Abstract
Pancreatic Ductal Adenocarcinoma (PDA) is a highly malignant tumor with poor prognosis. MicroRNAs (miRs) may offer novel therapeutic approaches to treatment. The polyphenol quercetin, present in many fruits and vegetables, possesses anti-carcinogenic properties. To unravel the effect of quercetin to miR signaling we performed miR profiling in PDA cells before and after quercetin treatment, followed by biostatistical analysis. miR let-7c was among the top up-regulated candidates after quercetin treatment, as measured by qRT-PCR and confirmed in two established and one primary PDA cell lines. By computational analysis we identified the Notch-inhibitor Numbl as let-7c target gene. This was strengthened by luciferase assays, where lipofected let-7c mimics induced a Numbl 3-UTR wild type construct, but not the mutated counterpart. Let-7c induced Numbl mRNA and protein expression but inhibited Notch just like quercetin. It also inhibited colony formation, wound healing, and protein expression of progression markers. In vivo xenotransplantation of PDA cells and subsequent intravenous injection of let-7c resulted in a significant decrease in tumor mass without obvious toxic effects in the fertilized chick egg model. The delivery rate of the miR mimics to the tumor mass was 80%, whereas minor amounts were present in host tissue. By immunohistochemistry we demonstrated that let-7c inhibited Notch and progression markers but up-regulated Numbl. These findings show that quercetin-induced let-7c decreases tumor growth by posttranscriptional activation of Numbl and indirect inhibition of Notch.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal disease that is mostly diagnosed in an advanced state for which there are little or no effective therapies [1]
We show that quercetin upregulates microRNA let-7c, which decreases tumor growth by posttranscriptional activation of Numbl and subsequent inhibition of Notch
Let-7c is observed to function like quercetin in the induction of Numbl expression, inhibitions of Notch, colony formation, wound healing and protein expression of progression markers
Summary
Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal disease that is mostly diagnosed in an advanced state for which there are little or no effective therapies [1]. MicroRNAs (miRs) are important players in the chemoresistance of PDA [3, 4]. They are small noncoding RNAs that regulate gene expression by sequencespecific binding to target genes [5]. MiRs mediate posttranscriptional down-regulation, translational repression and deadenylation-dependent decay of messages via partially complementary miR target sites in untranslated regions (UTRs) of mRNAs. They are small noncoding RNAs that regulate gene expression by sequencespecific binding to target genes [5]. MiRs mediate posttranscriptional down-regulation, translational repression and deadenylation-dependent decay of messages via partially complementary miR target sites in untranslated regions (UTRs) of mRNAs They have been found to post transcriptionally stimulate gene expression by direct and indirect mechanisms [6]. Aberrant miR expression and functions are linked to several types of tumors, immune diseases and developmental disorders and differentially expressed miRs may offer novel therapeutic approaches for future, more successful treatment of PDA [3, 4]
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