let-7在肿瘤中的研究进展

let-7是目前研究最为广泛的miRNA之一.在肿瘤中,let-7具有抑制细胞增殖、促进细胞分化和凋亡的多种生物学功能.同时在不同的人肿瘤组织和细胞中,let-7表达的下调伴随其靶基因的表达变化,表明let-7与肿瘤呈高度相关性.     

let-7在肺癌中的研究进展

目的总结let-7在肺癌发生发展中的研究现状,探讨let-7在肺癌诊断、治疗及预后方面发挥的作用。方法应用PubMed及CNKI期刊全文数据库检索系统,以"micro RNA、let-7和肺癌"为关键词,检索2008-01-01-2014-05-31相关文献,共检索到英文文献269篇,中文文献83篇。纳入标准:1)let-7在肺癌发生发展中的作用机制;2)let-7表达对肺癌诊断的关系;3)let-7在肺癌治疗中的潜在价值;4)let-7的表达对肺癌预后的意义。排除标准:1)综述类文献;2)重复及陈旧实验的文献;3)实验研究资料缺失或不全。符合分析的文献39篇。结果 let-7通过抑制相关癌基因的表达及肿瘤血管生成,抑制肺癌的发生、发展、侵袭和转移。let-7在多数肺癌组织中呈低表达,恢复let-7在肺癌组织中的表达,可以抑制肿瘤发展,提高肺癌患者对放疗及靶向治疗的敏感性。组织中let-7低表达的肺癌患者,往往提示预后不良。结论 let-7是肺癌组织中的重要标志,将对肺癌患者的诊断、治疗产生积极的影响。     

MicroRNA let-7与肺癌关系的研究进展

MicroRNAs(miRNAs)是一类内源性、非编码的单链小分子RNA,作用广泛,参与生命活动中的一系列重要进程,并与肿瘤的发生、发展密切相关.miRNA let-7是最早发现的miRNA之一,是线虫时序性发育的关键性调控因子;在哺乳动物中调节多种细胞增殖,且在细胞周期调节中起关键作用.let-7与人类多种癌症的发生、发展有关,其中与肺癌的关系最为密切;hsa-let-7在肺癌中表达显著降低,在非小细胞肺癌(NSCLC)中尤为多见,其低表达可能与肿瘤预后不良有关,而高表达则直接抑制肺癌生长;let-7作为肿瘤抑制因子负性调控多种癌基因,如RAS、高迁移率蛋白A2基因(hish mobility group protein A2,HMGA2)等;同时也负性凋控多种细胞周期调节冈子,如CDC25A、CDK6、Cyclin D2.let-7在肺癌组织中起到了肿瘤抑制因子的作用,有望成为肺癌基因治疗和预后判断的一个新靶标.     

微小RNA let-7与食管癌

微小RNA(miRNA)的发现为食管癌的诊断和治疗开辟了新的思路.let-7是目前研究最为广泛的miRNA之一,在多种肿瘤中表达下调.let-7能够靶向高迁移率蛋白A2 (HMGA2)从而抑制细胞增殖,发挥抑癌基因的作用.研究发现分化程度越低的细胞,let-7表达水平越低,其有望作为低分化肿瘤的标志.此外,let-7与食管癌放化疗敏感性也密切相关.     

MicroRNA let-7家族与肿瘤的研究进展

MicroRNA作为生物小分子参与调控机体内环境稳态和许多疾病发生与发展的过程。Let-7是目前研究最为广泛microRNA之一,在多种肿瘤中表达下调,提示let-7与肿瘤存在一些重要的联系。本文主要讨论let-7家族与肿瘤的研究进展,以进一步了解肿瘤发病机制,为肿瘤的预防和诊治提供新思路。     

MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression

Although dispensable for normal pancreatic function, STAT3 signaling is frequently activated in pancreatic cancers. Consistent downregulation of expression of microRNA let-7 is also characteristic of pancreatic ductal adenocarcinoma (PDAC) biopsy specimens. We demonstrate in this study that re-expression of let-7 in poorly-differentiated PDAC cell lines reduced phosphorylation/activation of STAT3 and its downstream signaling events and reduced the growth and migration of PDAC cells. Let-7 re-expression did not repress expression of STAT3 protein or its activator cytokine interleukin 6 (IL-6). However, let-7 re-expression enhanced cytoplasmic expression of suppressor of cytokine signaling 3 (SOCS3), which blocks STAT3 activation by JAK2. Our study thus identified a mechanism by which STAT3 signaling can be inhibited in pancreatic cancer cells by modifying let-7 expression.     

let-7在肿瘤中的表达及相关靶基因研究进展

let-7是发现较早的一类小分子RNA (miRNA).人let-7 miRNA家族共有13位成员,分别位于9个不同的染色体位点.let-7家族在细胞增殖、分化和肿瘤发生中扮演着重要的角色.研究表明在许多肿瘤的形成过程中,绝大部分let-7家族成员表达水甲降低,因此,let 7普遍认为是一种肿瘤抑制基因.let-7靶向作用于多个基因,干扰由let-7控制的网络可能起到治疗癌症的目的.研究在肿瘤的发展过程中let-7是如何表达调控,并恢复let-7家族的表达,在癌症的治疗中具有深远意义.本文就let-7在肿瘤中的表达及相关靶基因作一综述.     

微RNAlet-7d抑制胶质瘤生长和侵袭

背景与目的：let-7d与胶质瘤的关系尚不清楚,本研究探讨let-7d在人脑胶质瘤组织中表达及其对人脑胶质瘤U87细胞生物学特征的影响。方法：原位杂交法检测let-7d在人脑胶质瘤组织和正常脑组织中的表达,利用脂质体将let-7d寡核苷酸转入U87细胞,观察各组细胞生长、凋亡、侵袭情况。结果：人脑胶质瘤组织中let-7d较正常人脑组织低表达,转入let-7d寡核苷酸的U87细胞,生长减缓,凋亡增加,侵袭力减低。结论：微RNAlet-7d在胶质瘤的发生发展中可能起抑制作用。     

MicroRNA let-7c inhibits migration and invasion of human non-small cell lung cancer by targeting ITGB3 and MAP4K3

MicroRNAs play an important regulatory role in carcinogenesis and cancer metastasis. Different members of let-7 family have been reported to be decreased in human lung tumors. However, the effect of specific let-7 member on metastasis of NSCLC remains undefined. Our current study detected the expression of let-7 members in 94 cases of NSCLC and a significant association was noticed between low levels of let-7c expression and metastasis, venous invasion, advanced TNM stages and poor survival of NSCLC patients. Consistently, ectopic expression of let-7c in relatively highly metastatic cells remarkably suppressed their migration and invasion. Inhibition of let-7c in cells with relatively low metastatic potential promoted their motility and invasion. We then analyzed the potential targets of let-7c and found that ITGB3 and MAP4K3 were directly repressed by let-7c. Upon restoring the expression of ITGB3 and MAP4K3, the effects of let-7c on tumor metastasis were partially reversed, and more importantly, the expression levels of ITGB3 and MAP4K3 were inversely correlated with let-7c in 64 NSCLC tissues. Collectively, our results suggest that let-7c, by degrading ITGB3 and MAP4K3, prevents NSCLC metastasis.     

Overexpressed let-7a-3 is associated with poor outcome in acute myeloid leukemia

Dysregulation of microRNA let-7a-3 has been identified in several solid tumors and is associated with prognosis of patients. However, the pattern of let-7a-3 expression and the impact on prognosis has not yet been studied in acute myeloid leukemia (AML). The purpose of this study is to investigate the expression status of let-7a-3 and its clinical significance in AML patients using real-time quantitative PCR. Overexpression of let-7a-3 was identified in 25 of 102 (25%) de novo AML. There was no significant difference in age, blood parameters, FAB/WHO subtypes, karyotype risks and nine gene mutations (FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, C/EBPA and N/K-RAS) between patients with and without let-7a-3 overexpression (P > 0.05). The patients with let-7a-3 overexpression had similar rates of complete remission (CR) as those without let-7a-3 overexpression (50% vs. 56%, P = 0.693). Although the overall survival (OS) of AML patients with let-7a-3 overexpression (median 12 months,) was shorter than those without overexpression (median 25 months), the difference was not statistically significant (P = 0.228). However, among those 51 obtained CR, patients with let-7a-3 overexpression had significantly shorter OS than those without let-7a-3 overexpression (P = 0.029). The difference in relapse-free survival (RFS) was also significant between two groups (P = 0.005). These findings suggest that let-7a-3 overexpression is a common event and is associated with poor clinical outcome in AML.     

子宫内膜癌组织中 miR-10a 及 let-7i 的表达及临床意义

目的 探讨 miR-10a 及 let-7i 在子宫内膜癌组织中的表达及意义。方法 选取子宫内膜癌组织40 例、子宫内膜不 典型增生组织20例及正常子宫内膜组织30例,采用多聚腺苷酸加尾实时荧光定量逆转录聚合酶链反应[poly（A）-RT-qPCR] 测定miR-10a 及 let-7i 在三种子宫内膜组织中的表达,并将结果与临床及病理资料进行分析。结果 miR-10a 在子宫内膜癌 组织中高表达（高于正常及不典型增生的子宫内膜组织,P＜0.01）;在病理分级为3级的患者中高表达（高于1+2级者）; 在Ⅲ+Ⅳ期患者中高表达（高于Ⅰ+Ⅱ期者）;在有淋巴结转移的患者中高表达,在深肌层浸润（浸润深度≥1/2）的患者 中高表达;差异显著（P ＜ 0.05）。在不同年龄、雌激素受体（ER）及孕激素受体（PR）是否阳性的子宫内膜癌患者中其 表达量差异无统计学意义（P ＞ 0.05）。let-7i 在子宫内膜癌组织低表达（低于正常和不典型增生的子宫内膜组织,P ＜ 0.01）。结论 在子宫内膜癌组织中miR-10a 表达上调,let-7i 表达下调,miR-10a 可能参与并促进了子宫内膜癌的侵袭 和转移。     

晚期恶性肿瘤基因突变状态二代测序临床意义分析

目的 靶向治疗是晚期恶性肿瘤的重要治疗方法,二代测序能够准确、高通量地检测基因突变情况,对恶性肿瘤治疗有重要意义.本研究运用二代基因测序(next-generation sequencing,NGS)技术检测晚期恶性肿瘤的基因突变情况,并初步分析错义突变的临床意义.方法 2011-09-01-2016-09-30收集陕西省人民医院肿瘤内科93例晚期恶性肿瘤患者病理组织石蜡标本,利用离子个体化基因检测仪(Ion Personal Genome Machine,Ion Torrent PGM)平台检测标本16个肿瘤相关基因428个常见的突变位点的突变状态,并查询临床试验(Clinical Trails)与美国食品与药物管理局(Food and Drug Administration,FDA)官网数据资料.结果 共发现119个错义突变,其中TP53发生频率最高为34.5％(41/119);除TP53突变在各瘤种中均占较大比例外,肺癌突变频率最高为表皮生长因子受体(epidermal growth factor receptor,EGFR) 25.7％(9/35),结直肠癌为KRAS 31.6％ (6/19),胃癌为KDR 3/6,卵巢癌为KRAS 2/7,宫颈癌为KDR 3/5.70例(75.3％,70/93)检测发现＞1个的错义突变位点;93.8％(15/16)的被检测基因有正在研发中的小分子抑制剂和(或)单抗类制剂,75.0％(12/16)的被检测基因已有FDA批准用于特定瘤种的靶向药物,68.8％(11/16)的被检测基因有尚未被FDA批准的靶向药物.结论 晚期恶性肿瘤基因错义突变发生率较高,且不同瘤种的突变谱不同,目前基于NGS指导的恶性肿瘤个体化靶向治疗有广阔的应用前景.     

喉癌组织miRNA let-7a和HMGA2表达临床意义研究

目的 从分子水平阐明喉鳞癌发生和转移的分子机制,寻找分子靶向标志物进行靶向治疗是降低喉鳞癌患者病死率的有效途径之一.本研究初步探讨miRNA let-7a靶向调控高迁移率族蛋白(high mobility group A,HMGA2)抑制喉癌组织增殖、侵袭转移的分子机制,为喉癌的分子靶向治疗提供相关信息.方法 实时荧光定量PCR(qRT-PCR)标本为2013-01-01-2014-12-30湖南省人民医院耳鼻咽喉头颈外科经手术切除并经病理确诊为喉癌的25例患者新鲜喉癌组织,和对应的癌旁0.5～1 cm的正常喉黏膜上皮组织标本.qRT-PCR检测25例喉癌组织及癌旁正常黏膜上皮组织中miRNA let-7a和HMGA2 mRNA的表达.免疫组化标本为2013-01-01-2014-12-30湖南省人民医院耳鼻咽喉头颈外科经手术切除并经病理确诊的喉癌组织,及相应癌旁0.5～1 cm的正常喉黏膜上皮组织的石蜡标本各50例,通过免疫组化SP法检测50例喉癌组织及其癌旁正常上皮组织中HMGA2蛋白的表达.结果 喉癌组织及癌旁正常黏膜组织let-7a的相对表达量分别为0.454 0和2.576 5,差异有统计学意义,t＝-4.211,P＜0.05;HMGA2 mRNA的相对表达量分别为o.844 4和o.087 5,差异有统计学意义,t＝-4.292,P＜0.05.喉癌组织及癌旁正常黏膜组织HMGA2蛋白的阳性表达率分别为74.0％(37/50)和14.0％(7/50),x2＝36.526,P＜0.05. leb-7a及HMGA2的表达均与患者性别、年龄无相关性,而与TNM分期、淋巴结转移有显著相关性,P＜0.05.喉癌组织中miRNA let-7a与HMGA2的表达呈显著负相关,相关系数为-0.674,P＜0.05.结论 let-7a与HMGA2在喉癌组织中的表达与肿瘤的发生、侵袭和转移密切相关,且HMGA2有可能作为let-7a负向调控的靶基因之一,let-7a与HMGA2有可能成为喉癌分子靶向治疗中新的肿瘤标志物.     

珠子参多糖通过靶向let-7a/CDK6分子轴调控胃癌MKN45细胞的增殖 与凋亡

目的：探讨珠子参多糖（panax japlcus var polysaccharide,PJPS）对胃癌MKN45细胞增殖和凋亡的影响及其调控机 制。方法：选用人胃癌细胞系HGC27、MGC803、MKN45和胃黏膜上皮细胞株GES-1,分别将let-7a mimics、let-7a inhibitor转染 进MKN45细胞; 以100 μg/ml PJPS处理胃癌细胞系并挑选后续实验细胞株为MKN45细胞;分别添加0、10、50、100、120 μg/ml PJPS处理转染后各组MKN45细胞, 用CCK-8法、流式细胞术分别检测MKN45细胞增殖活力和细胞凋亡率, 用Western blotting 检测MKN45细胞中细胞周期依赖性激酶6（cycle dependent kinase 6,CDK6）和凋亡相关蛋白的表达, 用qPCR法检测调控胃癌细 胞增殖的miRNAs表达水平。用双荧光素酶报告基因实验验证let-7a和CDK6的靶向关系。结果：与其他胃癌细胞比较,100 μg/ml PJPS可显著抑制 MKN45 细胞的增殖活力（P<0.01）;同时,100 μg/ml PJPS 处理后,可显著上调MKN45细胞中let-7a的表达 （P<0.01）。双荧光素酶报告基因实验证实CDK6是let-7a的靶基因。进一步实验显示,PJPS通过上调let-7a靶向抑制CDK6的表 达,从而抑制MKN45细胞的增殖并诱导其凋亡（均P<0.01）。结论：PJPS通过调控let-7a/CDK6分子轴抑制胃癌MKN45细胞的 增殖并诱导其凋亡。     

Molecular pathogenesis of bone metastases in breast cancer: Proven and emerging therapeutic targets

Metastatic occurrence is the principal cause of death in breast cancer patients. The high osteotropism makes breast cancer the most common primary tumor type associated with metastatic bone disease. The peculiar clinical aspects associated with metastases limited to the skeletal system suggest considering these cases as a distinctive subset of metastatic patients with a better prognosis. Because bone is frequently the first metastatic site in disease relapse, it is feasible that the next improvement in therapeutic options for bone metastatic disease could be associated with an improvement of survival expectation and quality of life in breast cancer patients. Study of the molecular basis of bone remodeling and breast cancer osteotropism has allowed identification of several therapeutic candidates involved in formation and progression of bone metastases. These targets are frequently the determinants of positive feedback between the tumor and bone cells whose clinical outcome is osteolytic lesions. In this review, we discuss the physiopathologic features underlying targeted therapeutic strategies aimed at interfering with the aberrant bone remodeling associated with breast cancer metastases.     

阻断Hh信号通路活性增敏Let-7抑制三阴性乳腺癌细胞增殖的作用及机制研究

目的:目的:探讨阻断Hh信号通路活性增敏Let-7抑制三阴性乳腺癌细胞增殖的作用及机制研究.方法:应用qRT-PCR和Western Blot、免疫组化(IHC)和免疫荧光(IF)在内的多种生物学实验方法,从临床标本及体外细胞实验的角度探究Let-7增敏TNBC的作用及可能与Hh信号通路的相关性.结果:阻断Hh信号通路降低了MDA-MB-231及BT-20细胞的增殖能力,并且增强了Let-7对三阴乳腺癌细胞系增殖能力的抑制作用.Let-7对MDA-MB-231及BT-20细胞内Cyclin D1水平的影响微弱,但是通过Hh通路的抑制剂环巴胺则有效的增强了Let-7对Cyclin D1的抑制作用,进一步在肿瘤干细胞样细胞亚群中,Hh通路抑制剂降低了MDA-MB-231及BT-20细胞系中ALDH1阳性干细胞亚群的比例,增强了Let-7对乳腺癌干细胞亚群自我更新能力的抑制作用.结论:Hh通路抑制剂通过对Cyclin D1的共抑制可以增强Let-7抑制三阴性乳腺癌细胞的增殖.     

Modulating microRNAs in cancer: next-generation therapies

MicroRNAs(miRNAs) are a class of endogenously expressed non-coding regulators of the genome with an ability to mediate a variety of biological and pathological processes. There is growing evidence demonstrating frequent dysregulation of micro RNAs in cancer cells, which is associated with tumor initiation, development, migration, invasion, resisting cell death, and drug resistance. Studies have shown that modulation of these small RNAs is a novel and promising therapeutic tool in the treatment o...     

let-7及其在肺癌中的作用

肺癌中let-7表达普遍降低,而多种癌基因表达升高.导入let-7对肺癌细胞生长有明显的抑制作用.let-7有可能成为很好的靶点或者强有力的介入工具,将有望应用于肺癌的早期诊断、预后判断及治疗.     

Advances in the application of Let-7 microRNAs in the diagnosis,treatment and prognosis of leukemia

The lethal-7 (Let-7) family of microRNAs (miRNAs) controls the process of development and differentiation, but is also related to the occurrence of tumors and a poor prognosis of patients with tumors. Thus, a more comprehensive exploration of its functions will provide further insights into these processes, and may promote the diagnosis and treatment of tumors. Leukemia is a type of progressive malignant disease, and its pathogenesis involves a variety of epigenetic factors. Amongst the several related epigenetic factors, the Let-7 miRNAs are an important family of molecules that play a crucial role in maintaining a variety of critical biological processes, including development, differentiation and proliferation. In the present study, the role of Let-7 as a tumor suppressor gene and oncogene is reviewed, and the complex regulatory functions of several Let-7 family members in different subtypes of leukemia are described. The current body of knowledge thus far indicates that Let-7 is not only a potential diagnostic and prognostic marker of leukemia, but also a potential therapeutic target for the treatment of affected patients, with particular potential when targeted by adjuvant treatments alongside traditional treatment to improve their survival rate.