Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma.
Lipocalin 2 (LCN2) is a small secreted protein and its elevated expression has been observed in pancreatic as well as other cancer types. LCN2 has been reported to promote resistance to drug-induced apoptosis, enhance invasion through its physical association with matrix metalloproteinase-9, and promote in vivo tumor growth. LCN2 was found to be commonly expressed in patient PDAC samples and its pattern of immunohistochemical staining intensified with increasing severity in high-grade precursor lesions. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high LCN2 expression significantly reduced attachment, invasion, and tumour growth in vivo, but not proliferation or motility. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high expression significantly reduced attachment, invasion, and tumour growth in vivo. In contrast, LCN2 overexpression in PANC1, with low endogenous expression, significantly increased invasion, attachment, and enhanced tumor growth. Suppression of LCN2 in BxPC3 and HPAF-II cells increased their sensitivity to gemcitabine in vitro, and in vivo when BxPC3 was tested. Furthermore, LCN2 promotes expression of VEGF and HIF1A which contribute to enhanced vascularity. These overall results demonstrate that LCN2 plays an important role in the malignant progression of pancreatic ductal carcinoma and is a potential therapeutic target for this disease.
Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Lisa
L
Leung
Nikolina
N
Radulovich
Chang-Qi
CQ
Zhu
Shawna
S
Organ
Bizhan
B
Bandarchi
Melania
M
Pintilie
Christine
C
To
Devang
D
Panchal
Ming Sound
MS
Tsao
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D054834:Lipocalins / Q000378:metabolism*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
D054834:Lipocalins; D003841:Deoxycytidine; D000093542:Gemcitabine