Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer that lacks effective targets for therapy. Alteration of epidermal growth factor (EGF) expression has been recognized as an essential molecular event in pancreatic carcinogenesis. Accumulating studies have demonstrated that miRNAs play critical roles in EGF signaling regulation, tumor initiation, cell proliferation and apoptosis. Here, we demonstrated that miR-21 expression was induced by EGF in pancreatic cancer cells. miR-21 promoted EGF-induced proliferation, inhibited cell apoptosis and accelerated cell cycle progression. In vivo experiments confirmed the influence of miR-21 on tumor growth. Mechanistic studies revealed that miR-21 targeted MAPK/ERK and PI3K/AKT signaling pathways to modulate cell proliferation. In addition, Spry2 was proven to be a target of miR-21. Furthermore, miR-21 and Spry2 were significantly related to clinical features and may be valuable predictors of PDAC patient prognosis.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is highlighted by poor prognosis, and PDAC-associated mortality closely parallels incidence[1]
We observed that epidermal growth factor (EGF) had no effect on miR-21 level at the concentration of 5 and 10 ng/ml, while EGF at the concentration of 25 to 75 ng/ml increased the expression of miR-21 and its expression level reached a peak value at 50 ng/ml (Fig. 1a)
Numerous experiments have demonstrated that miR-21, as an oncogene in PDAC25–27, is upregulated in PDAC and in early pancreatic precursor lesions compared with normal pancreas[16]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is highlighted by poor prognosis, and PDAC-associated mortality closely parallels incidence[1]. Due to lack of effective modalities for early detection, most PDAC patients are in the late stages of disease and not candidates for surgical resection. New insight into the underlying molecular pathophysiology of PDAC is urgently needed to advance the development of early detection strategies and effective therapeutic targets. Pancreatic cancer exhibits high frequency of genetic alterations, including KRAS, TP53, CDKN2A and SMAD4 alterations, and aberrant activation of mitogenic signaling pathways as a consequence of overexpression of receptor tyrosine kinase (RTKs), such as epidermal growth factor (EGF) receptor (EGFR) and its ligands[4]. Elevated EGFR expression is detected during tumor progression from early pancreatic intraepithelial neoplasia to PDAC and has been recognized as the essential molecular alteration in pancreatic carcinogenesis[4]. It is important to identify the regulators of these pathways in PDAC
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