Oncogene database

407018

MIR27A

microRNA 27a;MIR27A;microRNA 27a

hsa-mir-27a

19p13.13

ncRNA

MicroRNAs (miRNAs) may function as oncogenes or tumor suppressors. Here, we show that miR-27a is up-regulated in human gastric adenocarcinoma. Suppression of miR-27a inhibits gastric cancer cell growth. Subsequently, prohibitin is identified as a potential miR-27a target, combining bioinformatics and microarray analysis. EGFP report experiment also confirms that the 3 untranslated region (3 UTR) of prohibitin carries the directly binding site of miR-27a. After knockdown of miR-27a in gastric cancer cells, mRNA level and protein level of prohibitin are both elevated. Down-regulation of prohibitin by miR-27a may explain why suppression of miR-27a can inhibit gastric cancer cell growth, further supporting that miR-27a functions as an oncogene.

The FOXO1 transcription factor orchestrates the regulation of genes involved in the apoptotic response, cell cycle checkpoints, and cellular metabolism. FOXO1 is a putative tumor suppressor, and the expression of this gene is dysregulated in some cancers, including prostate and endometrial cancers. However, the molecular mechanism resulting in aberrant expression of human FOXO1 in cancer cells is poorly understood. We show here that FOXO1 mRNA is down-regulated in breast tumor samples as compared with normal breast tissue. Silencing of the microRNA processing enzymes, Drosha and Dicer, led to an increase in FOXO1 expression. We also identified functional and specific microRNA target sites in the FOXO1 3 -untranslated region for miR-27a, miR-96, and miR-182, microRNAs that have previously been linked to oncogenic transformation. The three microRNAs, miR-27a, miR-96 and miR-182, were observed to be highly expressed in MCF-7 breast cancer cells, in which the level of FOXO1 protein is very low. Antisense inhibitors to each of these microRNAs led to a significant increase in endogenous FOXO1 expression and to a decrease in cell number in a manner that was blocked by FOXO1 siRNA. Overexpression of FOXO1 resulted in decreased cell viability because of inhibition of cell cycle traverse and induction of cell death. We have identified a novel mechanism of FOXO1 regulation, and targeting of FOXO1 by microRNAs may contribute to transformation or maintenance of an oncogenic state in breast cancer cells.

MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in breast cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with breast cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large familial breast cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced familial breast cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78-0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70-0.98, P = 0.0314), whereas no significant effect was observed in the age group >or= 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with familial breast cancer risk.

MicroRNAs are short regulatory RNAs. A growing body of data implicates altered miRNA participate in the development of cancers and miR-27a is abnormally upregulated in several types of cancers identified as an oncogene. Although overexpressed in pancreatic adenocarcinoma, the oncogenic role of miR-27a has not yet been reported. In this study, we showed that inhibition of miR-27a suppressed the growth, colony formation and migration of pancreatic cancer cells. By using a reporter-screening assay, we discovered that the 3 UTR of Sprouty2 (Spry2) carried a putative miR-27a binding site. Furthermore, the Spry2 protein, which has a low expression level in pancreatic adenocarcinoma, was upregulated by transfection with a miR-27a inhibitor. The data reported here are the first to indicate that miR-27a plays an oncogenic role by targeting Spry2 and modulating the malignant, biological behavior of pancreatic cancer cells. This suggests the potential for miR-27a to be used as a target in the diagnosis and treatment of pancreatic adenocarcinoma.

The introduction of the Simian virus 40 (SV40) early region, the telomerase catalytic subunit (hTERT) and an oncogenic allele of H-Ras directly transforms primary human cells. SV40 small T antigen (ST), which forms a complex with protein phosphatase 2A (PP2A) and inhibits PP2A activity, is believed to have a critical role in the malignant transformation of human cells. Recent evidence has shown that aberrant microRNA (miRNA) expression patterns are correlated with cancer development. Here, we identified miR-27a as a differentially expressed miRNA in SV40 ST-expressing cells. miR-27a is upregulated in SV40 ST-transformed human bronchial epithelial cells (HBERST). Suppression of miR-27a expression in HBERST cells or lung cancer cell lines (NCI-H226 and SK-MES-1) that exhibited high levels of miR-27a expression lead to cell growth arrested in the G(0)-G(1) phase. In addition, suppression of miR-27a in HBERST cells attenuated the capacity of such cells to grow in an anchorage-independent manner. We also found that suppression of the PP2A B56gamma expression resulted in upregulation of miR-27a similar to that achieved by the introduction of ST, indicating that dysregulation of miR-27a expression in ST-expressing cells was mediated by the ST-PP2A interaction. Moreover, we discovered that Fbxw7 gene encoding F-box/WD repeat-containing protein 7 was a potential miR-27a target validated by dual-luciferase reporter system analysis. The inverse correlation between miR-27a expression levels and Fbxw7 protein expression was further confirmed in both cell models and human tumor samples. Fbxw7 regulates cell-cycle progression through the ubiquitin-dependent proteolysis of a set of substrates, including c-Myc, c-Jun, cyclin E1 and Notch 1. Thus, promotion of cell growth arising from the suppression of Fbxw7 by miR-27a overexpression might be responsible for the viral oncoprotein ST-induced malignant transformation. These observations demonstrate that miR-27a functions as an oncogene in human tumorigenesis.

MicroRNAs (miRs) play an important role in the development of many complex human diseases and may have tumour suppressor or oncogenic (oncomir) properties. Prostate cancer is initially an androgen-driven disease, and androgen receptor (AR) remains a key driver of growth even in castration-resistant tumours. However, AR-mediated oncomiR pathways remain to be elucidated. We demonstrate that miR-27a is an androgen-regulated oncomir in prostate cancer, acting via targeting the tumour suppressor and AR corepressor, Prohibitin (PHB). Increasing miR-27a expression results in reduced PHB mRNA and protein levels, and increased expression of AR target genes and prostate cancer cell growth. This involves a novel mechanism for androgen-mediated miR regulation, whereby AR induces a transient increase in miR-23a27a24-2 transcription, but more significantly accelerates processing of the primiR-23a27a24-2 cluster. Androgens therefore regulate miR-27a expression both transcriptionally (via AR binding to the cluster promoter) and post-transcriptionally (accelerating primiR processing to the mature form). We further show that a miR-27a anti-sense oligonucleotide, by opposing the effects of mir-27a, has therapeutic potential in prostate cancer.

Glioma is a highly fatal malignant disease and its treatment options are limited. microRNAs represent a novel target for the treatment of cancer. In the present study, we used a lentiviral vector to stably express anti-microRNAs targeting the oncogenic miR-27a in U87 glioma cells. The stable expression of anti-miR-27a significantly reduced the proliferation and increased the accumulation of U87 cells in the sub-G1 phase as determined by Cell Counting kit-8 (CCK-8) assays and flow cytometry, respectively. Results from the Matrigel transwell assay also indicated that the inhibition of miR-27a substantially impaired the invasiveness of U87 cells. By combining bioinformatic and proteomic approaches, we identified the mRNAs of 8 proteins upregulated in anti-miR-27a-expressing U87 cells as putative direct targets of miR-27a. Collectively, these data suggest that the lentiviral expression of anti-miR-27a is a feasible approach for the suppression of malignant phenotypes of glioma cells.

MicroRNAs (miRNAs) are emerging as important regulators in various pathobiological processes in cancer. Genistein, as a major isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities particularly in cancer prevention. However, the molecular mechanisms by which genistein elicits its effects on ovarian cancer cells have not been fully elucidated. In this study, we reported that expression of miR-27a was higher in human ovarian cancer relative to benign ovarian tissues. Meanwhile, transfection of SKOV3 cells with the inhibitor of miR-27a suppressed growth and migration of tumor cells. Our study also found that treatment of ovarian cancer cells with genistein caused an inhibition of ovarian cancer cell growth and migration. Further cellular mechanistic studies revealed that genistein down-regulated miR-27a expression, which was accompanied by significantly increased expression of Sprouty2, a putative miR-27a target gene. Taken together, our findings reveal that oncogenic miR-27a plays an important role in ovarian cancer cell growth and metastasis, and genistein, as nontoxic inactivators of miRNA, can block ovarian cancer cell growth and migration, offering novel insights into the mechanisms of genistein therapeutic actions.