EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas

Mees, Soeren Torge; Mardin, Wolf Arif; Wendel, Claudia; Baeumer, Nicole; Willscher, Edith; Senninger, N.; Schleicher, Christina; Colombo-Benkmann, Mario; Haier, Joerg

doi:10.1002/ijc.24695

Cited by 138 publications

(102 citation statements)

References 50 publications

(76 reference statements)

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“…miR-194 has been reported to be involved in the regulation of pancreatic cancer metastasis 18 and miR-204 in pancreatic acinar cell carcinoma transformation and progression. 19 Cell adhesion …”

Section: Discussionmentioning

confidence: 99%

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Chung

Lau

Cheung

et al. 2011

Intl Journal of Cancer

155

128

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TXMicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3 0 -untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression-and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.Endometrial cancer is a common cause of gynecological cancer death. The most dominant subtype, endometrioid endometrial cancer (EEC), accounts for >80% of this cancer. Menopause and unopposed estrogenic stimulation are typical risk factors. Patients are generally treated with surgery, radiation, chemotherapy or hormone therapy. Patients with early stage disease have 5-year survival rates over 80%, however, about 15-20% develop metastasis. 1 These patients and those with advanced stage disease or recurrence have poor prognosis due to limitation of effective treatment. 2 Understanding the pathogenesis of this disease may provide insights for the development of novel therapeutic strategies.MicroRNAs (miRNAs) are small noncoding RNA molecules of 19-24 nucleotides that regulate gene expression posttranscriptionally through imperfect base pairing with the 3 0 -untranslated region (3 0 UTR) of target mRNAs, causing transcript degradation and translational inhibition. 3 Approximately 20-30% of all genes are targeted by miRNAs and a single miRNA may target as many as 200 genes. 4 In human cancers, >50% of the miRNA genes are located in chromosomal fragile sites, minimal regions containing loss of heterozygosity, minimal amplicons or common breakpoint regions. 5 DNA ...

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Section: Discussionmentioning

confidence: 99%

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Chung

Lau

Cheung

et al. 2011

Intl Journal of Cancer

155

128

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“…22 Both snoRNAs have been widely used as internal controls for quantitative RT-PCR. [23][24][25][26][27] The forward primers were as follows: SNORD44 (NR_002750.2), 5=-CCTGGATGATGATAGCAAATGCTG-3=; and SNORD48 (NR_002745.1), 5=-AGTGATGATGACCCCAGGTAACT-3=. …”

Section: Quantitative Real-time Rt-pcrmentioning

confidence: 99%

Silencing of the Imprinted DLK1-MEG3 Locus in Human Clinically Nonfunctioning Pituitary Adenomas

Cheunsuchon

Zhou

Zhang

et al. 2011

The American Journal of Pathology

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DLK1-MEG3is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) is selectively lost in clinically nonfunctioning adenomas (NFAs) of gonadotroph origin; however, expression status of other genes at this locus in human pituitary adenomas has not previously been reported. Using quantitative real-time RT-PCR, we evaluated expression of 24 genes from the DLK1-MEG3 locus in 44 human pituitary adenomas (25 NFAs, 7 ACTH-secreting, 7 GH-secreting, and 5 PRL-secreting adenomas) and 10 normal pituitaries. The effects on cell proliferation of five miRNAs whose expression was lost in NFAs were investigated by flow cytometry analysis. We found that 18 genes, including 13 miRNAs at the DLK1-MEG3 locus, were significantly down-regulated in human NFAs. In ACTH-secreting and PRL-secreting adenomas, 12 and 7 genes were significantly downregulated, respectively; no genes were significantly down-regulated in GH-secreting tumors. One of the five miRNAs tested induced cell cycle arrest at the G2/M phase in PDFS cells derived from a human NFA. Our data indicate that the DLK1-MEG3 locus is silenced in NFAs. The growth suppression by miRNAs in PDFS cells is consistent with the hypothesis that the DLK1-MEG3 locus plays a tumor suppressor role in human NFAs.

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“…Moreover, a growing number of miRNAs have been classified as oncogenes or tumor-suppressor genes (4,5). Over the past decade, an increasing number of studies have shown dysregulation of miRNA expression in numerous tumor types including esophageal (6), lung (7), liver (8), pancreatic (9), bladder (10), ovarian (11) and gastric cancer (12).…”

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confidence: 99%

microRNA-192, -194 and -215 are frequently downregulated in colorectal cancer

Chiang

Song

Wang

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. microRNAs (miRNAs) are small, non-coding RNAs of endogenous origin. They have been increasingly shown to have aberrant expression in a number of tumor types. miR-192, -194 and -215 have not been comprehensively investigated using a large number of cases in colorectal cancer (CRC). We extracted total RNA from 107 CRC tissues and three CRC cell lines. Following polyadenylation and reverse transcription, the expression levels of miR-192, -194 and -215 were determined for evaluation of the association between expression levels and clinicopathological characteristics by a quantitative real-time polymerase chain reaction (real-time PCR) method. Finally, we studied the impact of miR-194 on cell proliferation in HCT-116 cells by MTT assay. miR-192, -194 and -215 were significantly downregulated in CRC tissues (all p<0.001, paired t-test) and cancer cell lines (all p<0.05) compared to non-tumor counterparts. Moreover, the expression levels of miR-192, -194 and -215 were demonstrated to be associated with increased tumor sizes (p=0.027, p=0.018, and p=0.027, respectively; Mann-Whitney U test). Also, there were marked correlations among these miRNAs in CRC tissues (all p<0.001, Pearson's regression analysis). Furthermore, we found that the overexpression of miR-194 could significantly inhibit cell proliferation in may be important biological markers as tumor suppressors in the carcinogenesis of CRC.

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EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas

Cited by 138 publications

References 50 publications

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Silencing of the Imprinted DLK1-MEG3 Locus in Human Clinically Nonfunctioning Pituitary Adenomas

microRNA-192, -194 and -215 are frequently downregulated in colorectal cancer

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