Knockdown of microRNA-21 Inhibits Proliferation and Increases Cell Death by Targeting Programmed Cell Death 4 (PDCD4) in Pancreatic Ductal Adenocarcinoma

Bhatti, Imran; Lee, Andrew; James, Victoria; Hall, Richard; Lund, Jonathan N.; Tufarelli, Cristina; Lobo, Dileep N.; Larvin, Michael

doi:10.1007/s11605-010-1381-x

Cited by 79 publications

(63 citation statements)

References 55 publications

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“…In previous studies from our group, we found that miR-152 and miR-148a are down-regulated in gastrointestinal cancer tissues and cancer cell lines compared to non-tumorous controls (18). It has recently been reported that miR-148a expression is down-regulated in several types of cancer, such as pancreatic ductal adenocarcinoma (PDAC) (26), prostate cancer (27), and hepatoblastoma (HB) (28), however, studies on hepatocellular carcinoma (HCC) have shown that miR-148a is up-regulated in this disease (28,29). miR-152, which is one of the miRNA-148/152 family members, was found to be deregulated in many cancers as well.…”

Section: Mir-152 and Mir-148a Have No Effect On Invasion Of Skov3 Cellsmentioning

confidence: 88%

Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation

Zhou

Zhao²,

Wang

et al. 2011

Oncol Rep

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Abstract. microRNAs (miRs) are endogenous small noncoding RNAs that are aberrantly expressed in various carcinomas. miR-152 and miR-148a have not been comprehensively investigated in ovarian cancer. Thus, the aim of this study was to identify the role of miR-152 and miR-148a in epithelial ovarian cancer. Total RNA was extracted from tissues of 78 patients with epithelial ovarian cancer, 17 normal ovarian epithelium tissues and two ovarian cancer cell lines. Using quantitative real-time PCR (qRT-PCR) followed by the 2 -ΔΔCT method for calculating the results, we found that the expression levels of miR-152 were significantly decreased in ovarian cancer tissues compared to normal ovarian epithelium tissues (p<0.05). However, although the expression of miR148a was also decreased in 65% of patients, no statistically significant difference in expression was found. A strong correlation was found between the expression of miR-152 and miR-148a (p<0.001, Pearson's correlation). The relationship between miR-152 or miR-148a expression levels in ovarian cancer and clinicopathological features, response to therapy and short-term survival was analyzed and the results showed that no correlation existed. In addition, we found that both miR-152 and miR-148a were down-regulated in ovarian cancer cell lines. After miR-152 or miR-148a mimics were transfected into ovarian cancer cell lines, the MTT cell proliferation assay showed that cell proliferation was significantly inhibited. Taken together, miR-152 and miR-148a may be involved in the carcinogenesis of ovarian cancer through deregulation of cell proliferation. They may be novel biomarkers for early detection or therapeutic targets of ovarian cancer. IntroductionOvarian cancer is one of the most common causes of death from gynecological malignancies. In addition, with an incidence of ~15,000 deaths annually, it is the fifth leading cause of cancer-related deaths among women in the United States (1). More than 90% of ovarian cancers are epithelial ovarian cancers (EOCs), which are derived from the ovarian surface epithelium (2). Due to a lack of effective biomarkers, ineffective tools for ovarian cancer screening, and non-specific symptoms in its early stages, more than two-thirds of patients with ovarian cancer are not diagnosed until the disease is in an advanced stage (3). Despite advances in early detection and the current standard treatment for advanced ovarian cancer, the 5-year survival rate is only 20-25% (4,5), which makes the development of alternative approaches urgent. Understanding the molecular alterations of ovarian cancer will help identify novel diagnostic markers or therapeutic targets, thereby improving the survival rates in this population of cancer patients.microRNAs (miRNAs or miRs) are a class of highly conserved, non-coding RNAs, approximately 19-25 nucleotides in length. They function as post-transcriptional regulators by binding to the 3'UTR regions of protein-encoding genes, which results in translational repression and gene silencing (6,7). Almost 30% ...

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Section: Mir-152 and Mir-148a Have No Effect On Invasion Of Skov3 Cellsmentioning

confidence: 88%

Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation

Zhou

Zhao²,

Wang

et al. 2011

Oncol Rep

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“…20 More recently, it has been reported that inhibition of miR-21 in a pancreatic ductal adenocarcinoma cell line led to reduced cell proliferation and increased cell death, with a simultaneous increase in PDCD4. 21 In addition, the level of expression of PTEN, PDCD4, Maspin, and TPM1 was significantly reduced in drug-resistant pancreatic ductal adenocarcinoma cell lines. 12 Our data, showing a correlation between the expression of miR-21 and its targets in pancreatic ductal adenocarcinoma tissues, are in agreement with these observations, although the association of miR-21 with TIMP3 expression has not been previously examined in the pancreas.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2012

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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.

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“…Most reports showed that PDCD4 was a pro-apoptosis gene. [27][28][29][30] However, recently a study showed that PDCD4 was an antiapoptotic regulator that inhibited the translation of procaspase-3 mRNA in cells. 31 In our study, there was no significant difference in hepatocyte apoptosis between PDCD4-deficient mice and WT mice at 0 h after LPS/D-GalN injection.…”

Section: Discussionmentioning

confidence: 99%

The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury

Wang

Zhang

Wei

et al. 2013

Laboratory Investigation

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Programmed cell death 4 (PDCD4) acts as a tumor suppressor gene, which suppresses tumor growth, infiltration and metastasis. Our previous studies demonstrated that PDCD4 had an important role in the development of ovarian cancer and glioma. Recent studies show that PDCD4 is also involved in various inflammatory diseases. However, its exact effect on inflammation remains unclear. In our current study, we explored the role of PDCD4 in acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) using wild-type (WT) mice and PDCD4-deficient mice. Our results showed that liver-to-body weight ratios, as well as serum aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly increased in PDCD4-deficient mice than WT mice. Histological examination, immunohistochemical and TUNEL analysis revealed PDCD4-deficient mice had more necrotic and apoptotic hepatocytes, inflammatory cells infiltration and liver internal hemorrhage than WT mice. In addition, some inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) in the serum and liver tissues were also significantly increased in PDCD4-deficient mice. More importantly, we found that the aggravation of liver tissue injury in PDCD4-deficient mice was due to excessive mitogen-activated protein kinase and NF-kB activation, which induced the release of more inflammatory factors, and consequently resulted in higher levels of hepatocyte necrosis and apoptosis. These results indicate that PDCD4 has a protective role in LPS/D-GalN-induced acute liver injury. This finding may present new opportunities for PDCD4 to be explored as a therapeutic target in acute liver injury.

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Knockdown of microRNA-21 Inhibits Proliferation and Increases Cell Death by Targeting Programmed Cell Death 4 (PDCD4) in Pancreatic Ductal Adenocarcinoma

Abstract: miRNA expression profiles may be used as biomarkers for detecting pancreatic cancer. Moreover, miR-21 could be a predictor of disease progression and a possible therapeutic target in part by upregulating PDCD4 in pancreatic cancer.

Cited by 79 publications

References 55 publications

Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation

Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation

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

The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury

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