MicroRNA在肿瘤中的作用及机制

肿瘤的发生和发展是一个多因素、多步骤的过程。越来越多的证据表明,肿瘤的发生发展与表观遗传学机制所致的癌基因激活和抑癌基因失活有关。表观遗传学尤其是miRNA调控异常导致的癌基因和抑癌基因表达异常研究越来越深入,miRNA调控异常介导的肿瘤放化疗抗拒是目前成功治疗大多数肿瘤的主要阻碍。虽然表观遗传学中miRNA研究越来越多,但是miRNA介导放化疗抗拒的相关文献较少,本综述希望结合目前miRNA在肿瘤中的作用以及其放化疗耐受的机制作进一步的探讨,深入了解miRNA在肿瘤中的作用能有望为我们治疗肿瘤提供新思路。     

Circulating miR-133a and miR-423-5p fail as biomarkers for left ventricular remodeling after myocardial infarction

Background

Recent studies have suggested that the microRNAs miR-133a and miR-423-5p may serve as useful biomarkers in patients with left ventricular (LV) heart failure or with LV remodeling after myocardial infarction (MI). These results were however obtained in small series of patients and control subjects were used as reference groups. Whether these microRNAs may be indicators of the degree of LV remodeling after MI is unknown.

Methods

246 patients with a first anterior Q-wave MI were included. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI and analyzed at a core laboratory. We investigated the temporal profile (baseline, 1, 3 and 12 months) of circulating miR-133a and miR-423-5p and their relations with cardiac biomarkers (B-type natriuretic peptide, C-reactive protein, and cardiac troponin I) and LV remodeling during the 1 year follow-up.

Results

There were time-dependent changes in the levels of circulating miR-133a and miR-423-5p with significant increase of miR-133a at 12 months compared to 3 months and significant increase of miR-423-5p at 1, 3, and 12 months compared to baseline. However, miR-133a and miR-423-5p were not associated with indices of LV function and LV remodeling serially assessed during a 1 year period after an acute anterior MI, nor with B-type natriuretic peptide.

Conclusions

Circulating levels of miR-133a and miR-423-5p are not useful biomarkers of LV remodeling after MI.     

微小RNA在宫颈癌中的研究进展

早期诊断、早期治疗是降低肿瘤病死率的有效途径。微小RNA(miRNA)作为一种小分子的非编码调控的单链RNA,由于其与肿瘤发生、发展密切相关,被认为有可能成为一类新的肿瘤标志物和抗肿瘤治疗靶点,从而为肿瘤的早期诊断及治疗带来新的希望。目前,miRNA在宫颈癌的研究尚处于初级阶段,有研究发现miRNA通过与人乳头瘤病毒(HPV)之间的相互作用可以影响宫颈癌的发生、发展。该文对近年来miRNA在宫颈癌中的最新研究进展,特别是在宫颈癌的发生、发展中的作用及与HPV的相互关系予以综述。     

微小RNA与肿瘤研究进展

微小核糖核酸(miRNA)是一类在生物体中广泛表达的、非编码调节性小分子RNA。成熟的miRNA与RNA诱导沉默复合体结合后,通过与靶mRNA的特定序列互补或不完全互补结合,进而发挥阻遏翻译或引导酶切的功能。miRNA具有多种生物学功能,如调节细胞发育、分化、增殖、凋亡、免疫与应激反应等,并且具有肿瘤抑制因子及癌基因的作用,可能是诊断、治疗肿瘤的一种潜在手段。     

微小RNA与子宫内膜异位症

子宫内膜异位症(简称内异症)是生育年龄妇女的常见病,病因机制复杂。其病变广泛,极具侵袭性和复发性,呈现恶性临床行为。微小RNA(miRNA)在细胞增殖、分化和凋亡等多种细胞生长和发育过程中起重要的调控作用。其参与调控内异症黏附和侵袭、细胞生长和增殖及血管形成,在内异症恶性转化中具有重要作用。随着反义技术和基因治疗领域技术的发展,miRNA有望成为内异症诊断和治疗的新的切入点。     

Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I–III

Several biomarkers have been proposed as useful parameters to better specify the prognosis or to delineate new target therapy strategies for glioblastoma patients. MicroRNAs could represent putative target molecules, considering their role in tumorigenesis, cancer progression and their specific tissue expression. Although several studies have tried to identify microRNA signature for glioblastoma, a microRNA profile is still far from being well‐defined.In this work the expression of 19 microRNAs (miR‐7, miR‐9, miR‐9∗, miR‐10a, miR‐10b, miR‐17, miR‐20a, miR‐21, miR‐26a, miR‐27a, miR‐31, miR‐34a, miR‐101, miR‐137, miR‐182, miR‐221, miR‐222, miR‐330, miR‐519d) was evaluated in sixty formalin‐fixed and paraffin‐embedded glioblastoma samples using a locked nucleic acid real‐time PCR. Moreover, a comparison of miRNA expressions was performed between primary brain neoplasias of different grades (grades IV–I).The analysis of 14 validated miRNA expression in the 60 glioblastomas, using three different non‐neoplastic references as controls, revealed a putative miRNA signature: mir‐10b and miR‐21 were up‐regulated, while miR‐7, miR‐31, miR‐101, miR‐137, miR‐222 and miR‐330 were down‐regulated in glioblastomas. Comparing miRNA expression between glioblastoma group and gliomas of grades I–III, 3 miRNAs (miR‐10b, mir‐34a and miR‐101) showed different regulation statuses between high‐grade and low‐grade tumors. miR‐10b was up‐regulated in high grade and significantly down‐regulated in low‐grade gliomas, suggesting that could be a candidate for a GBM target therapy.This study provides further data for the identification of a miRNA profile for glioblastoma and suggests that different‐grade neoplasia could be characterized by different expression of specific miRNAs.     

MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer

Pancreatic cancer has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MUC13, a transmembrane mucin is highly involved in pancreatic cancer progression. Thus, understanding its regulatory molecular mechanisms may offer new avenue of therapy for prevention/treatment of pancreatic cancer. Herein, we report a novel microRNA (miR-145)-mediated mechanism regulating aberrant MUC13 expression in pancreatic cancer. We report that miR-145 expression inversely correlates with MUC13 expression in pancreatic cancer cells and human tumor tissues. miR-145 is predominantly present in normal pancreatic tissues and early Pancreatic Ductal Adenocarcinoma (PDAC) precursor lesions (PanIN I) and is progressively suppressed over the course of development from PanIN II/III to late stage poorly differentiated PDAC. We demonstrate that miR-145 targets 3′ untranslated region of MUC13 and thus downregulates MUC13 protein expression in cells. Interestingly, transfection of miR-145 inhibits cell proliferation, invasion and enhances gemcitabine sensitivity. It causes reduction of HER2, P-AKT, PAK1 and an increase in p53. Similar results were found when MUC13 was specifically inhibited by shRNA directed at MUC13. Additionally, intratumoral injections of miR-145 in xenograft mice inhibited tumor growth via suppression of MUC13 and its downstream target, HER2. These results suggest miR-145 as a novel regulator of MUC13 in pancreatic cancer.     

MiR-153-3p调控异丙肾上腺素诱导的心肌肥大机制研究

目的 本研究旨在利用异丙肾上腺素(isoproterenol,ISO)诱导心肌细胞肥大,研究miR-153-3p调控心肌肥大的作用机制。方法 体外分离培养大鼠乳鼠心肌细胞,通过ISO不同时间（0、8、12、18、24、48 h）梯度培养检测细胞肥大情况以及miR-153-3p的表达情况;转染miR-153-3p的拮抗剂(antagomir)于ISO诱导的大鼠原代心肌细胞中使miR-153-3p低表达,根据转染情况分为空白组,ISO组（药物诱导组）,ISO+NC组（阴性对照组）和ISO+miR-153-3p antagomir组（实验处理组）;用FITC Phalloidin FITC标记鬼笔环肽染色观察细胞表面积的变化,荧光定量PCR(real-time quantitative PCR,RT-qPCR)法检测心房利钠肽,β-肌球蛋白重链和miR-153-3p基因的表达。结果 在一定时间内随着ISO诱导时间的延长心肌细胞肥大效果逐步升高,到18 h和24 h呈显著差异（P<005）,48 h后细胞肥大效果降低;miR-153-3p的表达量与肥大效果呈一致趋势,表面积结果与RT-qPCR结果一致。结论 MiR-153-3p在大鼠心肌细胞中响应ISO诱导上调,并且敲低miR-153-3p显著降低心肌细胞的肥大效果。表明miR-153-3p是心肌肥大的重要调节因子,敲低miR-153-3p有抑制心肌肥大的作用,揭示了miRNA在控制心肌肥大发展中的新信号机制。     

转化医学研究新热点：微小RNA调控癌症

微小RNA(microRNA,miRNA)是一类具有调控基因表达功能的内源性非编码RNA。miRNA具有组织特异性表达,并在各类肿瘤和癌组织异常表达,参与癌细胞增殖、迁移、侵袭、转移、凋亡以及肿瘤干细胞成瘤能力。miRNA既具有基因治疗研发潜力,也可作为抗癌和抗肿瘤治疗靶点应用到癌症的防治。miRNA能够被癌细胞分泌到微环境和外周血,可作为新型生物标志物,研发应用于癌症的早期诊断和预后。本文对国内外miRNA基础研究和临床研发的最新进展作一综述,并客观、科学分析miRNA在调控肿瘤发生和癌转移领域的转化研究和应用前景。     

Effect of microRNA‐210 on prognosis and response to chemotherapeutic drugs in pediatric acute lymphoblastic leukemia

Many studies have demonstrated that microRNA‐210 (miR‐210) expression is intensively upregulated in hypoxic states and differentially regulated in most types of cancer cells. However, the clinical significance of miR‐210 and its effects on the response of leukemic cells to chemotherapeutic drugs in childhood acute lymphoblastic leukemia (ALL) remain unknown. In the current study, using real‐time qRT‐PCR to detect miR‐210 expression in bone marrow samples from 114 children at initial diagnosis of ALL, we investigated the prognostic significance of miR‐210 and determined its associations with common clinical characteristics and treatment outcome. We further examined its effect on the response to chemotherapeutic drugs in the Reh and RS4;11 cell lines. Results showed that miR‐210 expression was significantly lower in patients suffering from relapse and induction failure than in other patients (P < 0.001). Using the receiver operating characteristic curve, 3.8243 was selected as the cut‐off value of miR‐210 expression in our test cohort (38 cases). A significantly poorer treatment outcome (P < 0.05) was found in the low‐expression group and verified in the validation cohort (76 cases, P < 0.05). Patients with low expression of miR‐210 and positive minimal residual disease at the end of induction had a much higher rate of relapse or induction failure (P = 0.001). Increasing/decreasing miR‐210 expression using agomir/antagomir could enhance or reduce the response of Reh cells and RS4;11 cells to daunorubicin/dexamethasone/L‐asparaginase and daunorubicin/dexamethasone/vincristine, respectively. In conclusion, miR‐210 may be a good prognostic factor and a useful predictor of drug sensitivity, and is a potential therapeutic target for pediatric ALL.