乳腺癌相关microRNA的研究进展

微小核糖核酸(microRNA,miRNA)是近年来发现的长度约为22个核苷酸(nucleotide,nt)的内源性短链RNA,不编码蛋白质,可通过与编码蛋白质的mRNA互补结合,参与细胞增殖、分化、凋亡等多种重要细胞活动的调控.近年来发现miRNA与肿瘤的发生密切相关,研究表明miRNA可以同时调节多种癌基因或抑癌基因的表达,参与多种恶性肿瘤的演进,是肿瘤发生、发展过程中重要分子.miRNA的发现及其和肿瘤关系的揭示为寻找肿瘤新的生物治疗靶点提供了一个极有希望的研究方向.本文就miRNA在乳腺癌中的相关作用及研究进展作一综述.     

microRNA与胃癌研究进展

microRNA是一类由18～23个核苷酸构成的单链非编码RNA分子,具有调节基因表达活性的功能,microRNA与肿瘤发生发展密切相关,microRNA有可能成为一个新的肿瘤标志物和抗肿瘤治疗靶点。全文对近年来microRNA在胃癌发生、发展中的作用及其用于胃癌诊断、治疗的可能前景作一综述和分析。     

大肠癌相关microRNA研究进展

microRNA(miRNA)是一种大小约22个核苷酸的非编码单链小RNA分子,参与细胞增殖、分化、凋亡等多种重要细胞活动的调控。近来研究发现miRNA具有癌基因或抑癌基因样作用,参与多种恶性肿瘤的演进,是肿瘤发生、发展过程中重要分子。目前已发现多种miRNAs在大肠癌组织及大肠癌细胞系中异常表达,一部分在癌细胞中较正常细胞表达明显下降如miR-143、miR-145、let-7、miR-34a等,一部分表达则升高如miR-31、miR-21等。体外试验中将miR-143、miR-145的前体导入大肠癌细胞中,可观察到癌细胞生长受到抑制,且呈剂量依赖性。miRNA表达谱与大肠癌的生物学行为和临床分期相关,如Ⅳ期大肠癌miR-31的表达水平明显较Ⅱ期升高。而大肠癌细胞系中miRNA表达谱与癌组织差别较大,由细胞系中得到miRNA表达谱可能不适于用来推断临床样本的相应表达谱。目前研究比较多的miRNAs如miR-143、miR-145、miR-34a、let-7a等,均有抑制细胞生长增殖的作用,它们在癌细胞中表达下降导致细胞过度生长增殖,可能参与大肠癌的发生。一些化疗药物能明显影响大肠癌细胞中miRNA的表达水平,如阿霉素可明显上调miR-34的表达水平,人们推测miRNA可能是一些化疗药物发挥抗肿瘤作用的重要分子。综上,阐明大肠癌相关miRNA的作用机制将可能丰富大肠癌的病因学及分子病理学理论,为大肠癌诊断治疗提供新策略和思路。     

microRNA：一种新型肿瘤分子标志物

早期诊断、早期治疗是降低肿瘤死亡率的有效途径。microRNA是一类内源性的长约18~22个核苷酸的非编码小RNA,其在肿瘤组织以及循环中的特异表达,为肿瘤的早期诊断带来新的希望。肿瘤中microRNA的表达模式不但与肿瘤诊断有关,与肿瘤的分期、进展以及预后也密切相关。全文就microRNA在肿瘤早期诊断以及预后判断中的作用作一综述。     

三阴性乳腺癌分子标志物的研究进展

最新统计数据显示乳腺癌已成为中国女性发病率最高的恶性肿瘤,成为妇女健康的最大威胁[1]。三阴性乳腺癌（triple—negativebreastcancer,TNBC）是指ER、PR、HER-2表达均缺失的特殊亚型,约占15％～20％[2-3]。     

肿瘤干细胞与microRNA的研究进展

肿瘤干细胞是肿瘤的起源性细胞, 具有高度的致瘤性和耐药性。微小RNA(microRNA或miRNA)是由21~25个核苷酸组成的内源性非编码单链RNA, 是基因表达调控因子, 参与许多生物功能的调节。最近的研究发现, microRNA参与肿瘤干细胞的分化、自我更新等生物学特性的调控。肿瘤干细胞和microRNAs可以作为肿瘤研究的一个新的切入点。本文就近年来的研究进展做简要综述。      

妊娠相关乳腺癌的研究进展

妊娠相关乳腺癌（PABC）预后很差，肿瘤易于发生转移，所以越来越多地受到了人们的重视，PABC发生机制的研究主要集中在妊娠相关激素的作用和妊娠哺乳后乳腺的复旧上，妇女妊娠期间雌二醇、孕激素和人绒毛膜促性腺激素等激素水平升高与乳腺癌的发生发展关系密切，在妊娠哺乳期间乳腺组织的变化提供了有利于肿瘤发生和转移的微环境。     

胃癌相关microRNA的研究

microRNA通过对基因表达的调控参与生命过程中一系列重要进程。它对肿瘤的标记高效、敏感而特异,提示其可能成为众多疾病有价值的诊断标志物和治疗靶点。目前,microRNA作为生物学治疗靶标已经取得实验性进展。本文就胃癌相关microRNA的研究进展做一综述。     

乳腺癌干细胞研究进展

乳腺癌干细胞是乳腺肿瘤细胞中少数具有自我更新和分化潜能,并能维持乳腺肿瘤的生长和异质性的一类细胞。越来越多的证据表明,乳腺癌干细胞在乳腺癌的发生、生长、复发、转移和抗药性等方面起决定性的作用。因此,研究乳腺癌干细胞的调控机理和开发靶向乳腺癌干细胞的新药已经成为乳腺癌研究中的热点。文章简要综述乳腺癌干细胞的概念,分离鉴定及其在乳腺癌转移和治疗中的作用,并对其分子调控进行了探讨。     

乳腺癌相关染色体不稳定性的研究进展

人类大多数肿瘤都有基因组不稳定性（genomicinstabit—ity,GI）的表现…。基因组不稳定性包括两种类型：基因水平的微卫星不稳定（microsatellite instability,MSI／MIN）和染色体水平的染色体不稳定（chromosomalinstability,CIN）。微卫星（microsatellite）是由1～5个核苷酸组成的具有高度多态性的简单串联重复序列,MSI是这些简单重复序列的异常改变,多由于DNA错配修复系统失去正常修复能力引起。     

外泌体传输microRNA在肿瘤研究中的进展*

外泌体是一类可以在细胞间传递直径为30～100 nm的内吞衍生囊泡,可包含与其来源和功能相关的蛋白质和RNA 等物质。外泌体作为一种天然的载体,已被视为一种新型的药物传输系统用于肿瘤的治疗。microRNA（miRNA ）是一类新型的RNA调控基因,不仅仅存在于细胞内,亦存在于细胞外,这些细胞外miRNA 可作为分泌型信号分子影响受体细胞表型,并一定程度上反映出供体细胞内的分子改变,具有一定的诊断及潜在的治疗用途。肿瘤患者血液中外泌体高于正常人,并能够包裹肿瘤相关miRNA 行使生物学功能,因此机体通过外泌体传输特异性miRNA 可能在肿瘤的发病过程中扮演着重要的角色。本文将对外泌体作为miRNA 的传输载体在肿瘤发生发展以及肿瘤治疗等方面的研究进行综述。      

乳腺癌靶向治疗研究进展

乳腺癌靶向治疗是一种有效的治疗方案,其特异性强,毒副作用小,基本上不损伤正常组织。伴随药理学和分子生物学研究的深入,靶向药物的研究和应用取得了突破性进展,新治疗靶点药物的研发已成为人们关注的热点。本文主要对人类表皮生长因子受体2(HER-2)、哺乳动物雷帕霉素靶蛋白(mTOR)信号通路、血管内皮生长因子(VEGF)、上皮生长因子受体(EGFR)、聚腺苷二磷酸核糖聚合酶(PARP)、周期蛋白依赖性激酶4/6(CDK4/6)为靶点的乳腺癌靶向治疗药物研究进行综述。     

Novel genetic variants in microRNA genes and familial breast cancer

MicroRNA (miRNA) plays an important role in tumorigenesis, but whether miRNA is a cancer predisposition factor or not is still unknown. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis, we screened genetic variants in 17 selected miRNA genes, which are predicted to regulate key breast cancer genes, in 42 patients with familial breast cancer. Seven novel genetic variants were observed in 7 primary or precursor miRNA genes. Among them, 1 rare variant in the precursor of miR‐30c‐1 and 1 rare variant in the primary precursor of miR‐17 were only observed in noncarriers of BRCA1/2 mutations. In functional assays, these 2 variants resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR‐30c‐1 and miR‐17. In the target in vitro assay, we observed that miR‐17 could bind to the 3′UTR of BRCA1 mRNAs, which is predicted to be a target for miR‐17. Our findings suggest that functional genetic variants in miRNA genes can potentially alter the regulation of key breast cancer genes. Whether they confer genetic susceptibility to breast cancer remains to be determined. © 2008 Wiley‐Liss, Inc.     

循环微小RNA及其在结直肠癌中的研究

 在结直肠癌中已经发现多种微小RNA（miRNA）表达异常,推测其可能参与肿瘤发生发展过程。近年来越来越多的证据表明,miRNA比mRNA更稳定地存在于血液中,使循环miRNA有望成为一种非侵入性的可以指导结直肠癌诊断、治疗以及预后评价的肿瘤标志物。     

microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers

Triple Negative Breast Cancers (TNBC) is a heterogeneous disease at the molecular and clinical level with poor outcome. Molecular subclassification of TNBCs is essential for optimal use of current therapies and for development of new drugs. microRNAs (miRNA) are widely recognized as key players in cancer progression and drug resistance; investigation of their involvement in a TNBC cohort may reveal biomarkers for diagnosis and prognosis of TNBC. Here we stratified a large TNBC cohort into Core Basal (CB, EGFR and/or CK5, 6 positive) and five negative (5NP) if all markers are negative. We determined the complete miRNA expression profile and found a subset of miRNAs specifically deregulated in the two subclasses.We identified a 4-miRNA signature given by miR-155, miR-493, miR-30e and miR-27a expression levels, that allowed subdivision of TNBCs not only into CB and 5NP subgroups (sensitivity 0.75 and specificity 0.56; AUC=0.74) but also into high risk and low risk groups. We tested the diagnostic and prognostic performances of both the 5 IHC marker panel and the 4-miRNA expression signatures, which clearly identify worse outcome patients in the treated and untreated subcohorts. Both signatures have diagnostic and prognostic value, predicting outcomes of patient treatment with the two most commonly used chemotherapy regimens in TNBC: anthracycline or anthracycline plus taxanes. Further investigation of the patients'' overall survival treated with these regimens show that regardless of IHC group subdivision, taxanes addition did not benefit patients, possibly due to miRNA driven taxanes resistance. TNBC subclassification based on the 5 IHC markers and on the miR-155, miR-493, miR-30e, miR-27a expression levels are powerful diagnostic tools. Treatment choice and new drug development should consider this new subtyping and miRNA expression signature in planning low toxicity, maximum efficacy therapies.     

Novel combination of serum microRNA for detecting breast cancer in the early stage

MicroRNA (miRNA), which are stably present in serum, have been reported to be potentially useful for detecting cancer. In the present study, we examined the expression profiles of serum miRNA in several large cohorts to identify novel miRNA that can be used to detect early stage breast cancer. We comprehensively evaluated the serum miRNA expression profiles using highly sensitive microarray analysis. A total of 1280 serum samples of breast cancer patients stored in the National Cancer Center Biobank were used. In addition, 2836 serum samples were obtained from non‐cancer controls, 451 from patients with other types of cancers, and 63 from patients with non‐breast benign diseases. The samples were divided into a training cohort including non‐cancer controls, other cancers and breast cancer, and a test cohort including non‐cancer controls and breast cancer. The training cohort was used to identify a combination of miRNA that could detect breast cancer, and the test cohort was used to validate that combination. miRNA expressions were compared between patients with breast cancer and non‐breast cancer, and a combination of five miRNA (miR‐1246, miR‐1307‐3p, miR‐4634, miR‐6861‐5p and miR‐6875‐5p) was found to be able to detect breast cancer. This combination had a sensitivity of 97.3%, specificity of 82.9% and accuracy of 89.7% for breast cancer in the test cohort. In addition, this combination could detect early stage breast cancer (sensitivity of 98.0% for Tis).     

Vasopressin gene related products are markers of human breast cancer

Summary Immunohistochemical analysis for products of vasopressin and oxytocin gene expression was performed on acetone-fixed tissues from 19 breast cancers representing a variety of tumor sub-types. Studies employed the avidin-biotin complex (ABC) immunohistochemical procedure and utilized rabbit polyclonal antibodies to arginine vasopressin (VP), provasopressin (ProVP), vasopressin-associated human glycopeptide (VAG), oxytocin (OT), oxytocin-associated human neurophysin (OT-HNP), and a mouse monoclonal antibody to vasopressin-associated human neurophysin (VP-HNP). Western Blot analysis was performed on protein extracts of fresh-frozen tissues from 12 additional breast tumors. While VP gene related proteins were not detected in normal breast tissue, immunohistochemistry revealed the presence of VP, Pro VP, and VAG in all neoplastic cells for all of the tumor tissues examined. Vasopressin-associated human neurophysin was evident in only one of 19 acetone-fixed tumor preparations. However, Western blot analysis for all 12 fresh-frozen tumor samples showed the presence of two proteins, 42,000 and 20,000 daltons, that were immunoreactive with antibodies to VP, VP-HNP, and VAG. Oxytocin and OT-HNP, by immunohistochemistry, were found to be common to cells of normal breast tissues. For tumors, positive staining for OT was observed in 8 of 18 tumors, while OT-HNP was not detected in any of the tumors examined. These findings indicate that VP gene expression is a selective feature of all breast cancers, and that products of this expression might therefore be useful as markers for early detection of this disease and as possible targets for immunotherapy.     

组蛋白去乙酰化酶抑制剂治疗乳腺癌的临床研究

组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitors,HDACIs）作为第一个成功用于癌症治疗的表观遗传学相关药物,能够有效解除对抑癌基因转录的阻滞,已成为极具潜力的抗癌药物。近年来,HDACIs在乳腺癌治疗领域中的临床研究逐渐开展,已有个别HDACIs在大型临床研究中表现出较强的抗癌活性。本文针对HDACIs在乳腺癌治疗领域开展的临床研究作一综述,有利于临床医师更好的了解HDACIs在乳腺癌治疗中的现状与进展。     

乳房自体组织重建的研究进展

乳腺癌是全世界女性最常见的恶性肿瘤。这些患者必须面对手术治疗对其生活质量和身体外观的长期影响。因此,越来越多的患者亟需一种结合肿瘤治疗与乳房重建的方法来满足其对疾病的治疗和乳房外观的需求。在美国,20世纪80年代接受乳房切除术后即刻重建的患者只有不到20%。但近年来,越来越多的患者选择即刻重建。乳房自体组织重建因其美容效果好而成为了许多患者的首选方案,但其术前穿支血管的选择及术后并发症的发生仍是目前自体组织重建所面对的问题。本文就乳房重建技术中自体组织重建皮瓣的应用、相关并发症的发生及预防、皮瓣穿支血管的影像学评估及腔镜技术下乳房重建的研究进展进行了详细的总结。     

Post-operative serum sialyltransferase levels and prognosis in breast cancer

Summary Serum sialyltransferase (SST) activity was measured 10 days after mastectomy in 153 patients with operable breast cancer. Enzyme activity declined with time in storage (1–42 months). After correction for loss of activity in storage, patients with SST activity below the median value had a longer disease-free interval (DFI) than those with SST activity above the median, and this difference remained when patients were stratified by axillary nodal status, tumor size, and tumor grade. Survival was longer in patients with low SST activity. Postoperative elevation of SST indicates a poor prognosis in patients with operable breast cancer. Address for reprints: Dr R.D. Rubens, Imperial Cancer Research Fund, Breast Cancer Unit, Guy's Hospital, London SE1 9RT, United Kingdom.