MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is known for its very poor overall prognosis. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. We used 377 feature microRNA (miRNA) arrays to investigate miRNA expression in normal pancreas, chronic pancreatitis, and PDAC tissues as well as PDAC-derived cell lines. A pancreatic miRNome was established comparing the data from normal pancreas with a reference set of 33 human tissues. The expression of miR-216 and -217 and lack of expression of miR-133a were identified as characteristic of pancreas tissue. Unsupervised clustering showed that the three pancreatic tissues types can be classified according to their respective miRNA expression profiles. We identified 26 miRNAs most prominently misregulated in PDAC and a relative quantitative reverse transcriptase-polymerase chain reaction index using only miR-217 and -196a was found to discriminate normal pancreas, chronic pancreatitis and cancerous tissues, establishing a potential utility for miRNAs in diagnostic procedures. Lastly, comparing differentially expressed genes from PDAC with predicted miRNA target genes for the top 26 miRNAs, we identified potential novel links between aberrant miRNA expression and known target genes relevant to PDAC biology. Our data provides novel insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development and offers new candidate targets to be exploited both for diagnostic and therapeutic strategies.

MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

“…Nine of the significantly differentially expressed miRNAs described by Bloomston et al 20 were also found in our study (miR-21, miR-100*, miR-143/miR-143*, miR-148a, miR-148a*, miR-205, miR-210, miR-222 and miR-375). Eleven of the significantly differentially expressed miRNAs described by Szafranska et al 21,26 were found in our study with very similar dm-values and fold change (miR-31, miR-130b, miR-143/miR-143*, miR-148a, miR-196b, miR-205, miR-210, miR-216, miR-217, miR-222/miR-222* and miR-375).…”

“…All miRNAs either up-or down-regulated compared with normal pancreas in other studies 20,21,26 were also significantly differentially expressed in our study before the strict Bonferonni correction for multiple comparisons, except miR-155 that was not present in our microRNA array (Table 2).…”

“…Some selected microRNAs (selection based on P-values, dm-values, fold change and novelty) and comparison with other studies are shown in Table 3. MiR-148a was also found to be significantly down-regulated by Bloomston et al, 20 Szafranska et al 21,26 also found that miR-148a, miR-196b, miR-196a and miR-205 were differentially expressed in pancreatic adenocarcinoma and chronic pancreatitis (Table 3).…”

“…[15][16][17][18][19] In pancreatic adenocarcinomas, the expression of miR-15b, miR-21, miR-95, miR-103, miR-107, miR-148a, miR-155, miR-196a, miR-200, miR-210, miR-217, miR-221, miR-222 and miR-375 are different from tissue of normal pancreas and chronic pancreatitis. 17,[20][21][22][23][24][25][26][27] The results reported by Bloomston et al 20 and Szafranska et al 26 give promises of significant clinical impact of microRNA expression profiles to separate tissue from pancreatic adenocarcinomas from normal pancreas and chronic pancreatitis. The study by Szafranska et al 26 included a combination of two microRNAs (the difference between miR-196a and miR-217) to separate pancreatic adenocarcinomas and chronic pancreatitis (ASURAGEN-test).…”

“…20,21,23,24 MicroRNAs are stable in formalin-fixed paraffin-embedded samples. 28,29 Tumor cells in pancreatic ductal adenocarcinomas are often located in small groups surrounded by an abundant stromal tissue 30 and information related to microRNAs from the stromal tissue may be lost if micro-dissection is applied.…”