Abstract
BackgroundThe abnormal expression of leucine-rich-alpha-2-glycoprotein 1 (LRG-1) is reported to be associated with multiple malignancies, but its role in the progression of pancreatic ductal adenocarcinoma (PDAC) remains to be determined.MethodsThe expression of LRG-1 was assessed in PDAC tissues by RT-PCR, Western blot and immunohistochemistry. LRG-1-silenced or overexpressed cell lines were constructed using shRNA or LRG-1-overexpressing plasmids. EdU incorporation assay, Transwell invasion and wound-healing assays were performed to evaluate the proliferation, invasion and migration of PDAC cells. In addition, protein expression of the mitogen-activated protein kinase (MAPK) pathway was detected using Western blot. Finally, Co-immunoprecipitation assay was conducted in search of the potential interaction between LRG-1 and epidermal growth factor receptor (EGFR).ResultsThe expression of LRG-1 in PDAC tissue was significantly higher than that in adjacent normal tissue, and high LRG-1 expression predicted poor survival and a late tumor stage. In addition, LRG-1 markedly promoted the viability, proliferation, migration and invasion of PDAC cells in vitro and facilitated tumor growth in vivo. More importantly, we revealed that these bioactivities of LRG-1 might result from its selective interaction with EGFR, which might further activate the p38/MAPK signaling pathways.ConclusionLRG-1 may prove to be a promising biomarker for predicting prognosis of PDAC patients. Inhibition of LRG-1 or its downstream pathway could be a potential therapeutic target for the treatment of PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies [1] with a median survival less than 6 months and a 5-year survival rate of less than 6% [2,3,4,5]
We further analyzed the expression of leucine-rich-alpha-2-glycoprotein 1 (LRG-1) by IHC and other clinical factors in 127 pancreatic ductal adenocarcinoma (PDAC) patients
LRG-1 promotes PDAC growth in vivo To assess the function of LRG-1 in promoting the development of PDAC in vivo, a nude mice xenograft model was established and the results showed that both the tumor weight and size were reduced significantly at all designated time points in the nude mice injected with LRG-1 knock-down cells as compared with the nude mice injected with scramble plasmids (Fig. 3a, b, c)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies [1] with a median survival less than 6 months and a 5-year survival rate of less than 6% [2,3,4,5]. A variety of signaling pathways have been reported to be involved in the development and progression of PDAC including mitogen-activated protein kinase (MAPK) [8] and Notch [9] signaling pathways, growth factors such as epidermal growth factor (EGF) [8], fibroblast growth factor (FGF) [10] and insulin-like growth factor 1 (IGF-1) [11]. Based on these findings, scientists have uncovered various biological targets, and developed several corresponding targeted therapies [12, 13]. The abnormal expression of leucine-rich-alpha-2-glycoprotein 1 (LRG-1) is reported to be associated with multiple malignancies, but its role in the progression of pancreatic ductal adenocarcinoma (PDAC) remains to be determined
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