围生期缺血缺氧性脑病的微 RNA生物标志物筛选研究

目的研究围生期缺血缺氧性脑病( HIE)的微 RNA(miRNA)生物标志物的筛选情况。方法通过动态队列研究法获取 2020年 1月至 2021年 1月深圳市龙华区中心医院 144例 HIE病儿作为受试者。将其根据病情严重程度的差异分作轻度 HIE组 42例、中度 HIE组 62例以及重度 HIE组 40例,另取同期该院 50例健康新生儿作为对照组。分别采集所有新生儿脐带血进行测序比较分析差异表达 miRNA,筛选 3个和 HIE相关的 miRNA作为早期预测 HIE的生物标志物,并分析各组新生儿上述 3个 miRNA表达情况的差异。采用 Spearman相关性分析明确 HIE病情严重程度和 miRNA表达的关系。此外,将所有 HIE病儿按照是否合并脏器损伤分为合并脏器损伤组 102例以及未合并脏器损伤组 42例,比较两组上述 3个 miRNA表达情况的差异。此外,检测并比较 HIE组和对照组血清诱导型一氧化氮合酶( iNOS)、内皮素 -1水平。结果 miRNA芯片通过扫描、分析以及标准化处理,结果发现 miRNA芯片共检测 miRNA达 921种。相较于对照组, HIE病儿血浆中有 29种 miRNA表达异常升高, 26种 miRNA表达异常下降,选择差异有统计学意义的 miRNA实施生物学信息分析,发现了 miR-4472、miR-5195-3p以及 miR6794-5p可能具有潜在的预测 HIE作用。重度 HIE组 miR-4472、miR-5195-3p以及 miR-6794-5p表达水平分别为 0.71±0.12、2.34±0.28、2.24±0.24,均高于对照组的 0.20±0.04、0.78±0.15、0.47±0.11和轻度 HIE组的 0.37±0.08、0.92±0.18、0.89±0.15以及中度组的 0.55±0.09、1.45±0.23、1.46±0.20,且轻度 HIE组、中度 HIE组 miR-4472、miR-5195-3p以及 miR-6794-5p表达水平均高于对照组,中度 HIE组 miR-4472、miR-5195-3p以及 miR-6794-5p表达水平均高于轻度 HIE组(均 P<0.05)。 HIE病儿病情严重程度和 miR-4472、miR-5195-3p、miR-6794-5p表达均呈正相关关系(均 P<0.05)。合并脏器损伤 HIE病儿 miR-4472、miR-5195-3p、 miR-6794-5p表达水平分别为 0.60±0.09、2.05±0.18、1.70±0.31,均高于未合并脏器损伤组的 0.46±0.03、1.58±0.12、1.37±0.23(均 P<0.05)。 HIE组血清 iNOS及内皮素 -1水平均高于对照组(均 P<0.05)。结论 HIE的 miRNA生物标志物包括 miR-4472、miR5195-3p、miR-6794-5p,且上述 miRNA表达水平和病儿病情严重程度以及脏器损伤有关,值得临床重点关注。     

Circulating microRNA profiles altered in mice after 28 d exposure to perfluorooctanoic acid

Perfluorooctanoic acid (PFOA) is a stable man-made compound with many industrial and commercial uses. Recently, however, concern has been raised that it may induce various toxicological effects such as hepatotoxicity, immunotoxicity, and developmental toxicity. Because levels of circulating microRNAs (miRNAs) can be altered in several clinical diseases, they may serve as potential novel biomarkers. Here, we explored differences in the profiles of circulating miRNAs in mice after PFOA exposure. Using TaqMan miRNA arrays, we determined that the levels of 24 circulating miRNAs were altered in mice dosed with PFOA at 1.25 mg/kg/d and 73 were altered in mice dosed with 5 mg/kg/d. Eight miRNAs were further validated using TaqMan Real-Time PCR assays. Results were consistent with those obtained from the TaqMan miRNA arrays, except for miR-199a-3p. The most remarkable of the circulating miRNAs (miR-26b-5p and miR-199a-3p) were also up-regulated in the serum of occupational workers in our previous epidemiological study. We also found similar patterns in mice exposed to PFOS. These results demonstrated that circulating miRNA profiles were altered after exposure to high concentrations of PFOA and miR-28-5p, miR-32-5p, miR-122-5p, miR-192-5p, and miR-26b-5p in serum may be linked to effects of PFOA, especially in occupationally exposed people.     

Circulating miRNA-126, -145 and -155 levels in Mexican women exposed to inorganic arsenic via drinking water

The aim of this research was to investigate circulating expression levels of three miRNAs (miR-126, miR-155, and miR-145) proposed as predictive CVD biomarkers in Mexican women exposed to inorganic arsenic via drinking water. Mean UAs concentration of 19.5 ± 14.0 μg/g creatinine was found after urine samples were analyzed (n = 105). Significant associations between UAs levels and serum expression levels of miR-155 (p < 0.05) and miR-126 (p < 0.05) were observed after adjustment for assessed co-variables. Alterations in the serum expression levels of miR-155 and miR-126 may be associated with the onset and development of cardiovascular diseases, hence miRNAs could be proposed as prognostic CVD biomarkers. Data found in this study are of concern and risk reduction plans are necessary for the assessed communities to prevent cardiovascular events in this population of women.     

Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis

The refractory diabetic wound has remained a worldwide challenge as one of the major health problems. The impaired angiogenesis phase during diabetic wound healing partly contributes to the pathological process. MicroRNA (miRNA) is an essential regulator of gene expression in crucial biological processes and is a promising nucleic acid drug in therapeutic fields of the diabetic wound. However, miRNA therapies have limitations due to lacking an effective delivery system. In the present study, we found a significant reduction of miR-31-5p expression in the full-thickness wounds of diabetic mice compared to normal mice. Further, miR-31-5p has been proven to promote the proliferation, migration, and angiogenesis of endothelial cells. Thus, we conceived the idea of exogenously supplementing miR-31-5p mimics to treat the diabetic wound. We used milk-derived exosomes as a novel system for miR-31-5p delivery and successfully encapsulated miR-31-5p mimics into milk exosomes through electroporation. Then, we proved that the miR-31-5p loaded in exosomes achieved higher cell uptake and was able to resist degradation. Moreover, our miRNA-exosomal formulation demonstrated dramatically improved endothelial cell functions in vitro, together with the promotion of angiogenesis and enhanced diabetic wound healing in vivo. Collectively, our data showed the feasibility of milk exosomes as a scalable, biocompatible, and cost-effective delivery system to enhance the bioavailability and efficacy of miRNAs.     

神经母细胞瘤血浆外泌体差异表达miRNA靶基因预测及生物信息学分析

目的通过生物信息学分析筛选出神经母细胞瘤外周血血浆外泌体中差异表达miRNA,并对其靶基因功能进行分析预测。方法从高通量基因表达数据库下载数据集GSE128004,分析神经母细胞瘤血浆外泌体中miRNA的差异表达;通过miRTarBase数据库筛选差异表达miRNA的靶基因;进一步通过运用clusterProfiler进行靶基因的基因本体(GO)功能富集与京都基因与基因组百科全书数据库(KEGG)通路富集。结果经筛选发现,数据集GSE128004包含41个表达差异在2倍以上的血浆外泌体miRNA。靶基因预测显示,hsa-miR-199a-3p, hsa-miR-196b-5p, hsa-miR-127-3p, hsa-miR-410-3p和hsa-miR-487b-3p为靶基因最多的前5个差异表达miRNA。GO功能分析发现,这些靶基因大都在细胞运动正调节、细胞迁移正调节、血管生成等生物过程富集;在膜侧、细胞-基底连接、细胞-基底黏附连接、焦点黏连等细胞组成富集;在蛋白丝氨酸/苏氨酸激酶活性、蛋白异二聚体化活性、转录因子活性和RNA聚合酶Ⅱ核心启动子近端区序列特异性结合等分子功能富集。KEGG分析显示:这些差异表达miRNA的靶基因主要参与磷脂酰肌醇3激酶-蛋白激酶B信号通路、癌症相关miRNA、丝裂原活化蛋白激酶信号通路等通路富集。结论 hsa-miR-199a-3p, hsa-miR-127-3p和hsa-miR-410-3p可能作为神经母细胞瘤的潜在生物标志物或治疗靶标,进一步为该病的发病机制提供研究思路。     

Mechanisms of migration and invasion promoted by NSCLC cells-derived exosomes

OBJECTIVE To explore the function and mechanism of exosomes from non-small cell lung cancer(NSCLC) in promoting the invasion and metastasis of lung cancer cel s. METHODS The exosomes were isolated and identified by differential centrifugation, nanosight,transmission electron microscope and Western blotting.Observation of the exosome uptake was applied by immune fluorescent confocal experiments. Scratch test was used to detect the influence of exosomes to tumor cells migration ability and transwell assay were carried out to investigate the effect of exosomes on migration and invasion. Total RNAs from exosomes were used for miRNA library preparation and sequencing. RT-Q-PCR was employed to detect the miRNA levels. Western blotting was adopted to detect the protein expression levels and dual luciferase reporter assay was used to verify the predict target site of miRNA. RESULTS The extracellular vesicles in the supernatant of NSCLC cells were isolated by the differential centrifugation and confirmed as exosomes by nanosight, transmission electron microscope and Western blotting. Exosomes from NSCLC can promote migration and invasion of non-small cell lung cancer cells showing concentration-and time-dependent manner. By analyzing the differential expression profile of exosomes miRNA of lung epithelial cells and lung cancer cell A549,30 miRNAs were screened out. Then, hsa-miR-34c-3p was selected in combination with clinical specimen detection. The expression level of miR-34c-3p in exosomes from lung cancer was lower than that of the normal one.CONCLUSION Exosomes from NSCLC cells can be uptaken by cells and promote cell migration and invasion in dose-dependent manner. The expression level of miR-34c-3p in exosomes from NSCLC is significantly lower than normal tissues. The level of miR-34c-3p was further declined after incubating with exosomes. Exosomes from NSCLC cells can deliver miR-34c-3p to recepted cells and up-regulate the protein level of integrin α2β1.     

Differential and unique patterns of synaptic miRNA expression in dorsolateral prefrontal cortex of depressed subjects

Altered synaptic plasticity is often associated with major depressive disorder (MDD). Disease-associated changes in synaptic functions are tightly correlated with altered microRNA (miRNA) expression. Here, we examined the role of miRNAs and their functioning at the synapse in MDD by examining miRNA processing machinery at synapse and sequencing miRNAs and analyzing their functions in synaptic and total tissue fractions obtained from dorsolateral prefrontal cortex (dlPFC) of 15 MDD and 15 matched non-psychiatric control subjects. A total of 333 miRNAs were reliably detected in the total tissue fraction. Multiple testing following the Benjamini–Hochberg false discovery rate [FDR] showed that 18 miRNAs were significantly altered (1 downregulated 4 up and 13 downregulated; p < 0.05) in MDD subjects. Out of 351 miRNAs reliably expressed in the synaptic fraction, 24 were uniquely expressed at synapse. In addition, 8 miRNAs (miR-215-5p, miR-192-5p, miR-202-5p, miR-19b-3p, miR-423-5p, miR-219a-2-3p; miR-511-5p, miR-483-5p showed significant (FDR corrected; p < 0.05) differential regulation in the synaptic fraction from dlPFC of MDD subjects. In vitro transfection studies and gene ontology revealed involvement of these altered miRNAs in synaptic plasticity, nervous system development, and neurogenesis. A shift in expression ratios (synaptic vs. total fraction) of miR-19b-3p, miR-376c-3p, miR-455-3p, and miR-337-3p were also noted in the MDD group. Moreover, an inverse relationship between the expression of precursor (pre-miR-19b-1, pre-miR-199a-1 and pre-miR-199a-2) and mature (miR-19b-3p, miR-199a-3p) miRNAs was found. Although not significantly, several miRNA processing enzymes (DROSHA [95%], DICER [17%], TARBP2 [38%]) showed increased expression patterns in MDD subjects. Our findings provide new insights into the understanding of the regulation of miRNAs at the synapse and their possible roles in MDD pathogenesis.Subject terms: Depression, Depression     

Differential microRNAs expression in seminal plasma of normospermic patients with different sperm DNA fragmentation indexes

Sperm DNA fragmentation index (SDF), as an important supplement to routine semen parameters, has been proposed to discriminate between fertile and infertile men, and predicts the outcomes of natural conception and in vitro fertilization. Unfortunately there are uncertainty and contradictory evidences regarding the importance of SDF. An important reason is the fact that significant and fundamental research about SDF is rare. This study was designed to characterize the microRNA (miRNA) expression profile in seminal plasma of normospermic patients with different SDF and their implications in human fertility. Using next-generation sequencing (NGS), a total of 897 human miRNAs were detected from 10 seminal plasma samples, out of which 431 differentially expressed miRNAs in 5 pairs of seminal plasma samples (each pair of seminal plasma samples obtained from the same male), with 14 miRNAs were identified in all the pairs. According to the fold change and expression level, 7 miRNAs including miR-374b-5p, miR-429, hsa-miR-26b-5p, miR-21−5p, miR-4257, miR-135b-5p and miR-134−5p were selected for further excavation. MiR-374b-5p and miR-26b-5p were significantly different in 3 sets of individual seminal plasma samples with different SDF from total 90 infertile patients (30 patients each set). Our results demonstrate that the profile of miR-374b and miR-26b with significantly decreased expression could be used as a first indication of increased SDF. And miR-374b and miR-26b could serve as adjunct biomarkers for the diagnosis of idiopathic infertile males.     

Genome-wide miRNA expression profiling of human lymphoblastoid cell lines identifies tentative SSRI antidepressant response biomarkers

Aim: Over 30% of patients with major depression do not respond well to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). Using genome-wide expression profiling of human lymphoblastoid cell lines (LCLs) CHL1 was identified as a tentative SSRI sensitivity biomarker. This study reports on miRNAs implicated in SSRI sensitivity of LCLs. Methods: Eighty LCLs were screened from healthy adult female individuals for growth inhibition by paroxetine. Eight LCLs exhibiting high or low sensitivities to paroxetine were chosen for genome-wide expression profiling with miRNA microarrays. Results: The miRNA miR-151-3p had 6.7-fold higher basal expression in paroxetine-sensitive LCLs. This corresponds with lower expression of CHL1, a target of miR-151-3p. The additional miRNAs miR-212, miR-132, miR-30b*, let-7b and let-7c also differed by >1.5-fold (p < 0.05) between the two LCL groups. Conclusion: The potential value of these miRNAs as tentative SSRI response biomarkers awaits validation with lymphocyte samples of major depression patients. Original submitted 28 March 2012; Revision submitted 21 May 2012.     

Altered expression of microRNAs may predict therapeutic response in rheumatoid arthritis patients

BackgroundEpigenetic alternations of microRNAs (miRNAs) can contribute to the pathogenesis and progression of rheumatoid arthritis (RA). This study aimed to measure the expression level of peripheral blood miRNAs, as well as their target mRNAs, in RA patients and healthy controls (HCs), and to evaluate the potential of miRNAs as promising non-invasive biomarkers of treatment response.MethodsThe peripheral expression of miRNAs, including miR-146a, miR-146b, miR-150, miR-155, miR-125a-5p, miR-223, miR-26a, and miR-21, as well as their target mRNAs, was analyzed in 90 RA patients and 30 HCs via quantitative real-time polymerase chain reaction (RT-PCR) assay. We compared differences between the patients in terms of good response (GR; n = 55) and poor response (PR; n = 35) to the conventional therapeutic approach.ResultsAll miRNAs were significantly overexpressed in RA patients. The expression of miR-155, miR-150, miR-146a, miR-146b, miR-125a-5p, and miR-223 increased in both groups of RA patients, compared to HCs, and miR-26a and miR-21 were the only upregulated miRNAs in the GR group versus HCs. Among the upregulated miRNAs, miR-125a-5p expression significantly changed in GR and PR patients (P = 0.047). The ROC curve analysis indicated the potential involvement of miR-125a-5p in the pathogenesis of RA. We also observed the downregulated expression of GATA3, RORC, FOXP3, TBX21, STAT1, and TRAF6 in RA patients versus HCs.ConclusionOur findings indicated that different expression levels of miR-125a-5p in the GR and PR groups of patients may serve as a therapeutic response biomarker, which can be also used as a target for therapeutic interventions.     

MiR-22-3p in exosomes increases the risk of heart failure after down-regulation of FURIN

Heart failure (HF) is often the inevitable manifestation of myocardial ischemia. Hypoxia can induce cardiomyocytes to express many microRNAs (miRNAs), which are highly expressed in exosomes. In addition, miR-22-3p is a marker in heart failure. Therefore, miR-22-3p was taken as the research object to explore its role and mechanism in HF. HF differentially expressed miRNAs were screened by bioinformatic analysis. The HF rats model was constructed and identified by detecting serum brain natriuretic peptide (BNP) and ultrasound analysis [left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS)]. The extracted exosomes were identified by transmission electron microscopy, and Western blot was used to detect the expressions of Tsg101 and CD63. Quantitative real-time polymerase chain reaction detected miR-22-3p expression in serum, exosomes, and serum without exosomes, while the cardiomyocytes cytotoxicity was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and PKH26 staining. After overexpressing/silencing miR-22-3p in cells, cell viability, apoptosis, and apoptosis-associated markers were detected. Bioinformatic analysis screened the target gene of miR-22-3p, which was verified by dual-luciferase assay. Regulation of miR-22-3p on FURIN was measured by rescue tests. In vivo experiments were verified the above results. MiR-22-3p was identified as the research object. BNP was increased in the model group, while LVEF and LVFS were decreased. MiR-22-3p was overexpressed in HF-treated serum and exosomes. Normal exosomes did not affect cardiomyocyte function, while high concentrations of HF-treated exosomes were cytotoxic. By regulating apoptosis-related genes, overexpressed miR-22-3p inhibited cell activity and promoted cell apoptosis. Silenced miR-22-3p with opposite effects counteracted effects of HF-treated exosomes. FURIN, target gene of miR-22-3p, was negatively regulated by miR-22-3p, while overexpressed FURIN promoted cell activity and inhibited apoptosis. In vivo research was consistent with the results of cell experiments. By regulating FURIN, miR-22-3p in exosomes increases the risk of HF damage.     

Evaluation of microRNA responses in ARPE-19 cells against the oxidative stress

Purpose: This study aimed to determine microRNA (miRNA) expression profile of human retinal pigment epithelium cell (ARPE-19) against the oxidative stress induced by hydrogen peroxide (H₂O₂).

Methods: ARPE-19 cells were incubated with different concentrations of H₂O₂ (200, 600 and 800?μM) for 18?h, and then cell viability, vascular endothelial growth factor levels and total oxidant status were evaluated. Expressions of 1152 miRNA were determined by quantitative real-time PCR in each group.

Results: Expressions of 90 miRNA were significantly changed in the ARPE-19 cells incubated with H₂O₂ compared to control group. However, miR-143-3p was only found to be expressed in groups incubated with H₂O₂. While 24 miRNA (hsa-miR-200c-3p, miR-192-5p, miR-194-5p, miR-141-3p, miR-658, miR-18?b-5p, miR-486-5p, miR-525-3p, miR-493-3p, miR-518d-3p, miR-29?b-1-5p, miR-675-3p, miR-1238-3p, miR-195-3p, miR-1539, miR-490-5p, miR-3200-5p, miR-1273d, miR-130a-5p, miR-30?b-5p, miR-1247-5p, miR-1910-5p, miR27a-5p and miR-200?b-3p) upregulated due to the increased dose of H₂O₂, nine miRNA (hsa-miR-96-5p, miR-33a-5p, miR-345-5p, miR-106?b-3p, miR-1285-3p, miR-23?b-5p, miR-27?b-5p, miR-103a-3p and miR-4289) were also found to be downregulated.

Conclusion: This study suggests that oxidative stress may be an important factor on expression of miRNAs in ARPE-19 cells. These miRNAs may have a role in the pathogenesis of age-related macular degeneration related to oxidative stress. However, this relationship needs to be examined in new studies by evaluation of pathways and target genes.     

Aberrant expression of microRNAs in gastric cancer and biological significance of miR-574-3p

The discovery of microRNAs (miRNAs) provides a new and powerful tool for studying the mechanisms, diagnosis and treatments of cancer. In this study, we employed AFFX miRNA expression chips to search for miRNAs that may be aberrantly expressed in gastric cancer tissues and to investigate the potential roles that miRNAs may play in the development and progression of gastric cancer. 14 miRNAs were found to be down-regulated and 2 miRNAs up-regulated in gastric cancer tissues compared to the normal gastric tissues. Among the aberrantly expressed miRNAs, miR-574-3p was selected to further study its expression features and functional roles. Interestingly, the reduced expression of miR-574-3p occurred mainly in the early stages of gastric cancer or in cancers with high level of differentiation, suggesting that it can be used as a marker for a mild case of gastric cancer. Functional study revealed that cell proliferation, migration and invasion were significantly inhibited in miR-574-3p-transfected gastric cancer SGC7901 cells. Computational prediction and experimental validation suggest that Cullin2 may be one of the targets of miR-574-3p. Overall our study suggests that the aberrantly expressed miRNAs may play regulatory and functional roles in the development and progression of gastric cancer.     

MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1

Objectives: We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance.

Design and methods: We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip.

Results: We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change ≥ 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Conclusion: This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor.     

miR-27a在妇科肿瘤中的研究进展 #br#

微小 RNA（miRNA）是一类内源性的非编码小 RNA,通常可通过特异性降解 mRNA或抑制蛋白质的翻译, 在转录后水平调控靶基因的表达,参与机体的多个生理或病理过程。miRNA可通过调节癌基因和抑癌基因的表达 来参与肿瘤的发生发展,在不同类型的肿瘤中及肿瘤的不同发展阶段,miRNA分子的表达谱呈现不同的特征。其 中,miR-27a定位于人类 19号染色体,在子宫内膜癌、宫颈癌、卵巢癌等多种妇科肿瘤中异常表达。本文对 miR-27a 在子宫内膜癌、宫颈癌和卵巢癌中的作用及其临床应用进展进行综述,为开发新型的肿瘤分子标志物或靶向药物提 供理论依据。     

Aberrant expression of miR-638 contributes to benzo(a)pyrene-induced human cell transformation

Identification of aberrant microRNA (miRNA) expression during chemical carcinogen-induced cell transformation will lead to a better understanding of the substantial role of miRNAs in cancer development. To explore whether aberrant miRNAs expression can be used as biomarkers of chemical exposure in risk assessment of chemical carcinogenesis, we analyzed miRNA expression profiles of human bronchial epithelial cells expressing an oncogenic allele of H-Ras (HBER) at different stages of transformation induced by benzo(a)pyrene (BaP) by miRNA array. It revealed 12 miRNAs differentially expressed in HBER cells at both pretransformed and transformed stages. Differentially expressed miRNAs were confirmed in transformed cells and examined in 50 pairs of primary human non-small-cell lung cancer (NSCLC) tissues using real-time PCR. Among these miRNAs, downregulation of miR-638 was found in 68% (34/50) of NSCLC tissues. However, the expression of miR-638 in HBER cells increased upon treatment of BaP in a dose-dependent manner. The expression of miR-638 was also examined in peripheral lymphocytes from 86 polycyclic aromatic hydrocarbons (PAHs)-exposed (PE) workers. We found that the average expression level of miR-638 in peripheral lymphocytes from 86 PE workers increased by 72% compared with control group. The levels of miR-638 were correlated with the concentration of urinary 1-hydroxypyrene (1-OHP) and external levels of PAHs. Overexpression of miR-638 aggravated cell DNA damage induced by BaP, which might be mediated by suppression of breast cancer 1 (BRCA1), one of the target genes of miR-638. In summary, we suggest that miR-638 is involved in the BaP-induced carcinogenesis by targeting BRCA1.     

Role of microRNAs in gynecological pathology

microRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in biological processes. These small molecules bind to target mRNAs, leading to translational repression and/or mRNA degradation. Aberrant miRNA expression is associated with several human diseases such as cancer, cardiovascular disorders, inflammatory diseases and gynecological pathology. The present article reviews the role of miRNAs in four gynecological disorders that affect the ovary or the uterus, one benign and frequent disease (endometriosis) that is classified as a tumor-like lesion and three malignant gynecological diseases (endometrial, cervical and ovarian cancers). Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent benign gynecological diseases. Similarly to tumor metastasis, endometriotic implants require neovascularization to proliferate, invade the extracellular matrix and establish an endometriotic lesion. Despite its high prevalence and incapacitating symptoms, the exact pathogenic mechanism of endometriosis remains unsolved. A relationship between endometriosis and gynecological cancer, especially ovarian cancer, has been reported. Endometriosis is a multifactorial and polygenic disease, and emerging data provide evidence that a dysregulation of miRNA expression may be involved. miRNAs appear to be potent regulators of gene expression in endometriosis, raising the prospect of using miRNAs as biomarkers and therapeutic tools in this disease. In cancer, miRNAs have an important role as regulatory molecules, acting as oncogenes (oncomiRs) or tumor suppressors. Endometrial cancer is one of the most frequent gynecological malignancies in the developed countries. Cervical cancer, also one of the most common cancers in women, is associated with high-risk human papillomaviruses although this infection alone may not be enough to induce the malignant transformation. Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. Over 80% of cases are diagnosed at an advanced stage, with a reduced five-year survival rate. Recent studies have shown that miRNAs are aberrantly expressed in different human cancer types, including endometrial, cervical and ovarian cancer, and that specific dysregulated miRNAs may act as biomarkers of patients' outcome. Recently, miRNAs have been detected in serum and plasma, and circulating miRNA expression profiles have now been associated with a range of different tumor types. Their accessibility in peripheral blood and stability given the fact that miRNAs circulate confined within exosomes, make researchers foster hope in their role as emerging biomarkers of cancer and other disorders. The development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for any of the aforementioned gynecological disorders.