Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development

Zhang, Shuyu; Hao, Jun; Xie, Fang; Hu, Xinyu; Liu, Cong; Tong, Jian; Zhou, Jundong; Wu, Jinchang; Shao, Chenghao

doi:10.1093/carcin/bgr105

Cited by 135 publications

(97 citation statements)

References 37 publications

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“…RB1 was found to be a target of miR-192, which mediates an effect on cell apoptosis through the caspase pathway (19). miR-192 inhibits nucleotide excision repair by targeting ERCC3 and ERCC4 in HepG2.2.15 cells (27). Our present data suggest SIP1 as a potential target of miR-192, as overexpression of miR-192 led to a marked repression of SIP1 protein expression in PANC-1 cells.…”

Section: Discussionsupporting

confidence: 54%

Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma

Zhao

Zhang

et al. 2013

Oncology Reports

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Abstract. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of human cancer. In the present study, we evaluated serum as a potential biomarker in patients with PDAC and investigated its biological functions in this disease. miRNA expression profiling of human PDACs and adjacent normal pancreatic tissues identified 16 upregulated miRNAs including miR-192 and 8 downregulated miRNAs. Quantitative real-time polymerase chain reaction (PCR) revealed elevation of serum miR-192 levels in PDAC patients relative to these levels in duodenal adenocarcinoma patients and healthy controls. Receiver operating characteristic analysis demonstrated that serum miR-192 had a sensitivity of 76% and a specificity of 55% for detecting PDAC. Ectopic expression of miR-192 in PANC-1 pancreatic cancer cells enhanced cell proliferation and migration, reduced apoptosis and promoted cell cycle progression from the G0/G1 to the S phase. Western blot analysis showed that enforced expression of miR-192 decreased the expression of smad-interacting protein 1 (SIP1) and altered a set of cell cycle-related genes in the PANC-1 cells. miR-192 overexpression increased tumor volume in an orthotopic pancreatic cancer mouse model, coupled with suppression of SIP1 and elevation of collagen I. In conclusion, serum miR-192 may serve as a sensitive diagnostic biomarker for PDAC. Overexpression of miR-192 contributes to tumor growth and progression in PDAC, which is associated with repression of SIP1 and alteration of cell cycle regulatory genes.

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Section: Discussionsupporting

confidence: 54%

Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma

Zhao

Zhang

et al. 2013

Oncology Reports

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“…2c), whereas 5-Aza significantly increased the relative expression of checkpoint kinase 2 (CHEK2) and microoRNA-132, as reported previously. (16,19) Moreover, treatment of cells with TSA, a histone deacetylase inhibitor, increased the expression of protocadherin 17 (PCDH17), (20) but not POLI (Fig. 2d).…”

Section: Resultsmentioning

confidence: 95%

“…Cells were grown in an incubator at 37°C with 5% CO 2 . To block DNA methylation or histone deacetylation, Eca-109 and TE-1 cells were treated with 10 lmol/L 5-aza-2′-deoxycytidine (5-Aza) or 2 lmol/L trichostatin A (TSA; Sigma-Aldrich) for 72 h. (16) The cells were then collected for mRNA analysis using realtime PCR.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of DNA polymerase iota (Polι) in esophageal squamous cell carcinoma

et al. 2012

Self Cite

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The present study investigated the transcriptional regulation of low-fidelity translesion DNA synthesis (TLS) polymerases in human esophageal carcinoma. Significantly higher mRNA expression of polymerase zeta (Polξ), RAD18, polymerase iota (Polι), and polymerase kappa (Polj) was found in esophageal carcinomas. The increased expression of Polι in tumor samples was further confirmed by immunohistochemistry. The promoter of POLI that encodes Polι was found to be hypomethylated, although the overexpression of this gene was unlikely to be associated with methylation in tumors. We further identified Sp1 and Oct-1 binding sites present in the POLI promoter. We observed that the binding affinity of Sp1 to the POLI promoter was significantly increased in cancerous tissues and that Sp1 activated POLI gene transcription in cultured cell lines. The present study demonstrates overexpression of the TLS genes in esophageal carcinoma and identifies a key role for Sp1 in upregulating POLI gene expression. (Cancer Sci 2012; 103: 1574-1579

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“…miR-376a and miR-301 were found to be significantly overexpressed in PDAC tissues [73]. miR-132 [74,75], miR-96 [37], miR-34a [27] and miR-21 [76] have been reported to be altered in PDAC as compared with normal adjacent tissue. Since discriminating PDAC from chronic pancreatitis may prevent from unnecessary surgery, several studies focus on this issue.…”

Section: Review Vorvis Koutsioumpa and Iliopoulos Future Science Groupmentioning

confidence: 96%

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

2016

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Pancreatic cancer is a devastating malignancy that ranks as the fourth leading cause of cancerrelated deaths worldwide. Dismal prognosis is mainly attributable to limited knowledge of the molecular pathogenesis of the disease. miRNAs have been found to be deregulated in pancreatic cancer, affecting several steps of initiation and aggressiveness of the disease by regulating important signaling pathways, such as the KRAS and Notch pathways. Moreover, the effect of miRNAs on regulating cell cycle events and expression of transcription factors has gained a lot of attention. Recent studies have highlighted the application of miRNAs as biomarkers and therapeutic tools. The current review focuses on latest advances with respect to the roles of miRNAs in pancreatic ductal adenocarcinoma associated signaling pathways and miRNA-based therapeutics. KEYWORDS• antisense oligonucleotides • miRNAs • pancreatic cancer Pancreatic cancer overview Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic neoplasms and accounts for greater than 85% of the clinical cases [1]. The disease develops via acinar-ductal metaplasia and neoplastic precursor lesions [2]. In the USA alone, 48,960 new cases of pancreatic cancer were expected to occur in 2015, with an estimated 40,560 deaths, about the same number in women (19,850) as in men (20,710). Over 96% are cancers arising from exocrine pancreas. Endocrine carcinomas are often diagnosed at a younger age and exhibit a better prognosis. From 2007 to 2011, mortality rates increased slightly by 0.3% per year. For all stages combined, the 1-and 5-year relative survival rates are 28 and 7%, respectively. For the small percentage of people diagnosed with local disease (9%), the 5-year survival is 26%, while more than half of patients (53%) are diagnosed at a late stage for which 1-and 5-year survival rates reach 15 and 2%, respectively [3]. These numbers are a staggering example of the poor prognosis associated with PDAC.While new therapeutic options are emerging for nonhematologic malignancies, molecular-targeted therapies for pancreatic cancer have failed to make any positive impact on patient survival. In 1993, the Nobel Prize-winning discovery of small interference RNAs (siRNAs) led to an outburst of knowledge on RNA interference and gene regulation [4]. Since then, thousands of research studies have described the functional role of small noncoding RNAs, named miRNAs, in a vast panel of human pathologies. In 2002, a small genomic region in chromosome 13q14 comprising miR-15a and miR-16-1 genes was found to be commonly deleted in chronic lymphocytic leukemia, For reprint orders, please contact: reprints@futuremedicine.com

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Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development

Cited by 135 publications

References 37 publications

Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma

Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma

Overexpression of DNA polymerase iota (Polι) in esophageal squamous cell carcinoma

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

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