AREG mediates the epithelial‑mesenchymal transition in pancreatic cancer cells via the EGFR/ERK/NF‑κB signalling pathway

Wang, Li; Wang, Lili; Zhang, Hui; Lu, Junliang; Zhang, Zhiwen; Wu, Huanwen; Zeng, Liang

doi:10.3892/or.2020.7523

Cited by 39 publications

(41 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genes regulated by YAP are involved in proliferation and invasion in PDAC. 42 43 We sought to evaluate the role of YAP in mediating the phenotype observed on modulation of the EVNet, which occurs mainly through CSC agrin + EVs signalling. To this end, we performed an MTT assay using NSCC treated with CSC EVs in the presence or absence of verteporfin, a YAP inhibitor.…”

Section: Agrin-positive Csc Evs Promote Yap Activationmentioning

confidence: 99%

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

Ruivo

Bastos

Adem

et al. 2022

Gut

View full text Add to dashboard Cite

ObjectiveIntratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour.DesignWe have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs).ResultsWe demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression.ConclusionPDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.

show abstract

Section: Agrin-positive Csc Evs Promote Yap Activationmentioning

confidence: 99%

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

Ruivo

Bastos

Adem

et al. 2022

Gut

View full text Add to dashboard Cite

show abstract

“…Our results also reinforce the hypothesis that OSA may be considered a systemic inflammatory disease, with an imbalance in pro/anti-inflammatory cytokines contributing to its development and the progression of comorbidities. Of note, AREG, ATF3, DUSP1 , and ZFP36 were all related to cancers or pathways in cancer, and numerous studies have reported a role for these genes in different tumors ( 51 – 54 ). OSA is a recognized risk factor for cancer, mainly through hypoxia ( 55 ), but the exact mechanisms remain unclear.…”

Section: Discussionmentioning

confidence: 99%

The Discovery, Validation, and Function of Hypoxia-Related Gene Biomarkers for Obstructive Sleep Apnea

Pan

Liu

et al. 2022

Front. Med.

View full text Add to dashboard Cite

While there is emerging evidence that hypoxia critically contributes to the pathobiology of obstructive sleep apnea (OSA), the diagnostic value of measuring hypoxia or its surrogates in OSA remains unclear. Here we investigated the diagnostic value of hypoxia-related genes and explored their potential molecular mechanisms of action in OSA. Expression data from OSA and control subjects were downloaded from the Gene Expression Omnibus database. Differentially-expressed genes (DEGs) between OSA and control subjects were identified using the limma R package and their biological functions investigated with the clusterProfiler R package. Hypoxia-related DEGs in OSA were obtained by overlapping DEGs with hypoxia-related genes. The diagnostic value of hypoxia-related DEGs in OSA was evaluated by receiver operating curve (ROC) analysis. Random forest (RF) and lasso machine learning algorithms were used to construct diagnostic models to distinguish OSA from control. Geneset enrichment analysis (GSEA) was performed to explore pathways related to key hypoxia-related genes in OSA. Sixty-three genes associated with hypoxia, transcriptional regulation, and inflammation were identified as differentially expressed between OSA and control samples. By intersecting these with known hypoxia-related genes, 17 hypoxia-related DEGs related to OSA were identified. Protein-protein interaction network analysis showed that 16 hypoxia-related genes interacted, and their diagnostic value was further explored. The 16 hypoxia-related genes accurately predicted OSA with AUCs >0.7. A lasso model constructed using AREG, ATF3, ZFP36, and DUSP1 had a better performance and accuracy in classifying OSA and control samples compared with an RF model as assessed by multiple metrics. Moreover, GSEA revealed that AREG, ATF3, ZFP36, and DUSP1 may regulate OSA via inflammation and contribute to OSA-related cancer risk. Here we constructed a reliable diagnostic model for OSA based on hypoxia-related genes. Furthermore, these transcriptional changes may contribute to the etiology, pathogenesis, and sequelae of OSA.

show abstract

“…As a molecule downstream of IL-35, ICAM1 facilitates endothelial adhesion and transendothelial migration, which accelerates PC metastasis 73 . As an epidermal growth factor, AREG significantly influences EMT upregulation in PC via the EGFR signaling pathway 74 . The expression of COL1A1, COL1A2, and COL3A1, members of the collagen family, is increased in lung adenocarcinomas and is associated with its poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma

Zhao¹,

Li²,

Lyu³

et al. 2021

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Pancreatic adenosquamous carcinoma (PASC) — a rare pathological pancreatic cancer (PC) type — has a poor prognosis due to high malignancy. To examine the heterogeneity of PASC, we performed single-cell RNA sequencing (scRNA-seq) profiling with sample tissues from a healthy donor pancreas, an intraductal papillary mucinous neoplasm, and a patient with PASC. Of 9,887 individual cells, ten cell subpopulations were identified, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and cancer cells. Cancer cells were divided into five clusters. Notably, cluster 1 exhibited stem-like phenotypes expressing UBE2C, ASPM, and TOP2A. We found that S100A2 is a potential biomarker for cancer cells. LGALS1, NPM1, RACK1, and PERP were upregulated from ductal to cancer cells. Furthermore, the copy number variations in ductal and cancer cells were greater than in the reference cells. The expression of EREG, FCGR2A, CCL4L2, and CTSC increased in myeloid cells from the normal pancreas to PASC. The gene sets expressed by cancer-associated fibroblasts were enriched in the immunosuppressive pathways. We demonstrate that EGFR-associated ligand-receptor pairs are activated in ductal-stromal cell communications. Hence, this study revealed the heterogeneous variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered intercellular interactions following PASC progression.

show abstract

AREG mediates the epithelial‑mesenchymal transition in pancreatic cancer cells via the EGFR/ERK/NF‑κB signalling pathway

Cited by 39 publications

References 35 publications

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

The Discovery, Validation, and Function of Hypoxia-Related Gene Biomarkers for Obstructive Sleep Apnea

Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma

Contact Info

Product

Resources

About