H1975 cells. It can also lead to an increase ratio of F-actin/G-actin. In addition, phosphorylated S308 and S310 in CAP1 promoted lung cancer cell proliferation, migration, and metastasis both in vitro and in vivo. When de-phosphorylated, these two sites in CAP1 showed the opposite effect. Phosphorylation of CAP1 can promote epithelial–mesenchymal transition (EMT). Conclusion These findings indicated that CAP1 phosphorylation can promote lung cancer proliferation, migration, and invasion. Phosphorylation sites of CAP1 might be a novel target for lung cancer treatment.

scholarly journals Epithelial-mesenchymal transition-associated secretory phenotype predicts survival in lung cancer patients

2014 ◽  
Vol 35 (6) ◽  
pp. 1292-1300 ◽  
Author(s):  
A. K. Reka ◽  
G. Chen ◽  
R. C. Jones ◽  
R. Amunugama ◽  
S. Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Lung Cancer Patients ◽  
Secretory Phenotype

Targeting β-tubulin/CCT-β complex induces apoptosis and suppresses migration and invasion of highly metastatic lung adenocarcinoma

2019 ◽  
Vol 41 (5) ◽  
pp. 699-710 ◽  
Author(s):  
Yan-Jin Liu ◽  
Yu-Ju Chang ◽  
Yu-Ting Kuo ◽  
Po-Huang Liang
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Prognostic Marker ◽  
Epithelial Mesenchymal Transition ◽  
Lung Cancer Cell Line ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Metastatic Lung ◽  
Β Tubulin

Abstract Metastasis, the movement of cancer cells from one site to another, is responsible for the highest number of cancer deaths, especially in lung cancer patients. In this study, we first identified a prognostic marker of lung adenocarcinoma, TCP-1 β subunit (chaperonin-containing TCP-1β; CCT-β). We showed a compound that disrupted the interaction of CCT-β with β-tubulin killed a highly metastatic non-small cell lung cancer cell line CL1-5 through inducing Endoplasmic reticulum stress and caspases activation. Moreover, at the dosage of EC20, the compound inhibited migration and invasion of the lung cancer cells by suppressing matrix metalloproteinase (MMP)-2/9 and epithelial–mesenchymal transition (EMT)-related proteins through downregulating mitogen-activated protein kinases (MAPKs), Akt/β-catenin and integrin–focal adhesion kinase signaling pathways. Unlike the anticancer drugs, such as Taxol, that target the adenosine triphosphate site of β-tubulin, this study reveals a therapeutic target, β-tubulin/CCT-β complex, for metastatic human lung adenocarcinoma. The study demonstrated CCT-β as a prognostic marker. Targeting β-tubulin/CCT-β complex caused apoptosis and inhibited invasion/migration of CCT-β overexpressed, highly metastatic lung adenocarcinoma.

scholarly journals KRT6A Promotes EMT and Cancer Stem Cell Transformation in Lung Adenocarcinoma

2020 ◽  
Vol 19 ◽  
pp. 153303382092124
Author(s):  
Bin Yang ◽  
Wei Zhang ◽  
Mengmeng Zhang ◽  
Xuhong Wang ◽  
Shengzu Peng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Lung Adenocarcinoma ◽  
Biological Function ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Normal Lung ◽  
Mesenchymal Transition

Aim: Keratin 6A is a type II cytokeratin which is important in forming nail bed, filiform papillae, the epithelial lining of oral mucosa, and esophagus; recently, keratin 6A was found hyperexpressed in different types of cancer. But, the biological function of keratin 6A in lung adenocarcinoma still remains unclear. Therefore, in current study, we investigated the biological role of keratin 6A in lung adenocarcinoma. Methods: By utilizing The Cancer Genome Atlas database, we investigated the expression profile of keratin 6A and its relationship with other clinical parameters in lung adenocarcinoma. The biological function of keratin 6A in lung adenocarcinoma was also investigated by using A549 and PC-9 lung cancer cell lines in vitro. Results: Our data indicate that, compared with normal lung tissue samples, keratin 6A was hyperexpressed in lung adenocarcinoma. Moreover, keratin 6A hyperexpression was positively correlated with lymph node positive and aggressive tumor T stage. Keratin 6A knockdown inhibited the cell proliferation, migration, and colony formation ability but not cell death in lung adenocarcinoma cells. In addition, we found keratin 6A exerted its phenotype via promoting cancer stem cells (CXCR4high/CD133high) transformation and epithelial–mesenchymal transition. Conclusion: In conclusion, current study suggests that hyperexpressed keratin 6A in lung adenocarcinoma promotes lung cancer proliferation and metastasis via epithelial–mesenchymal transition and cancer stem cells transformation.

scholarly journals Extracellular and macropinocytosis internalized ATP work together to induce epithelial–mesenchymal transition and other early metastatic activities in lung cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yanyang Cao ◽  
Xuan Wang ◽  
Yunsheng Li ◽  
Maria Evers ◽  
Haiyun Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Purinergic Receptor ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
Western Blots ◽  
Mesenchymal Transition

Abstract Background Extracellular ATP (eATP) was shown to induce epithelial–mesenchymal transition (EMT), a very important early process in metastasis, in cancer cells via purinergic receptor signaling. However, the exact induction mechanisms are far from fully known. We previously described that eATP is internalized by cancer cells in vitro and in vivo by macropinocytosis in human non-small cell lung cancer A549 and other cancer cells, drastically elevates intracellular ATP levels, enhances cell proliferation and resistance to anticancer drugs. In this study, we tested the hypothesis that eATP and macropinocytosis-internalized eATP also induces EMT and other early steps of metastasis. Methods Floating cells, fencing, and transwell assays were used to show that ATP induces cell detachment, new colony formation, migration and invasion in human A549 and other lung cancer cells. Western blots were used to detect ATP-induced changes in EMT-related proteins; Confocal microscopy was used to demonstrate ATP-induced metastasis-related cell morphological changes. Inhibitors and siRNA knockdowns were used to determine P2X7’s involvement in the ATP-induced EMT. CRISPR–Cas9 knockout of the SNX5 gene was used to identify macropinocytosis’ roles in EMT and cancer cell growth both in vitro and in vivo. Student t-test and one-way ANOVA were used to determine statistical significance, P < 0.05 was considered significant. Results eATP potently induces expression of matrix metallopeptidases (MMPs), and detachment, EMT, migration, and invasion of lung cancer cells. The induction was independent of TGF-β and semi-independent of P2X7 activation. eATP performs these functions not only extracellularly, but also intracellularly after being macropinocytically internalized to further enhance P2X7-mediated EMT, filopodia formation and other early steps of metastasis. The knockout of macropinocytosis-associated SNX5 gene significantly reduces macropinocytosis, slows down tumor growth, and changes tumor morphology in nude mice. Conclusions Collectively, these results show that eATP's functions in these processes not only from outside of cancer cells but also inside after being macropinocytotically internalized. These findings shed light on eATP’s initiator and effector roles in almost every step in early metastasis, which calls for rethinking and rebalancing energy equations of intracellular biochemical reactions and the Warburg effect, and identifies eATP and macropinocytosis as novel targets for potentially slowing down EMT and preventing metastasis.

scholarly journals Correlation of exosomal microRNA clusters with bone metastasis in non-small cell lung cancer

2020 ◽  
Author(s):  
Xiao-Rong Yang ◽  
Can Pi ◽  
Ruoying Yu ◽  
Xiao-Jun Fan ◽  
Xiao-Xiao Peng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Pathway Analysis ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Lung Cancer Patients

Abstract20–40% of lung cancer patients develop bone metastasis (BM) with significantly decreased overall survival. Currently, BM is mainly diagnosed by computerized tomography (CT) scan or magnetic resonance imaging (MRI) when symptom develops. Novel biomarkers with higher prediction value of BM are needed. Plasma-derived exosomal microRNAs had been isolated and sequenced of total 30 non-small cell lung cancer (NSCLC) patients including 16 with bone metastasis and 14 without bone metastasis. Hierarchical clustering based on the total miRNA profile can clearly separate cancer patients and healthy individuals (H), but not patients with (BM +) or without (BM−) BM. Weight Co-expression network of miRNAs (WGCNA) analyses identified three consensus clusters (A, B, C) of highly correlated miRNAs, among which cluster B (144 miRNAs) showed significantly differential expression in lung cancer patients, especially in BM + group. Pathway analysis of cluster B miRNAs revealed enrichment in metabolic pathways that may involve in preconditioning of the metastatic niche. Three differentially expressed miRNAs between BM + and BM− patients within cluster B were identified as miR-574-5p, a suppressor of Wnt/β-catenin pathway, was down-regulated, while miR-328-3p and miR-423-3p, two activators of the same pathway, were up-regulated in BM + patients. Cluster A miRNAs (n = 49) also showed trend of upregulation in BM + patients. Interestingly, pathway analysis indicated that 43 of them are associated with chromosome14, which has been suggested to promote epithelial-mesenchymal transition (EMT) and bone metastasis.

scholarly journals LncRNA ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of lung adenocarcinoma

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Rong-Hang Hu ◽  
Zi-Teng Zhang ◽  
Hai-Xiang Wei ◽  
Lu Ning ◽  
Jiang-Shan Ai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Mesenchymal Transition

Abstract Background Growing evidence suggests that suppressor of tumorigenicity 7 antisense RNA 1 (ST7-AS1) is an oncogenic long noncoding RNA (lncRNA). However, little is known on its clinical significance, biological functions, or molecular mechanisms in lung adenocarcinoma (LUAD). Methods The expression of ST7-AS1 and miR-181b-5p were examined by qRT-PCR. The correlations between ST7-AS1 level and different clinicopathological features were analysed. In vitro, LUAD cells were examined for cell viability, migration and invasion by MTT, wound healing and Transwell assay, respectively. Epithelial-mesenchymal transition (EMT) biomarkers were detected by Western blot. The regulations between ST7-AS1, miR-181b-5p, and KPNA4 were examined by luciferase assay, RNA immunoprecipitation, RNA pulldown. Both gain- and loss-of-function strategies were used to assess the importance of different signalling molecules in malignant phenotypes of LUAD cells. The in vivo effect was analysed using the xenograft and the experimental metastasis mouse models. Results ST7-AS1 was upregulated in LUAD tissues or cell lines, correlated with tumours of positive lymph node metastasis or higher TNM stages, and associated with shorter overall survival of LUAD patients. ST7-AS1 essentially maintained the viability, migration, invasion, and EMT of LUAD cells. The oncogenic activities of ST7-AS1 were accomplished by sponging miR-181b-5p and releasing the suppression of the latter on KPNA4. In LUAD tissues, ST7-AS1 level positively correlated with that of KPNA4 and negatively with miR-181b-5p level. In vivo, targeting ST7-AS1 significantly inhibited xenograft growth and metastasis. Conclusions ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of LUAD cells. Targeting ST7-AS1 and KPNA4 or up-regulating miR-181b-5p, therefore, may benefit the treatment of LUAD.

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