Abstract
Lysyl oxidase-like 2 (LOXL2) is associated with invasiveness and metastasis in cancer. We analyzed the prognostic impact of LOXL2 in pancreatic cancer patients and investigated the role of LOXL2 in pancreatic cancer cell lines. Immunohistochemical analysis was performed in samples from 80 patients and showed LOXL2 expression in 81.2% of patients with pancreatic cancer. Regarding recurrence patterns, LOXL2-positive tumors showed a significantly higher rate of distant recurrence. The 1-year and 3-year disease-free survival rates were 84.6% and 0.0%, respectively, for LOXL2-negative patients, and 27.8 % and 0.0 %, respectively, for LOXL2-positive patients. On univariate analysis, combined resection of major vessels, depth of invasion, tumor stage, and LOXL2- positive status were significant factors for poor prognosis. After identification of LOXL2 expression in pancreatic cancer cell lines, LOXL2-silenced and LOXL2-overexpressed cell lines were used to perform transwell invasion and transendothelial migration assays.In vitro studies indicated that LOXL2 silencing in MIA PaCa-2 and PANC-1 cells induced a mesenchymal–epithelial transition (MET)-like process associated with decreased invasive and migratory properties. LOXL2 overexpression in AsPC-1 and BxPC-3 cells enhanced the epithelial-mesenchymal transition (EMT)-like process and increased migratory and invasive activity. These clinical and preclinical data confirm that higher LOXL2 expression is associated with the invasiveness of pancreatic cancer cells and the low survival rate of pancreatic cancer patients. Our results suggest the clinical value of LOXL2 as a therapeutic target in pancreatic cancer.
Highlights
Pancreatic cancer is one of the most aggressive and lethal malignancies
Lu et al reported that the increased collagen cross-linking in mouse mammary stroma induced by lysyl oxidase (LOX)-like 2 (LOXL2) activity is associated with extracellular matrix (ECM) stiffness and tumor invasion and progression [14]
These studies are in agreement with the notion that tumor fibrosis increases the invasive behavior of tumors by activating LOXL2 signals and suggest that LOXL2 is involved in cell adhesion, cell migration and invasion, and epithelial-mesenchymal transition (EMT) transformation [6, 9]
Summary
Pancreatic cancer is one of the most aggressive and lethal malignancies. pancreatic cancer is a relatively rare disease, it is the fourth leading cause of cancer-related mortality in Korea. Despite the availability of several treatment modalities, the 5-year survival rate is reported to be lower than 5% [1] This poor clinical prognosis is mainly associated with early local invasion and a high incidence of recurrence, both of which are characteristic of the disease. Several studies have shown that LOXL2 down-regulates E-cadherin expression and promotes epithelial-mesenchymal transition (EMT) [6,7,8] Due to these mechanisms, LOXL2 is associated with aggressive cancer characteristics and poor patient prognosis. Several studies have reported that LOXL2 is associated with poor prognosis in cancer patients [9,10,11,12,13], www.impactjournals.com/oncotarget and that overexpression of LOXL2 promotes invasion activity among cancer cells [10,11,12, 14, 15]. There is a paucity of clinical evidence regarding the role of LOXL2 and its functions in pancreatic cancer
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