Abstract
Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets.
Highlights
Cancer is a compendium of perturbed genome functions and is characterized by the deregulation of several genes and their regulatory molecules, including microRNAs [1, 2]
Our previous study using the KrasG12D;Pdx1Cre (KC/floxed KrasG12D) pancreatic cancer (PC) mouse model showed the presence of pancreatic intraepithelial neoplasia (PanIN) lesions as early as 10 weeks of age; these lesions progressed to pancreatic ductal adenocarcinoma (PDAC) and metastasized to the liver, lungs, and intestines by 50 weeks of age [26]
At 40 weeks of age, the majority of the parenchyma was replaced by PanIN III and extensive desmoplasia, whereas at 50 weeks of age, animals replaced the pancreatic parenchyma with full-blown PDAC, and metastatic spread involving the colon, liver, and lungs in 60–70% of the animals [26]
Summary
Cancer is a compendium of perturbed genome functions and is characterized by the deregulation of several genes and their regulatory molecules, including microRNAs (miRNAs) [1, 2]. MiRNAs are 19–24 nucleotides long, noncoding RNA molecules that regulate the expression of 30% of protein-coding genes at the posttranscriptional level [3, 4]. These miRNAs are transcribed by RNA polymerase II as pre-miRNAs, which www.impactjournals.com/oncotarget are processed by Drosha, to form hairpin-like intermediates called pre-miRNAs, which are approximately 70–100 nucleotides long and have two nucleotide overhangs at their 3′ ends [5,6,7,8]. Exportin-5 transports pre-miRNAs out of the nucleus and into the cytoplasm for further processing by dicer [9, 10], which converts the pre-miRNA into a 19–24 nucleotide long, double-stranded, mature miRNA [11]. Recent reports have shown that miRNAs can play an important role in diverse biological functions, such as development, normal cell physiology and pathological conditions, like abnormal cell proliferation [13,14,15] and cancer [16, 17] including pancreatic cancer (PC)
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