Triple-amiRNA VEGFRs inhibition in pancreatic cancer improves the efficacy of chemotherapy through EMT regulation

• Published in: Journal of controlled release 2017-01, Vol.245, p.1-14
• Main Authors: Huang, Jianfei, Mei, Haijun, Tang, Zhiyuan, Li, Jieying, Zhang, Xiaojing, Lu, Yixiang, Huang, Fang, Jin, Qin, Wang, Zhiwei
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Cell Line; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cisplatin - therapeutic use; Combined Modality Therapy; EMT; Epithelial-Mesenchymal Transition - drug effects; Female; Fluorouracil - therapeutic use; Humans; Kaplan-Meier Estimate; Male; Mice, Nude; MicroRNAs - administration & dosage; MicroRNAs - therapeutic use; Middle Aged; Pancreas - metabolism; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; PDAC; Receptors, Vascular Endothelial Growth Factor - genetics; Receptors, Vascular Endothelial Growth Factor - metabolism; Treatment Outcome; Triple-amiRNA; VEGFRs
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.11.024

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal outcome. Both novel prognostic markers and therapeutic targets are needed to improve the overall outcome of patients. Although single or double VEGFRs have been studied in PDAC, little is known about the role of triple combination of VEGFRs (VEGFR1, 2, and 3) in prognosis and therapy. We determined VEGFRs protein expression in 241 pancreatic tissues by tissue microarray immunohistochemistry (TMA-IHC), and correlated with patients' clinical characteristics and overall survival. Subsequently, we inactivated VEGFRs expression using artificial microRNAs (amiRNAs) in vitro. Triple combination of amiRNAs to VEGFRs reduced cell proliferation, increased apoptosis, and reduced cell migration and invasion in pancreatic cancer cell lines. In the mouse xenograft pancreatic cancer model, triple VEGFRs silencing significantly reduced tumor growth, had synergistic effect with standard chemotherapy, and was associated with inhibition of epithelial mesenchymal transition (EMT). We conclude that triple combination of VEGFRs is a prognostic marker for PDAC, and inhibition of VEGFRs expression via amiRNA represents a novel targeted therapy in PDAC through regulating EMT. [Display omitted]