Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma

Abstract

Since the discovery of small non-coding RNAs, the analyses of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. miRNA-21 has been suggested to be one of the miRNAs that have an important role in the development or biological behavior of a variety of malignancies, including pancreatic cancer. This study was conducted to evaluate the relationship between the expression of miRNA-21 and that of its molecular targets, programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinase (TIMP3), in pancreatic ductal adenocarcinoma. The study included 65 pancreatic ductal adenocarcinomas and 5 normal pancreatic tissue specimens for comparison. The miRNA expression profiling of five selected pancreatic ductal adenocarcinomas and five normal pancreatic specimens was performed using a microarray platform, and was evaluated by a hierarchical clustering analysis. The miRNA most highly expressed in pancreatic ductal adenocarcinomas (ie, miRNA-21) was further assessed by quantitative real-time reverse transcription PCR (RT-PCR) assays in the 65 pancreatic ductal adenocarcinoma cases. The expression pattern of its molecular targets (eg, PDCD4 and TIMP3) in pancreatic ductal adenocarcinoma was examined immunohistochemically. In the microarray analyses, 28 miRNAs were upregulated in pancreatic ductal adenocarcinoma compared with normal pancreatic tissue, whereas 48 miRNAs were downregulated. miRNA-21 was the most significantly overexpressed miRNA in the pancreatic ductal adenocarcinomas analyzed, and was also highly expressed in 75% of the 65 pancreatic ductal adenocarcinomas examined by real-time RT-PCR. High miRNA-21 expression was correlated with a worse prognosis in the pancreatic ductal adenocarcinoma patients (P ¼ 0.045). The immunohistochemical expression patterns of PDCD4 (reduced nuclear staining pattern) and TIMP3 (downregulated expression) were significantly associated with both the upregulated miR-21 expression (Po0.05) and the poor survival of the patients (Po0.001 and P ¼ 0.001, respectively). Our data suggest that an overexpression of miRNA-21 is, therefore, associated with the biological behavior of pancreatic ductal adenocarcinoma via the downregulation of the expression of tumor suppressors, PDCD4 and TIMP3, thus resulting in tumor progression and the adverse clinical course of pancreatic ductal adenocarcinoma.

MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

“…MiR-21 was up-regulated in pancreatic adenocarcinomas in this and other studies and has been related to short survival. 20,22,38,39 Increased miR-21 expression increases the proliferative and invasive potential in several types of cancer, it has anti-apoptotic and pro-angiogenesis properties and its expression may represent an adaptation to a hypoxic environment that favors cancer cell survival. 40 In accordance with others, we found that miR-148a, miR-216b and miR-217b were some of the miRNAs with the most significantly decreased expression in pancreatic adenocarcinomas compared with chronic pancreatitis and normal pancreas.…”

“…40 In accordance with others, we found that miR-148a, miR-216b and miR-217b were some of the miRNAs with the most significantly decreased expression in pancreatic adenocarcinomas compared with chronic pancreatitis and normal pancreas. 21,39 Over-expression of miR-217 in pancreatic adenocarcinoma cells inhibits tumor cell growth in vivo and in vitro. 41 Expression of miR-217 is negatively related to KRAS expression.…”

MiR-21 Upregulation Induced by Promoter Zone Histone Acetylation is Associated with Chemoresistance to Gemcitabine and Enhanced Malignancy of Pancreatic Cancer Cells

“…Various studies have reported that miR-21 plays an important role not only in tumor growth but also in the invasion and metastasis by targeting multiple tumor suppressor genes including PTEN, PDCD4, BCL-2, TPM1, and RECK (Zhu et al, 2007;Asangani et al, 2008;Gabriely et al, 2008;Zhang et al, 2008b;Zhu et al, 2008;Nagao et al, 2012;Zhang et al, 2012). PTEN (phosphatase and tensin homolog deleted on chromosome 10) (Li et al, 1997) is one of the most frequently inactivated tumor suppressors indifferent tumor types.…”

“…The expression of miR-21 has been shown to be involved in the progression of several types of cancers (Kwak et al, 2011;Yang et al, 2011), including PDAC (Bloomston et al, 2007;Szafranska et al, 2007;Nagao et al, 2012), and the up-regulation of miR-21 expression has been shown to correlate with a lower cancer survival rate (Dillhoff et al, 2008;Jamieson et al, 2012). Recent studies also demonstrated that miR-21 modulates the chemosensitivity of cancer cells primarily by targeting PTEN or PDCD4 (Moriyama et al, 2009;Ali et al, 2010;Giovannetti et al, 2010;Tomimaru et al, 2010).…”

Cząsteczki mikroRNA jako istotny składnik mechanizmów regulacji ekspresji genów związanych z nowotworami

“…Cząsteczka miRNA-21 funkcjonuje jako onkogen w przebiegu gruczolakoraka trzustki i w znacznej liczbie przypadków chorych obserwowana jest jej nadekspresja, co jest związane z wystąpieniem przerzutów do węzłów chłonnych oraz gorszym rokowaniem [16].…”