Open AccessHypoxia‐driven paracrine osteopontin/integrin αvβ3 signaling promotes pancreatic cancer cell epithelial–mesenchymal transition and cancer stem cell‐like properties by modulating forkhead box protein M1
Author(s) -
Cao Junyu,
Li Jie,
Sun Liankang,
Qin Tao,
Xiao Ying,
Chen Ke,
Qian Weikun,
Duan Wanxing,
Lei Jianjun,
Ma Jiguang,
Ma Qingyong,
Han Liang
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12399
Subject(s) - pancreatic cancer , cancer research , epithelial–mesenchymal transition , paracrine signalling , osteopontin , metastasis , tumor microenvironment , mapk/erk pathway , cancer stem cell , biology , protein kinase b , downregulation and upregulation , cancer cell , microbiology and biotechnology , chemistry , cancer , signal transduction , stem cell , endocrinology , receptor , biochemistry , genetics , tumor cells , gene
Pancreatic stellate cells ( PSC s), a key component of the tumor microenvironment, contribute to tumor invasion, metastasis, and chemoresistance. Osteopontin ( OPN ), a phosphorylated glycoprotein, is overexpressed in pancreatic cancer. However, OPN expression in PSC s and its potential roles in tumor–stroma interactions remain unclear. The present study first showed that OPN is highly expressed and secreted in activated PSC s driven by hypoxia, and this process is in a ROS ‐dependent manner; in addition, OPN was shown to be involved in the PSC ‐induced epithelial–mesenchymal transition ( EMT ) and cancer stem cell ( CSC )‐like properties of pancreatic cancer cells ( PCC s). Mechanistically, OPN from activated PSC s interacts with the transmembrane receptor integrin αvβ3 on PCC s to upregulate forkhead box protein M1 (FOXM1) expression and induce malignant phenotypes of PCC s. Moreover, the Akt and Erk pathways participate in OPN /integrin αvβ3 axis‐induced FOXM 1 expression of PCC s. Our further analysis showed that OPN and FOXM 1 are significantly upregulated in pancreatic cancer tissues and are associated with poor clinical outcome, indicating that OPN and FOXM 1 might be considered as diagnostic and prognostic biomarkers for patients with pancreatic cancer. In conclusion, we show here for the first time that OPN promotes the EMT and CSC ‐like properties of PCC s by activating the integrin αvβ3‐Akt/Erk‐ FOXM 1 cascade in a paracrine manner, suggesting that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.