Asparaginyl endopeptidase enhances pancreatic ductal adenocarcinoma cell invasion in an exosome-dependent manner and correlates with poor prognosis

Abstract

Pancreatic cancer is one of the most lethal types of cancer; owing to low early detection rates and high metastasis rates, it is associated with an extremely poor prognosis. Therefore, a better understanding of the molecular mechanisms that underlie its metastasis and the identification of potential prognostic biomarkers are urgently required. Although high expression levels of asparaginyl endopeptidase (AEP) have been detected in various types of solid tumor, the expression and functions of AEP in pancreatic carcinomas have yet to be determined. The present study aimed to examine the putative functions of AEP in pancreatic carcinoma. Immunohistochemical analysis revealed that AEP was highly expressed in pancreatic cancer tissues compared with adjacent normal tissues. Patients with high AEP expression exhibited a significantly shorter overall survival time. Results from multivariate Cox regression analysis revealed that AEP was an independent prognostic factor for overall survival. Gain- and loss-of-function experiments demonstrated that knockdown of AEP expression significantly reduced the invasive ability of pancreatic cancer cells, whereas overexpression of AEP increased the invasive ability. In addition, AEP was detected in exosomes that were derived from cultured pancreatic ductal adenocarcinoma cells (PDACs) and in the serum from patients with PDAC. The Matrigel-Transwell invasion assay revealed that exosomes enriched with AEP were able to enhance the invasive ability of PDAC cells, whereas exosomes lacking AEP decreased the invasive ability. Furthermore, results from the present study suggested that AEP may be crucial for activation of the phosphoinositide 3-kinase/RAC‑α serine/threonine-protein kinase signaling pathway in PDAC cells. The present study data indicated that high AEP expression may be important for pancreatic carcinoma progression in an exosome-dependent manner, and that AEP may be an independent indicator of poor prognosis in patients with PDAC and may be a novel prognostic biomarker or therapeutic target in pancreatic carcinoma.

Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression

“…Also, asparaginyl endopeptidase (AEP), delivered by EVs secreted by PC cells, was shown to promote invasion. Indeed, this protein is able to activate the PI3K pathway in recipient cells leading to increased invasion in vitro [96]. Another protein abundant in PC EVs is the CD44 variant isoform 6 (CD44v6).…”

ELK1 Enhances Pancreatic Cancer Progression Via LGMN and Correlates with Poor Prognosis

“…Though LGMN is highly expressed in the majority of human solid tumors and is associated with a more invasive and metastatic phenotype, the underlying mechanisms of its tumor-promoting effects have yet to be fully elucidated ( Mai et al, 2017 ). We previously found that high expression of LGMN is involved in the progression of pancreatic carcinoma in an exosome-dependent manner and that LGMN independently indicated poor prognosis; however, the upstream regulation of LGMN remains unknown ( Yan et al, 2018 ). The regulation of gene expression by transcription factors is a common cellular event.…”

“…Recently, LGMN has been shown to exhibit a vesicular staining pattern, and high expression of LGMN was significantly related to an advanced tumor stage, a high Gleason score, perineural invasion, and large pancreatic adenocarcinoma tumors ( Zhu et al, 2016 ). Although we previously found that high LGMN expression was involved in the progression of pancreatic carcinoma in an exosome-dependent manner and LGMN could independently indicate poor prognosis, the upstream regulation of LGMN remains unknown ( Yan et al, 2018 ).…”

The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer

“…Specific metabolic enzymes were also transferred by PDA tumor cells-derived EVs. Protease asparaginyl endopeptidase (AEP), expressed in several carcinomas and previously associated with increased metastases and MMP activity, was shown to be transferred via PDA tumor cells derived-EVs and consequently, in recipient PDA tumor cells, increased migratory and invasive capacity, going along with the finding that AEP is usually found at the invasive front of tumors [ 46 ]. Finally, hypoxic PDA cells, with the aid of upregulated HIF-1-alpha, were found to release larger quantities of smaller-sized EVs and promoted their survival even under extremely hypoxic conditions, indicative of yet another communicative aspect of EV structure and cargo between heterogeneous cancer cells [ 47 ].…”