表观遗传学与子宫内膜癌的研究进展

长期以来人们一直认为基因突变或缺失参与肿瘤的形成,近年来越来越多证据表明,表观遗传修饰在肿瘤进展中同样具有非常重要的作用。DNA甲基化、组蛋白修饰及microRNA表达调控等表观遗传机制是子宫内膜癌发生、发展的重要原因之一。表观遗传学的研究进展不仅有助于子宫内膜癌的早期诊断,对分子靶向治疗子宫内膜癌亦显示出良好的应用前景。     

子宫内膜癌的临床诊断、形成机理及临床治疗

子宫内膜癌是妇科生殖道肿瘤中最常见的癌症,每年每10万妇女中就有15～25位子宫内膜癌患者.子宫内膜癌(Endometrial cancer)是指源自子宫内膜的癌症,其病因是由于细胞的异常生长,并且具有了能够侵袭或扩散到身体其他部位的能力.子宫内膜癌最常发生在更年期之后,组织病理学上最常见的子宫内膜癌属于恶性子宫内膜上皮癌,其比例超过80％.约20％左右的子宫内膜癌与肥胖相关.子宫内膜癌一般通过子宫内膜刮除术,取得子宫内膜的活体组织进行诊断.目前的治疗以手术移除子宫为主,早期发现并接受治疗的子宫内膜癌预后较好.     

表观遗传学与子宫内膜癌的研究进展

长期以来人们一直认为基因突变或缺失参与肿瘤的形成,近年来越来越多证据表明,表观遗传修饰在肿瘤进展中同样具有非常重要的作用。DNA甲基化、组蛋白修饰及micro RNA表达调控等表观遗传机制是子宫内膜癌发生、发展的重要原因之一。表观遗传学的研究进展不仅有助于子宫内膜癌的早期诊断,对分子靶向治疗子宫内膜癌亦显示出良好的应用前景。     

抑癌基因PTEN及其假基因PTENP1在子宫内膜癌中的研究进展

子宫内膜癌的发病率在逐年上升,引起了人们的广泛关注,但其发病的分子遗传学机制仍不十分清楚。近年来基因改变致癌的研究成为热点。国内外研究报道发现：PTEN（与张力蛋白同源第10染色体丢失的磷酸酶基因）是目前已知的子宫内膜癌中突变率最高的基因,常发生在子宫内膜癌的早期,对其突变的检测有助于子宫内膜癌的早期诊断、治疗及预后评价,并为子宫内膜癌的基因治疗提供了新的靶点。另外,研究发现,PTENP1（PTEN的假基因）转录调控PTEN的表达,被认为与一些肿瘤的发生有关。本文就PTEN基因的结构、功能及在子宫内膜癌中的突变情况、临床意义及PTENP1的研究现状进行综述。     

胰腺癌相关肿瘤标志物研究进展

胰腺癌起病隐匿,进展快,预后差,发病率约等于死亡率。胰腺癌死亡率高的原因有发病机制不明,缺乏有效的早期诊断和预后的肿瘤标志物,进展期相关治疗效果不理想。近年来在血清标志物、基因标志物、表观遗传学标志物等分子生物技术及生物信息学方面的发展为胰腺癌的诊断,尤其是早期诊断、评估预后和监测早期复发提供了新的途径。本文就近期胰腺癌相关肿瘤标志物的研究进展作一综述。     

S100A4在子宫内膜癌中的表达及其临床病理意义

目的:检测S100A4在子宫内膜癌中的表达并分析其与子宫内膜癌临床病理指标的相关性,为子宫内膜癌的临床诊断、治疗及与预后预测提供参考依据。方法:采用免疫组织化学技术检测比较70例子宫内膜癌和40例正常子宫内膜组织中S100A4的表达,并分析子宫内膜癌组织中S100A4的表达与患者临床病理指标和生存期的相关性。结果:70例子宫内膜癌组织中S100A4的阳性表达率为57.14%(40/70),40例正常子宫内膜组织中S100A4的阳性表达率为10%(4/40),显著低于子宫内膜癌组织(P0.05)。子宫内膜癌组织中S100A4的表达与患者的年龄和淋巴结转移无显著相关,但与肿块浸润子宫肌壁深度、分化程度、临床分期均呈显著相关(P0.05)。S100A4呈阳性表达的子宫内膜癌患者的生存率和生存期均较S100A4呈阴性表达病例显著降低或缩短(P=0.01)。结论:子宫内膜癌组织中S100A4呈异常高表达,与子宫内膜癌的发生发展和预后密切相关,可能作为子宫内膜癌诊断和预后预测的参考标志物。     

MIF和CerbB-2在子宫内膜癌中的表达及临床意义

目的:探讨MIF和Cerb B-2的表达与子宫内膜癌的关系,进一步探讨其表达与子宫内膜癌的发生、发展的关系,为早期诊断子宫内膜癌,判断预后和寻找子宫内膜癌的新的治疗方法奠定基础。方法:应用实时荧光定量RT-PCR和免疫组织化学技术检测正常子宫内膜、不典型增生和子宫内膜癌组织中MIF m RNA、Cerb B-2 m RNA和MIF蛋白、Cerb B-2蛋白的表达,其中免疫组化中子宫内膜癌组根据临床病理特征,如年龄,临床分期,组织学分级,肌层浸润深度和有无淋巴结转移进行分组。结果:正常子宫内膜、不典型增生内膜和子宫内膜癌组织中都有MIF和Cerb B-2的表达,子宫内膜癌中MIF m RNA和Cerb B-2 m RNA扩增含量显示高水平,其阳性表达率随着病变程度的加重而逐渐升高,差异具有统计学意义(P=0.037);MIF主要表达于子宫内膜腺上皮的细胞质中,少量表达于细胞质,在阳性表达的子宫内膜癌组织中,蛋白含量在I期(P=0.033)、G1期(P=0.034)、无淋巴结转移的组织中水平较高(P=0.041),差异具有统计学意义。Cerb B-2蛋白主要表达在子宫内膜的细胞质,少量在细胞膜中表达,阳性表达率子宫内膜癌不典型增生正常子宫内膜,差异具有统计学意义(P=0.013);Cerb B-2蛋白在III-IV(P=0.009)、G2-3期(P=0.033),有淋巴结转移(P=0.018)的子宫内膜癌中表达含量较高,与年龄和肌层浸润深度无关。结论:MIF和Cerb B-2在正常子宫内膜、不典型增生和子宫内膜癌中都有表达,提示着MIF和Cerb B-2与子宫内膜癌的发生和发展有关,MIF在子宫内膜癌的早期表达含量较高,可以作为子宫内膜癌的早期诊断指标,Cerb B-2在子宫内膜癌的晚期表达含量较高,可以促进肿瘤的侵袭转移,可作为判断疾病的严重程度和预后的指标之一。     

波形蛋白的表达与子宫内膜癌患者术后预后的关系

目的:检测子宫内膜癌组织中波形蛋白的表达。方法:用免疫组化SP法检测173例子宫内膜癌组织中波形蛋白的表达,分析波形蛋白的表达与子宫内膜癌患者临床病例特征及预后的关系,使用探讨其表达与子宫内膜癌的病理特征及患者术后预后的关系Kaplan-Meier法计算手术后患者的总体生存率和无复发生率,采用Cox比例风险模型检验进行单因素和多因素预后分析,应用ROC曲线分析波形蛋白的表达对子宫内膜癌患者预后及术后复发或转移的诊断效能。结果:所有患者子宫内膜癌组织中波形蛋白表达的总阳性率达71.10%。Cox比例风险模型显示病理类型、组织学分级和波形蛋白表达(均有P0.001)是患者的总体生存的独立危险因素,肿瘤FIGO分期(P=0.014)、病理类型(P0.001)、组织学分级(P=0.045)、淋巴结转移(P0.001)和波形蛋白表达(P0.001)是患者的无复发生存的独立危险因素。ROC曲线分析的结果表明波形蛋白的表达预测肿瘤的生存和复发的ROC曲线下面积分别为0.887、0.796。结论:子宫内膜癌患者癌组织波形蛋白表达显著上调,与患者术后生存和复发密切相关,可能作为预测子宫内膜癌患者预后的有效参考指标。     

糖抗原sTn是Ⅰ型子宫内膜癌的新型标记物

Sialyl-Tn(sTn)是肿瘤相关糖抗原的一种,在多种上皮来源的肿瘤组织中都存在sTn的过表达．但是,关于sTn在子宫内膜癌中的表达情况目前研究得很少,而且仅有的报道也互相矛盾．为了阐明这一问题,我们选取了111例临床样本,其中包括82例子宫内膜癌,16例非典型增生内膜,13例正常内膜,利用免疫组化的方法分析了sTn的表达情况．结果表明,sTn在子宫内膜癌中高表达,但仅限于Ⅰ型子宫内膜癌(80%),而在Ⅱ型子宫内膜癌中表达率仅为45%,二者具有显著性差异(P < 0.05)．这是我们首次报道sTn特异性与Ⅰ型子宫内膜癌相关,有利于解释过去前后不一的矛盾结果．在非典型组织中,sTn的表达率较正常组织高,分别为31%(正常组织)和44%(非典型组织)．这说明sTn参与了子宫内膜癌的发生发展．同时,我们的结果表明,sTn的表达与肿瘤的组织分级具有相关性,其在高、中分化的肿瘤组织中表达率明显高于低分化的肿瘤组织．这预示着sTn可能与子宫内膜癌的良好预后相关．我们的研究为诊断Ⅰ型子宫内膜癌提供了一个新的标记物和诊断试剂,同时提示我们,将来对于子宫内膜癌的研究,有必要对Ⅰ型子宫内膜癌和Ⅱ型子宫内膜癌区别对待．     

胸苷激酶1在恶性肿瘤中的作用

目前恶性肿瘤在人群的发病率逐渐上升,严重威胁着人类的健康。许多恶性肿瘤患者早期无特异性的临床表现,检查确诊时肿瘤已处于中晚期,治疗效果及预后较差,因此对于恶性肿瘤的早期诊断刻不容缓。随着目前对于血清中肿瘤标志物的研究的深入开展,一种新的细胞增殖标志物,即胸苷激酶1(thymidine kinase 1, TK1),已被证实在肿瘤的早期诊断、治疗效果评估及预后的判断等方面具有重要作用。本文就胸苷激酶1的结构、功能、作用机制以及在恶性肿瘤中的研究进展等进行综述。     

Stem cells: are they the answer to the puzzling etiology of endometriosis?

Endometriosis is a chronic benign disease characterized by the presence of abnormally located tissue resembling the endometrium with glands and stroma. This disease has a high degree of morbidity due to chronic pelvic pain and infertility. The disease is likely to be polygenic and multifactorial, but the exact pathogenic mechanisms are still not entirely clear. Recently, adult stem cells have been identified in several tissues, including the endometrium. These cells are probably involved in the regenerative ability of the endometrial cycle, and also in the pathogenesis of proliferative gynaecological diseases, such as endometriosis. The identification of stem cells in animal and human tissues is very complex and the putative stem cells are supposed to be found through several assays such as clonogenicity, label-retaining cells, "side-population" cells, undifferentiation markers, and cellular differentiation. Bone marrow-derived stem cells transplanted into humans and animals have also been identified in eutopic endometrium and endometriotic implants. This review evaluates the available evidence regarding stem/progenitor cells in the human endometrium and explores the possible involvement of these cells in the etiology of endometriosis.     

Aromatase and comparative response to its inhibitors in two types of endometrial cancer

Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p = 0.02). Although no positive correlation was revealed between AA in EC tissue and percentage of cells with DNA damage in normal endometrium from the same patients, the rate of DNA damage (percent of comets, comet's tail average length, etc.) was higher in intact endometrium collected from patients with type II of the disease. In 19 tumor samples, CYP19 gene expression was evaluated by RT-PCR and level of mRNA signal demonstrated positive correlation with AA (R_s = +0.63, p = 0.05) in the whole this material. Of note, though, CYP19 mRNA expression was not revealed in six cases, and all of them belonged to the type I of disease. Finally, in 23 EC patients (15 with type I and 8 with type II of the disease) effects of 2 weeks treatment with letrozole (10 pts) and exemestane (13 pts) were evaluated in neoadjuvant setting. Although diminishing of endometrial M-echo signal and the increases in FSH and LH concentration after treatment were more pronounced in type I patients, decrease in tumor PR content (p = 0.04) was more revealing in patients with type II of EC; besides, the decreases in AA in tumor tissue by the end of treatment were noted predominantly in patients with lower body weight (BMI <27.5). Thus, although type II of EC is frequently considered as hormone-independent, increased ability of this type of the tumor to estrogen biosynthesis (at CYP19 gene and protein level) may lead to the reconsideration of such conclusion and warrants further investigation. The search of possible ethnic differences in AA and in the biologic response to aromatase inhibitors in EC can be of importance too.     

上皮间质转化标记物及Snail在子宫内膜异位症中的表达

目的:研究上皮间质转化标志物(E-cadherin、β-catenin、vimentin)和Snail在子宫内膜异位症(endometriosis,EMs)中的表达。方法:选取40例EMs患者(实验组)异位内膜及在位内膜,同时获取20例非EMs患者(对照组)的正常子宫内膜,采用免疫组化法研究Snail、EMT上皮标志物(E-cadherin、β-catenin)、间质标志物(vimentin)在各内膜组织中的表达,并比较其表达水平。结果:EMs患者异位内膜和在位内膜的EMT上皮标志物E-cadherin、β-catenin表达均显著低于正常内膜的表达(P0.05);EMs患者异位内膜和在位内膜的EMT间质标志物vimentin表达均显著高于正常内膜的表达(P0.05);EMs患者异位内膜和在位内膜中Snail表达显著高于正常内膜的表达(P0.05)。结论:在子宫内膜异位症(EMs)中,Snail、vimentin表达上调,E-cadherin、β-catenin表达下调可能与子宫内膜异位症(EMs)的发生、发展及浸润转移有关。     

Estrogens,MSI and Lynch syndrome-associated tumors

Estrogens play a major role in the biology of hormone-responsive tissues but also in the normal physiology of various non-typical hormone-responsive tissues. In disease, estrogens have been associated with tumor development, in particular with tumors such as breast, endometrium, ovary and prostate.     

Implementing biological markers as a tool to guide clinical care of patients with pancreatic cancer

A major obstacle for the effective treatment of pancreatic ductal adenocarcinoma (PDAC) is its molecular heterogeneity, reflected by the diverse clinical outcomes and responses to therapies that occur. The tumors of patients with PDAC must therefore be closely examined and classified before treatment initiation in order to predict the natural evolution of the disease and the response to therapy. To stratify patients, it is absolutely necessary to identify biological markers that are highly specific and reproducible, and easily measurable by inexpensive sensitive techniques. Several promising strategies to find biomarkers are already available or under development, such as the use of liquid biopsies to detect circulating tumor cells, circulating free DNA, methylated DNA, circulating RNA, and exosomes and extracellular vesicles, as well as immunological markers and molecular markers. Such biomarkers are capable of classifying patients with PDAC and predicting their therapeutic sensitivity. Interestingly, developing chemograms using primary cell lines or organoids and analyzing the resulting high-throughput data via artificial intelligence would be highly beneficial to patients. How can exploiting these biomarkers benefit patients with resectable, borderline resectable, locally advanced, and metastatic PDAC? In fact, the utility of these biomarkers depends on the patient''s clinical situation. At the early stages of the disease, the clinician''s priority lies in rapid diagnosis, so that the patient receives surgery without delay; at advanced disease stages, where therapeutic possibilities are severely limited, the priority is to determine the PDAC tumor subtype so as to estimate the clinical outcome and select a suitable effective treatment.     

伊立替康联合阿帕替尼治疗术后转移性胃癌患者临床疗效和安全性分析

摘要 目的：探讨伊立替康联合阿帕替尼治疗术后转移性胃癌患者临床疗效和安全性。方法：选取我院2017年5月-2018年10月期间收治的术后一线化疗失败转移性胃癌患者105例,根据随机数字表法分为研究组（53例）和对照组（52例）,对照组患者给予伊立替康静脉滴注治疗,研究组在此基础上使用阿帕替尼进行联合治疗,4周为一个周期,连续治疗两个周期。比较两组患者疾病控制率、生存情况,并对治疗前后两组患者肿瘤标志物[癌胚抗原（CEA）、糖类抗原125（CA125）和糖类抗原199（CA199）]水平、基质金属蛋白酶-9（MMP-9）和血管内皮生长因子（VEGF）水平进行比较,观察治疗过程中两组患者不良反应发生情况。结果：治疗后,研究组疾病控制率、中位生存时间和中位进展时间均优于对照组（P<0.05）。治疗后,两组肿瘤标志物、MMP-9和VEGF水平均降低,且研究组低于对照组（P<0.05）。研究组不良反应发生率低于对照组（P<0.05）。结论：伊立替康联合阿帕替尼治疗术后转移性胃癌患者临床疗效确切,可延长患者生存时间,延缓疾病进展,且安全性较好,其作用机制可能与降低肿瘤标志物及MMP-9、VEGF水平有关。     

Serum markers in small cell lung cancer: Opportunities for improvement

Lung cancer is one of the leading causes of death from malignancy worldwide. In particular small cell lung cancers, which comprise about 15–20% of all lung cancers, are extremely aggressive and cure rates are extremely low. Therefore, new treatment modalities are needed and detection at an early stage of disease, as well as adequate monitoring of treatment response is essential in order to improve outcome. In this respect, the use of non-invasive tools for screening and monitoring has gained increasing interest and the clinical applicability of reliable, tumor-related substances that can be detected as tumor markers in easily accessible body fluids is subject of intense investigation. Some of these indicators, such as high LDH levels in serum as a reflection of the disease, have been in use for a long time as a general tumor marker. To allow for improved monitoring of the efficacy of new therapeutic modalities and for accurate subtyping, there is a strong need for specific and sensitive markers that are more directly related to the biology and behavior of small cell lung cancer. In this review the current status of these potential markers, like CEA, NSE, ProGRP, CK-BB, SCC, CgA, NCAM and several cytokeratins will be critically analyzed with respect to their performance in blood based assays. Based on known cleavage sites for cytoplasmic and extracellular proteases, a prediction of stable fragments can be obtained and used for optimal test design. Furthermore, insight into the synthesis of specific splice variants and neo-epitopes resulting from protein modification and cleavage, offers further opportunities for improvement of tumor assays.     

人组织激肽释放酶4在激素依赖性肿瘤中的研究进展

人组织激肽释放酶基因家族由KLK1-KLK15构成,编码一组丝氨酸蛋白酶。研究发现KLK基因家族涉及癌细胞的多种生物学功能,且其表达受类固醇激素的调节。人组织激肽释放酶4是丝氨酸蛋白酶家族的一个成员,在多种激素依赖性肿瘤如卵巢癌、前列腺癌、乳腺癌、子宫内膜癌中高表达,且表达量受雌激素、孕激素、雄激素不同程度的调节。近年来很多文献报道人组织激肽释放酶4涉及癌细胞的增殖、上皮间质转化及细胞外基质的降解等过程,可能促进了肿瘤的发生、发展,且与激素依赖性肿瘤的预后不良有关。这些研究显示人组织激肽释放酶4与激素依赖性肿瘤关系密切,是其潜在的肿瘤标记物和治疗靶点,随着研究的进一步深入,有望应用于激素依赖性肿瘤的早期诊断、病程监测和治疗。