TGFβ信号通路与肿瘤

TGFβ影响细胞的增殖和分化 ,在肿瘤发生与进展、细胞外基质形成和免疫调节等过程中发挥重要作用。TGFβ通过胞膜上的受体和胞内 Sm ads家族向核内传递信号 ,调控靶基因。肿瘤中的 TGFβ信号通路异常有其多样性和复杂性。近年来 ,TGFβ信号通路的研究取得了突破性进展 ,本文综述了恶性肿瘤中的 TGFβ信号通路的异常。     

miRNA对肝纤维化TGF-β/smad信号通路的影响

正肝纤维化由多种因素导致肝实质细胞坏死和胶原纤维异常沉积,以细胞外基质(extracellular matrix,ECM)的过量产生和沉积为主要表现,若不积极干预则有可能发展为肝硬化或肝癌。miRNA是一类具有调控功能的内源性非编码小分子RNA,参与许多疾病的发生发展过程,已有研究证实miRNA的异常表达与肝炎、肝硬化和恶性转化相关[1,2]。     

肿瘤干细胞与肿瘤靶向治疗

肿瘤干细胞(TSC)理论认为,肿瘤内部存在的一小部分具有干细胞特性的细胞,是肿瘤形成、生长、转移和复发的根源,只有靶向肿瘤干细胞的治疗才能使恶性肿瘤治愈.目前肿瘤的治疗只能杀死大部分已分化的肿瘤细胞,不能杀死肿瘤干细胞,造成了肿瘤治疗效果的不理想.扰乱维持肿瘤干细胞自我更新的信号通路和微环境;或诱导肿瘤干细胞的分化;或针对肿瘤干细胞所表达的区别于正常干细胞的表面标志的靶向治疗都是可行的策略.     

TGF-β信号通路与造血系统肿瘤

转化生长因子β(TGF-β)是造血细胞生长的负调控因子,TGF-β/SMAD信号途径在造血系统恶性肿瘤的发生中起到重要的作用,TGF-β表达及受体或受体后水平缺陷都可导致造血细胞的恶性增殖。深入研究该信号通路对于探寻造血系统恶性肿瘤的发病机制及开发以该通路环节为靶点的靶向治疗具有积极意义。     

WNT信号通路与肿瘤

WNT信号通路在肿瘤发生中有重要意义,它调节细胞生长、迁移和分化。由于它在众多人类肿瘤的发生中广泛活化,近年来这条通路在肿瘤研究方面受到很多关注。本文将介绍该通路与肿瘤发生的关系,以及目前该通路的研究在抗肿瘤治疗中的应用前景。     

肿瘤中雌激素信号转导通路的研究进展

雌激素（estrogen,E₂）可通过特异性结合并激活其受体传递信号,广泛调控机体的各种功能,如生殖功能、骨骼及其它组织的分化和维持等。雌激素受体属于核受体超家族,有3个亚类即雌激素受体α（estrogenreceptorα,ERα）、ERβ和最近发现的G蛋白偶联受体——GPR（G protein-coupled receptor）30/GPER（G protein-coupled estrogen receptor）。典型的ER作     

Wnt信号通路成员APC蛋白和β—catenin与肿瘤的关系

APC蛋白和β—catenin是Wnt信号通路β—catenin降解复合体的重要组分，在Wnt信号通路异常导致甲状腺肿瘤的发生中，它们发挥重要的作用。     

ATM信号通路与肿瘤的发展及治疗

人类ATM基因位于染色体11q22.3,研究发现其编码产物ATM参与多个信号通路,如氧化应激条件下死亡受体诱导的凋亡通路、受体酪氨酸激酶通路、代谢相关通路、缺氧与血管生成相关通路等.这些通路与肿瘤的发生发展以及治疗密切相关.由于ATM的突变往往会增加罹患肿瘤的风险,在过去的二十年中ATM逐渐成为了研究的热点.本文就ATM与肿瘤发生发展以及治疗的研究进展进行综述.     

内皮-单核细胞激活多肽-Ⅱ增强血肿瘤屏障通透性的信号通路

目的探索内皮-单核细胞激活多肽-Ⅱ(EMAP-Ⅱ)增强血肿瘤屏障(BTB)通透性的可能信号通路。方法荷瘤Wistar大鼠被随机分成3组(每组10只):对照组、EMAP-Ⅱ组和H7+EMAP-Ⅱ组。采用Western blot法检测脑微血管内皮细胞上紧密连接蛋白ZO-1和磷酸化肌球蛋白轻链(pMLC)的表达水平变化,免疫荧光法检测ZO-1和肌动蛋白F-actin的分布与表达水平变化。结果与对照组相比,EMAP-Ⅱ组脑微血管内皮细胞上ZO-1和F-actin的表达水平显著降低,pMLC的表达水平显著增高;EMAP-Ⅱ的上述作用受到蛋白激酶C(PKC)抑制剂H7预处理的显著抑制。结论 PKC-pMLC信号通路参与调控EMAP-Ⅱ增加BTB通透性的过程。     

Wnt信号通路成员APC蛋白和β-Catenin与肿瘤的关系

APC蛋白和β- catenin是 Wnt信号通路β- catenin降解复合体的重要组分 ,在 Wnt信号通路异常导致甲状腺肿瘤的发生中 ,它们发挥重要的作用     

Role of miRNAs in immune responses and immunotherapy in cancer

In the past decade, the study of mechanisms of cancer immunity has seen a prominent boom, which paralleled the increased amount of research on the clinical efficacy of immune checkpoint blockade in several lethal types of cancers. This conspicuous effort has led to the development of successful immunotherapy treatment strategies, whose medical impact has been recognized by the awarding of 2018 Nobel Prize in Physiology or Medicine to the two pioneers of check point inhibitor research, Tasuku Honjo and James Allison. Despite these promising achievements, the differences in the clinical response rate in different cancer patients and the high risk of toxicity of immune‐based therapies represent crucial challenges. More remarkably, the causes responsible for different outcome (success vs failure) in patients with tumor having same histotype and clinical characteristics remain mostly unknown. MicroRNAs (miRNAs), small regulatory noncoding RNA molecules representing the most studied component of the dark matter of the human genome, are involved in the regulation of many pathways of cancer and immune cells. Therefore, understanding the role of miRNAs in controlling cancer immunity is necessary, as it can contribute to reveal mechanisms that can be modulated to improve the success of immunetherapy in cancer patients. Here, we discuss the latest findings on immune pathways regulated by miRNAs in cancer, miRNA‐mediated regulation of immune cells in the tumor microenvironment, and miRNAs as potential target for immunotherapies.     

结直肠癌发生发展中miRNAs机制的研究进展

microRNhs(miRNAs)是在动植物和病毒中发现的一个非编码单链小RNA,在肿瘤的发生和发展中起重要作用.目前认为,miRNAs对肿瘤的调控属于表观遗传学范畴.近年来,众多研究者开始关注人类结直肠癌的miRNAs表达谱,并深入探究miRNAs所处的调节网络.作者综述了有关结直肠癌miRNAs表达异常及作用机制的最新研究,以期为结直肠癌表观遗传学干预找到新的切入点.     

Tumour angiogenesis and c-Met pathway activation – implications in breast cancer

Breast cancer is a heterogeneous disease with wide range of clinical behaviour. Tumour angiogenesis and metastasis have been considered as prognostic markers of the breast carcinoma, and c-Met, a transmembrane receptor tyrosine kinase has been implicated in both these processes of tumour progression. This study was conducted to elucidate c-Met and downstream signalling pathways in breast cancer and correlate with angiogenesis as assessed by microvessel density (MVD) and other prognostic parameters including lymph node metastases. Microvessel density (MVD) was assessed by endothelial cell (CD34) marker in breast cancers. c-Met was evaluated by immunohistochemistry for protein expression and by copy number assay for amplification at gene level. PCR array for gene expression related to c-Met, RAS-MAPK, PI3K-AKT and angiogenesis pathway was performed by real-time PCR. c-Met protein, copy number and mRNA expression did not differ significantly with the lymph node status or MVD. However, Her-2 overexpressing group showed c-Met protein overexpression and amplification. c-Met protein overexpression was also noted in the Luminal B subtype though no amplification was noted. Thus, the c-Met immunohistochemistry score and the c-MET copy numbers did not correlate with each other. c-Met downstream pathway genes (RAS-MAPK, PI3K-AKT and angiogenesis pathway) showed significant upregulation in Luminal B molecular subtype, lymph node-positive cases and cases with high MVD. The downstream signalling pathways (angiogenesis, RAS-MAPK and PI3K-AKT) were associated high MVD, lymph node metastases, and Her-2 and Luminal B subtype. Since inhibitors of these pathways are commercially available, these can be of therapeutic significance.     

27-羟基胆固醇激活LXR信号通路调节肺癌细胞的增殖

目的:探讨胆固醇代谢产物27-羟基胆固醇(27-OHC)对肺癌细胞增殖的影响。方法:采用不同浓度(0、0.3125、0.625、1.25、2.5、5和10μmol/L)的27-OHC处理人肺癌A549细胞24～48 h,随后使用细胞计数试剂盒(CCK-8法)评估细胞活力,采用流式细胞术检测细胞周期,Ed U实验检测细胞增殖状况,采用总胆固醇检测试剂盒检测细胞内胆固醇水平,real-time PCR及Western blot法分别检测胆固醇代谢相关分子的表达。结果:27-OHC以剂量和时间依赖性显著降低A549肺癌细胞的活力(P 0.01),抑制细胞增殖(P 0.05)。27-OHC通过上调肝X受体(LXR)信号通路下游靶蛋白ATP结合盒转运蛋白A1(ABCA1)的表达,促进细胞内胆固醇的外排,同时下调低密度脂蛋白受体(LDLR)和3-羟基-3-甲基戊二酰辅酶A还原酶(HMG-CR)的表达,减少胆固醇的摄入和从头合成,导致细胞内胆固醇水平降低,细胞活力下降(P 0.01)。此外,LXR通路被5μmol/L GSK2033部分阻断后,27-OHC对A549细胞活力的抑制作用显著减弱(P 0.05)。结论:27-OHC通过激活LXR通路抑制A549细胞增殖。     

前列腺癌组织中miRNAs的表达及意义

目的研究前列腺癌组织中6种miRNAs的表达及其意义,并探讨它们在前列腺癌诊断中的应用价值。方法采用核酸分子原位杂交(in situ hybridizationI,SH)技术,结合组织微阵列平台分别检测38例良性前列腺增生(benign prostate hyperpla-sia,BPH)和52例前列腺癌(prostatic cancer,PCa)中6种miRNAs的表达情况。结果 6种miRNAs在PCa中的表达率与BPH比较差异均有统计学意义(P<0.05)。6种miRNAs的表达均与PCa的Gleason评分相关(P<0.05);与患者的年龄及血清PSA水平均无明显相关性(P>0.05)。miR-15b、miR-182和miR-96的表达与PCa的临床分期相关(P<0.05);miR-96的表达与肿瘤累及前列腺叶数相关(P<0.05)。结论 miRNAs与PCa的发生、发展以及生物学行为有关,并可能作为PCa诊断及判断预后的生物标记物。     

The role of microRNAs during the genesis of medulloblastomas induced by the hedgehog pathway

Constitutive hedgehog (Hh) signaling is associated with the genesis of medulloblastomas (MB). The objective of this study is to identify special microRNAs (miRNAs) regulated by the Hh pathway, and to clarify the role of miRNAs during the genesis of MB induced by sustained Hh activation. In the primary screening, we used stemloop RT-PCR to test the expression of 90 different miRNAs in the wildtype (WT) and Ptc-/- MEF cell lines. In the secondary screening, the miRNAs screened from the first screening were validated in the Sufu-/- MEF cell lines. We then verified the expression of miRNAs both in the normal cerebellar tissues and the MB induced by activated Hh pathway, and examined the expression of the other 21 miRNA members of the miR-154 cluster in the MB and normal cerebellum. In the first screening, 13 miRNAs showed significant differential expression in WT and Ptc-/- MEF cell lines, while 10 of them had significant difference in the Sufu-/- MEF cell line. Compared to the normal mouse cerebellum, only 2 miRNAs in 15 miRNAs were differentially expressed between the MB and normal cerebellar tissues. Among 21 members of the miR-154 cluster, 6 miRNAs were downregulated in the MB. Our study demonstrated that miR-154 may be regulated by the Hh pathway, and the activation of the Hh pathway led to the downregulation of the miR-154 cluster, resulting in the genesis of MB.     

泛素-蛋白酶体途径降解胰腺癌细胞系中凝溶胶蛋白

目的 探讨胰腺癌中泛素-蛋白酶体途径对凝溶胶蛋白(gelsolin)的降解作用.方法 用特异性蛋白酶体抑制剂lactacystin处理胰腺癌细胞系BxPC-3和PANC-1,经Westem blot检测凝溶胶蛋白的表达,免疫沉淀细胞内凝溶胶蛋白,分析沉淀蛋白的泛素化.结果 BxPC-3细胞系经lactacystin作用12 h后,细胞内凝溶胶蛋白含量较对照组和处理前明显升高(P＜0.05),而且细胞内的凝溶胶蛋白表现出与泛素分子的相互作用.结论 泛素-蛋白酶体途径对凝溶胶蛋白的降解作用,可能是胰腺癌中凝溶胶蛋白表达降低的原因之一.     

肝内及肝外胆管癌表达下调microRNAs表达谱的鉴定

目的筛选并鉴定肝内及肝外胆管癌组织表达下调的miRNAs,进行初步的功能研究。方法利用miRNA-基因芯片方法筛选肝内、肝外胆管癌组织特异表达下调或共同表达下调的miRNAs,选择real-time PCR方法进行验证;根据肝内及肝外胆管癌不同的下调miRNAs表达谱,选择差异明显且具有代表性的miRNAs,利用miRNA特异模拟物转染胆管癌细胞系QBC939,利用MTT试剂盒分析细胞增殖变化,研究表达下调miRNAs与胆管癌细胞增殖的关系。结果表达分析显示,肝外胆管癌组织特异表达下调的miRNAs共25个,肝内胆管癌组织特异表达下调的miRNAs共15个,在肝内及肝外胆管癌组织均表达下调的miRNAs共6个。在胆管癌细胞系QBC939中分别过表达miR-181a、miR-596、miR-492以及miR-602可以明显抑制细胞增殖。结论肝内及肝外胆管癌具有不同的miRNAs表达谱,表达下调的miRNAs可以明显抑制胆管癌细胞增殖。