scholarly journals LncRNA-ZFAS1 Induces Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells During Nutrient Deprivation by Promoting AMPK-Mediated Phosphorylation and Stabilization Of ZEB1 Protein

2021 ◽  
Author(s):  
ZHU ZENG ◽  
Shengbo Han ◽  
Yang Wang ◽  
Yan Huang ◽  
Yuhang Hu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Nutrient Deprivation ◽  
Loss Of Function ◽  
Western Blot Assay ◽  
Normal Medium ◽  
Mesenchymal Transition ◽  
Glucose Depletion ◽  
Pancreatic Cancer Cells ◽  
Glutamine Deprivation

Abstract Background: Nutrient deprivation is a distinct feature of the tumor microenvironment that plays a crucial role in various cancers. However, the contribution and regulatory mechanism of nutrient deprivation on metastasis of pancreatic cancer (PC) have not been identified. Methods: PC cells were treated with normal medium, glucose-depletion or glutamine-depletion medium to observe the epithelial-mesenchymal transition (EMT). RT-qPCR and western blot assay were applied to evaluate the alteration of mRNA and protein of zinc finger E-box binding homeobox 1 (ZEB1), a crucial EMT regulator factor. Co-IP assay was utilized for evaluating the interaction between AMP-activated protein kinase (AMPK) and ZEB1. LncRNA microarray was adopted to detect the potential lncRNA, which facilitates the association between AMPK and ZEB1. Gain- and loss-of-function experiments were performed to evaluate the roles of ZNFX1 antisense RNA 1 (ZFAS1) in EMT and metastasis of PC. Results: The present study reveals that nutrient deprivation including glucose and glutamine deprivation significantly induces EMT of PC cells, which is dependent on stabilization of ZEB1. We further discover that nutrient deprivation induces upregulation of lncRNA ZFAS1, which promotes the association between AMPK and ZEB1 to phosphorylate and stabilize ZEB1 protein. Notably, ZEB1 reciprocally promotes the transcription of ZFAS1 by binding to the promoter of ZFAS1, forming feedback with ZFAS1. Consistently, depletion of ZFAS1 obviously inhibits nutrient deprivation-induced EMT of PC cells and lung metastasis of PC in nude mice. Meanwhile, clinical data displays that ZFAS1 is overexpressed in PC tissues and correlated with high expression of ZEB1 and Vimentin (VIM), low expression of E-cadherin (E-cad), as well as poor prognosis in PC patients. Conclusions: Our study implicates that glucose and glutamine deprivation promotes EMT and metastasis of PC through lncRNA-mediated stabilization of ZEB1.

MicroRNA-1252-5p, regulated by Myb, inhibits invasion and epithelial-mesenchymal transition of pancreatic cancer cells by targeting NEDD9 

2020 ◽  
Author(s):  
Yuzheng Xue ◽  
Tielong Wu ◽  
Yingyue Sheng ◽  
Yao zhong ◽  
Benshun Hu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mechanistic Study ◽  
Loss Of Function ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Abstract Background: MicroRNAs (miRNAs) are known to be involved in the development and progression of pancreatic cancer (PAC). The expression level and role of miR-1252-5p in PAC remain unclear. Methods: qRT-PCR and in situ hybridization were used to detect miR-1252-5p expression in PAC cells and tissues. Associations between miR-1252-5p expression and clinical characteristics or overall survival (OS) were assessed based on 102 patients with PAC who underwent surgical resection. Gain and loss of function of miR-1252-5p was studied in the PAC cell lines, Panc-1 and BxPC 3 in vitro and in vivo. The direct targets of miR-1252-5p were analyzed using public databases and a dual-luciferase reporter assay.Results: The expression levels of miR-1252-5p are downregulated in PAC cell lines and tissue samples compared to control, and its expression is negatively associated with adverse clinical features and poor prognosis. In vitro and in vivo experiments show that miR-1252-5p overexpression inhibits the proliferation, migration, invasion and epithelial-mesenchymal transition of PAC cells, whereas miR-1252-5p knockdown enhances these biological behaviors. In addition, miR-1252-5p negatively regulates neural precursor cell expressed, developmentally downregulated 9 (NEDD9) by directly binding its 3'-UTR. NEDD9 restoration at least partially abolishes this effect of miR-1252-5p in PAC cells. Further mechanistic study revealed that the SRC/STAT3 pathway is involved in miR-1252-5p/NEDD9 mediation of biological behaviors in PAC. We also verified that Myb inhibited miR-1252-5p by directly binding at its promoter.Conclusion: MiR-1252-5p may act as a tumor-suppressing miRNA in PAC and may be a potential therapeutic target for PAC patients.

scholarly journals Long noncoding RNA LINC00941 promotes pancreatic cancer progression by competitively binding miR-335-5p to regulate ROCK1-mediated LIMK1/Cofilin-1 signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jie Wang ◽  
Zhiwei He ◽  
Jian Xu ◽  
Peng Chen ◽  
Jianxin Jiang
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Loss Of Function ◽  
Mesenchymal Transition

AbstractAn accumulation of evidence indicates that long noncoding RNAs are involved in the tumorigenesis and progression of pancreatic cancer (PC). In this study, we investigated the functions and molecular mechanism of action of LINC00941 in PC. Quantitative PCR was used to examine the expression of LINC00941 and miR-335-5p in PC tissues and cell lines, and to investigate the correlation between LINC00941 expression and clinicopathological features. Plasmid vectors or lentiviruses were used to manipulate the expression of LINC00941, miR-335-5p, and ROCK1 in PC cell lines. Gain or loss-of-function assays and mechanistic assays were employed to verify the roles of LINC00941, miR-335-5p, and ROCK1 in PC cell growth and metastasis, both in vivo and in vitro. LINC00941 and ROCK1 were found to be highly expressed in PC, while miR-335-5p exhibited low expression. High LINC00941 expression was strongly associated with larger tumor size, lymph node metastasis, and poor prognosis. Functional experiments revealed that LINC00941 silencing significantly suppressed PC cell growth, metastasis and epithelial–mesenchymal transition. LINC00941 functioned as a molecular sponge for miR-335-5p, and a competitive endogenous RNA (ceRNA) for ROCK1, promoting ROCK1 upregulation, and LIMK1/Cofilin-1 pathway activation. Our observations lead us to conclude that LINC00941 functions as an oncogene in PC progression, behaving as a ceRNA for miR-335-5p binding. LINC00941 may therefore have potential utility as a diagnostic and treatment target in this disease.

scholarly journals YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells

2015 ◽  
Vol 13 (1) ◽  
pp. 237-242 ◽  
Author(s):  
YANLI YUAN ◽  
DEYU LI ◽  
HAIBO LI ◽  
LIANCAI WANG ◽  
GUANGJIN TIAN ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

scholarly journals Pancreatic Cancer Cells Respond to Type I Collagen by Inducing Snail Expression to Promote Membrane Type 1 Matrix Metalloproteinase-dependent Collagen Invasion

2011 ◽  
Vol 286 (12) ◽  
pp. 10495-10504 ◽  
Author(s):  
Mario A. Shields ◽  
Surabhi Dangi-Garimella ◽  
Seth B. Krantz ◽  
David J. Bentrem ◽  
Hidayatullah G. Munshi
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Three Dimensional ◽  
Type I ◽  
Collagen Gels ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Membrane Type

Pancreatic ductal adenocarcinoma (PDAC) is characterized by pronounced fibrotic reaction composed primarily of type I collagen. Although type I collagen functions as a barrier to invasion, pancreatic cancer cells have been shown to respond to type I collagen by becoming more motile and invasive. Because epithelial-mesenchymal transition is also associated with cancer invasion, we examined the extent to which collagen modulated the expression of Snail, a well known regulator of epithelial-mesenchymal transition. Relative to cells grown on tissue culture plastic, PDAC cells grown in three-dimensional collagen gels induced Snail. Inhibiting the activity or expression of the TGF-β type I receptor abrogated collagen-induced Snail. Downstream of the receptor, we showed that Smad3 and Smad4 were critical for the induction of Snail by collagen. In contrast, Smad2 or ERK1/2 was not involved in collagen-mediated Snail expression. Overexpression of Snail in PDAC cells resulted in a robust membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14)-dependent invasion through collagen-coated transwell chambers. Snail-expressing PDAC cells also demonstrated MT1-MMP-dependent scattering in three-dimensional collagen gels. Mechanistically, Snail increased the expression of MT1-MMP through activation of ERK-MAPK signaling, and inhibiting ERK signaling in Snail-expressing cells blocked two-dimensional collagen invasion and attenuated scattering in three-dimensional collagen. To provide in vivo support for our findings that Snail can regulate MT1-MMP, we examined the expression of Snail and MT1-MMP in human PDAC tumors and found a statistically significant positive correlation between MT1-MMP and Snail in these tumors. Overall, our data demonstrate that pancreatic cancer cells increase Snail on encountering collagen-rich milieu and suggest that the desmoplastic reaction actively contributes to PDAC progression.

scholarly journals Mesenchymal stem cells regulate epithelial-mesenchymal transition and tumor progression of pancreatic cancer cells

2013 ◽  
Vol 104 (2) ◽  
pp. 157-164 ◽  
Author(s):  
Ayano Kabashima-Niibe ◽  
Hajime Higuchi ◽  
Hiromasa Takaishi ◽  
Yohei Masugi ◽  
Yumi Matsuzaki ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells
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