Hypoxia-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.

Junyu Cao,Tao Qin,Ying Xiao,Weikun Qian,Qingyong Ma,Jianjun Lei,Ke Chen,Jiguang Ma,Wanxing Duan,Liankang Sun,Liang Han,Jie Li

doi:10.1002/1878-0261.12399

Abstract

Pancreatic stellate cells (PSCs), 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 PSCs and its potential roles in tumor–stroma interactions remain unclear. The present study first showed that OPN is highly expressed and secreted in activated PSCs 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 (PCCs). Mechanistically, OPN from activated PSCs interacts with the transmembrane receptor integrin αvβ3 on PCCs to upregulate forkhead box protein M1 (FOXM1) expression and induce malignant phenotypes of PCCs. Moreover, the Akt and Erk pathways participate in OPN/integrin αvβ3 axis‐induced FOXM1 expression of PCCs. Our further analysis showed that OPN and FOXM1 are significantly upregulated in pancreatic cancer tissues and are associated with poor clinical outcome, indicating that OPN and FOXM1 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 PCCs by activating the integrin αvβ3‐Akt/Erk‐FOXM1 cascade in a paracrine manner, suggesting that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.

Highlights

With a 5-year survival rate less than 8% and more than 44 000 deaths per year, pancreatic cancer represents one of the most lethal human cancers and is the fourth leading cause of cancer-related death in the United States (Siegel et al, 2018)
NAC, a reactive oxygen species (ROS) scavenger, abolished the ROS generation and attenuated the pancreatic stellate cell (PSC) activation induced by hypoxia, which was consistent with our previous results (Lei et al, 2014)
According to the results derived from Gene Expression Profiling Interactive Analysis (GEPIA), we observed that the expression levels of OPN and forkhead box protein M1 (FOXM1) were significantly upregulated in pancreatic cancer tissues compared to normal pancreatic tissues (Fig. 7D and G)

Summary

Introduction

With a 5-year survival rate less than 8% and more than 44 000 deaths per year, pancreatic cancer represents one of the most lethal human cancers and is the fourth leading cause of cancer-related death in the United States (Siegel et al, 2018). The quality of life and prognosis of patients with pancreatic cancer are dismal due to the early invasion and metastasis, as well as the limited efficacy of therapeutic strategies (Ryan et al, 2014). Pancreatic cancer remains a substantial fortress awaiting conquest. Hypoxia is a characteristic feature of human solid tumors, including pancreatic cancer. Molecular Oncology 13 (2019) 228–245 a 2018 The Authors.

Objectives

Methods

Results

Discussion

Conclusion