Asporin promotes pancreatic cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition (EMT) through both autocrine and paracrine mechanisms.

Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE

Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.

Autocrine Communication* ; Cell Proliferation* ; Epithelial-Mesenchymal Transition* ; Paracrine Communication*; Biomarkers, Tumor/*metabolism ; Extracellular Matrix Proteins/*metabolism ; Pancreatic Neoplasms/*metabolism; Aged ; Biomarkers, Tumor/genetics ; Cell Line, Tumor ; Extracellular Matrix Proteins/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Humans ; Hyaluronan Receptors/metabolism ; Male ; Middle Aged ; Neoplasm Invasiveness ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Pancreatic Stellate Cells/metabolism ; Pancreatic Stellate Cells/pathology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; Signal Transduction ; Stromal Cells/metabolism ; Stromal Cells/pathology ; Transcription Factor RelA/metabolism ; Transfection ; Tumor Microenvironment

Pancreatic cancer is histopathologically characterized by excessive desmoplasia induced by pancreatic stellate cells (PSCs). Asporin, an extracellular matrix (ECM) protein, is highly expressed in cancer-associated fibroblasts (CAFs). Asporin expression in PSCs and its roles in PSC-pancreatic cancer cell (PCC) interaction remain unclear. The present study firstly showed that Asporin is highly expressed in activated PSCs and is involved in PSC-mediated invasion and migration of PCCs. Exogenous Asporin interacted with the transmembrane receptor CD44 on PCCs to activate NF-κB/p65 and promoted the epithelial-mesenchymal transition (EMT) in PCCs. Furthermore, AKT and ERK pathways participated in Asporin/CD44-induced NF-κB/p65 activation in pancreatic cancer. Asporin had similar effects on PCCs via an autocrine mechanism. Consistent with our in vitro experiments, we showed that Asporin in peritumoral stroma of pancreatic cancer tissues was associated with poor clinical outcome. In conclusion, this is the first study to show that Asporin promotes EMT, invasion, and migration of PCCs by activating CD44-AKT/ERK-NF-κB pathway in paracrine and autocrine manners. Moreover, our results indicate that Asporin may be a prognostic marker and suggest that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.
(Copyright © 2017 Elsevier B.V. All rights reserved.)

Keywords: Asporin; EMT; Invasion; Migration; Pancreatic cancer

0 (ASPN protein, human)
0 (Biomarkers, Tumor)
0 (CD44 protein, human)
0 (Extracellular Matrix Proteins)
0 (Hyaluronan Receptors)
0 (RELA protein, human)
0 (Transcription Factor RelA)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)

Date Created: 20170413 Date Completed: 20170821 Latest Revision: 20180414

20240829

10.1016/j.canlet.2017.04.001

28400334