Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT-330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities. A similar result was obtained with forced expression of miR-145 in PDAC cells. To this end, SINE compound treatment mediated the down-regulation of known miR-145 targets genes including EGFR, MMP1, MT-MMP, c-Myc, Pak4 and Sox-2. In addition, selinexor induced the expression of two important tumor suppressive miRNAs miR-34c and let-7d leading to the up-regulation of p21WAF1. These results are the first to report that targeted inhibition of the nuclear export machinery could restore tumor suppressive miRNAs in PDAC that warrants further clinical investigations.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States with an estimated 53,000 new cases and 42,000 deaths in 2016 [1]
We found that the expression level of miR-145 expression was significantly increased upon XPO1 inhibitor selinexor treatment in MiaPaCa-2, AsPC-1, L3.6pl, PANC-1 and HPAC PDAC cells (Figure 2A-2E), suggesting that selinexor increased miR-145 expression is mediated through XPO1 signal transduction
Since we have observed the growth inhibition of PDAC cells by selinexor [7], these results suggest that the miR-145 induced by selinexor could be an inhibitory molecule for PDAC development and progression
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States with an estimated 53,000 new cases and 42,000 deaths in 2016 [1]. It is expected that PDAC will become the second leading cause of cancer-related death by 2030 [2]. The poor outcome and aggressiveness of PDAC could be caused by high instances of drug resistance and the invasive characteristic that develop during disease progression. It is important to design new therapeutic strategies to inhibit proliferation, invasion and metastasis based on the novel molecular mechanism in order to successfully treat PDAC. PDAC development is marked by alterations in several critical signal transduction proteins such as Ras, p53, EGFR and NF-κB.
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