The Silencing of MicroRNA 148a Production by DNA Hypermethylation Is an Early Event in Pancreatic Carcinogenesis

Abstract

BACKGROUND:The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is accounted for by the absence of early diagnostic markers and effective treatments. MicroRNAs inhibit the translation of their target mRNAs. The production of microRNAs is strongly altered in cancers, but the causes of these alterations are only partially known. DNA hypermethylation is a major cause of gene inactivation in cancer. Our aims were to identify microRNAs whose gene expression is inactivated by hypermethylation in PDAC and to determine whether this hypermethylation-mediated repression is an early event during pancreatic carcinogenesis. We also sought to investigate whether these differentially methylated regions can serve as a diagnostic marker for PDAC.

MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B

“…6 Hanoun et al have reported that hypermethylation of the promoter region encoding miR-148a is responsible for its repression not only in PDAC samples but also in preneoplastic-pancreatic-intraepithelial-neoplasia (PanIN) and can serve as an ancillary marker for the differential diagnosis of PDAC and chronic pancreatitis. 21 Consistent with this observation, we report that miR-148a is significantly down-regulated in micro-dissected PDAC samples. Therefore the expression of miR-148a in TGFb non-responsive IMIM-PC2 pancreatic cancer cells is probably regulated by DNA-methylation.…”

“…6,21,27 In colon, lung, breast, and head and neck carcinoma and melanoma, miR-148a-promoter hypermethylation has been correlated with a higher metastatic potential. 6 Hanoun et al have reported that hypermethylation of the promoter region encoding miR-148a is responsible for its repression not only in PDAC samples but also in preneoplastic-pancreatic-intraepithelial-neoplasia (PanIN) and can serve as an ancillary marker for the differential diagnosis of PDAC and chronic pancreatitis.…”

“…The mean transcription level of miR-148a was significantly lower in PDACs compared with non tumor samples by a factor of four (P ¼ 0.008) (Figure 1a). To further investigate the potential mechanism underlying the miR-148a down-regulation in PDAC, 6,21 we investigated its expression in the pancreatic cancer tissue cell line IMIM-PC2 post 5-aza-treatment a demethylating reagent. After five days of 5-aza-dC treatment, IMIM-PC2-cells demonstrated a significant 8-fold increase in miR-148a-expression (Po0.05) (Figure 1b).…”

MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

“…41 Down-regulation of miR-148a is an early marker of pancreatic adenocarcinoma and is already decreased in pre-neoplastic PanIN lesions. 42 At least 27 target genes are known for miR-148a, including bladder cancer associated protein. 43 In our study, miR-148a expression is related to KRAS mutations in pancreatic and ampullary adenocarcinoma.…”

Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies

“…Other studies have shown that miRNA profiles can also differentiate between benign and malignant cystic lesions [14][15][16][17][18][19]. In addition, a few small studies have shown that the detection of miRNAs in FNA samples taken at EUS is feasible and may increase the sensitivity and specificity of detecting malignant change in cystic lesions of the pancreas [17,[20][21][22][23].…”