细胞角蛋白8与肿瘤

细胞角蛋白8（CK8）是一种中间丝蛋白,属于细胞骨架蛋白家族.研究表明,CK8表达或翻译后修饰异常将影响其活性,是相关肿瘤发生发展的重要原因之一.对CK8在肿瘤发生发展中作用的深入研究,可以为肿瘤的预防及治疗提供帮助.     

细胞角蛋白8与肿瘤

细胞角蛋白8(CK8)是一种中间丝蛋白,属于细胞骨架蛋白家族.研究表明,CK8表达或翻译后修饰异常将影响其活性,是相关肿瘤发生发展的重要原因之一.对CK8在肿瘤发生发展中作用的深入研究,可以为肿瘤的预防及治疗提供帮助.     

钙结合蛋白S100家族成员与肿瘤的关系

肿瘤是体细胞自律性、无目的过度增殖.S100蛋白家族是钙结合蛋白中最大的亚族之一,拥有20余个成员,包括S100A1-A5、S100B、S100P等.因可在中性饱和硫酸铵溶液中100％溶解而得名.S100蛋白通过改变Ca2＋浓度而影响蛋白磷酸化,从而作用于某些离子通道及神经电生理过程.尽管众多研究已经报道了一些成员的物理性质、功能及表达,但对其他成员知之甚少.研究发现S100蛋白参与一些生物过程,如细胞周期调控、细胞生长、分化和胞外活动.许多报道认为S100蛋白在大量肿瘤中高表达,与肿瘤细胞的增值、浸润及疾病的发展密切相关.本文对近年国内外S100蛋白与肿瘤发生、发展的关系研究进行综述.     

高迁移率族蛋白N在肿瘤中的研究进展

高迁移率族蛋白N(HMGN)是细胞内普遍存在的一类核蛋白,属于高迁移率族蛋白家族.它们能直接与DNA和核小体结合,诱导染色质纤维结构的改变,进而影响细胞内转录、细胞分化过程和细胞对受损DNA的修复能力.肿瘤的发生与累积突变导致的转录异常密切相关,转录异常促使肿瘤细胞得以逃脱细胞周期的严密调控.研究显示,HMGN可以通过参与细胞周期调节及影响肿瘤细胞的生物学行为等方式,在肿瘤发生发展中发挥重要作用.     

Pygopus蛋白及其与肿瘤相关研究进展

Pygopus蛋白是2002年在Wnt信号通路β-环连蛋白(β-catenin)下游发现的新功能蛋白.目前发现其具有调控组织发育、转录共激活及染色质重塑作用,并且与多种恶性肿瘤有密切关系.了解Pygopus蛋白在生长发育中的作用及肿瘤调控中的机制对认识肿瘤发生和演进、临床诊断及治疗有十分重要的意义.     

S100蛋白家族成员与肿瘤关系的研究进展

侵袭和转移是恶性肿瘤的标志,是肿瘤细胞和周围正常组织相互作用的结果.钙离子结合蛋白S100蛋白家族在肿瘤发生发展中起着重要作用,S100成员至少有20个,其中很多成员都与肿瘤有关.本文对近年来国内外S100与肿瘤发生、发展的关系研究进展进行简要综述.     

C-反应蛋白在肾癌预后评价中的意义

越来越多的证据显示炎症在肿瘤发生发展过程中扮演了极其重要的角色.C-反应蛋白（CRP）作为最具代表性的炎症反应指标,被认为与肾癌等多种肿瘤的预后密切相关.许多研究表明,CRP可以为实施手术、细胞因子治疗和分子靶向治疗的肾癌患者提供有价值的预后信息,并且已有预后模型将CRP纳入其中应用于患者的预后评估.     

FLIP:抗癌靶向治疗的新位点

肿瘤细胞过度表达凋亡抑制蛋白而耐受凋亡是肿瘤发生、发展的标志之一.最近的研究表明FLIP是一种重要的凋亡抑制蛋白,在许多不同类型的肿瘤细胞FLIP过度表达.c-FLIP过度表达抑制死亡配体如FasL和TRAIL与 DISC的结合而抑制caspase-8的活化,从而阻止肿瘤细胞凋亡,同时c-FLIP的下游调节能敏化肿瘤细胞的凋亡.所以,从mRNA和蛋白水平研究FLIP,能为今后开发靶向抗癌药物和肿瘤治疗提供新的方法和思路.     

泛素连接酶Pirh2与恶性肿瘤相关性的研究进展

泛素连接酶Pirh2(p53-induced RING-H2 protein)是一种具有E3连接酶活性的新蛋白,能促进p53发生泛素化而降解,从而使p53抑制肿瘤生长的功能减弱或消失,导致肿瘤发生和进一步恶化。近年来研究发现,多种恶性肿瘤中Pirh2蛋白的表达量有明显变化,这提示Pirh2在恶性肿瘤的发生、发展中可能具有重要的作用;Pirh2可能作为一个癌基因,在肿瘤发生过程中调节一些信号转导通路。因此,推测Pirh2可作为肿瘤基因治疗的一个潜在靶点。本文就Pirh2与恶性肿瘤相关性的最新研究进展作一简要综述。     

肿瘤研究中的蛋白质组学研究策略

 众所周知，基因表达调控存在严格的时空特异性，其表达产物mRNA由于存在贮存、转运、降解、翻译调控及产物的翻译后加工，难以准确地反映蛋白质的质与量。恶性肿瘤是由环境与遗传因素相互作用而导致的一种多基因复杂疾病，严重危害人类生命健康。蛋白质组学研究直接从生物功能的执行体——蛋白质人手，能够动态、整体地考察肿瘤发生、发展过程中蛋白质种类、数量的改变，从而能够在整体水平上发掘肿瘤发病机制、肿瘤分类、早期诊断、预后判断的蛋白标志物，并寻求潜在药靶。     

CK8/18 expression, the basal phenotype, and family history in identifying BRCA1-associated breast cancer in the Ontario site of the breast cancer family registry

BACKGROUND.

BRCA1‐associated breast cancer had been shown to be morphologically and genetically distinct from sporadic cancers. The aim of this study was to determine the association of CK8/18 with BRCA1‐associated tumors and if, by using CK8/18 and basal biomarkers in conjunction with morphologic features and family history characteristics, the specificity of the BRCA1‐associated tumor profile in a pathologically well‐characterized cohort would be improved.

METHODS.

Fifty‐eight patients with known BRCA1 germline mutations and 221 control (familial non‐BRCA) patients were selected from the Ontario Familial Breast Cancer Registry. From this database, information on family history and morphologic features was abstracted. Tissue microarrays were constructed and immunohistochemistry to determine expression of several biomarkers was performed. After a logistic regression fit, a best‐subsets variable‐selection procedure using model performance and predictive ability measures was applied to find a best predictor to distinguish BRCA1‐associated tumors from non‐BRCA associated tumors.

RESULTS.

BRCA1‐associated tumors differed significantly from control tumors in terms of morphology, family history, and biomarker profile. CK8/18 was highly significantly associated with BRCA1 tumors. Consistently, BRCA1 cancers showed low levels of CK8/18 compared to non‐BRCA tumors, whether they were basal‐like or not. A combination of 7 factors, including CK8/18 and family history, best predicted the BRCA1‐associated cancers.

CONCLUSIONS.

CK8/18 expression was independently associated with BRCA1‐associated breast cancers. Reduced CK8/18 expression in conjunction with the basal‐like phenotype and family history may have improved the ability to identify which tumors were likely to be associated with a BRCA1 germline mutation and thereby help streamline genetic testing. Cancer 2011. © 2010 American Cancer Society.     

宫颈癌患者外周血中CK19 mRNA和HPV16 mRNA基因的检测及其意义

目的：检测宫颈癌患者外周血标本中的组织特异性标志物(CK19 mRNA)与宫颈癌相对特异性标志物(HPV16 mRNA)的表达。方法：采用RT-PCR技术检测了Ⅰb～Ⅱb期宫颈癌患者的外周血标本30例。远处转移宫颈癌患者8例，妇科良性疾病患者16例，健康人9例：结果：30例外周血标本中3例扩增出CK19的特异性条带，检出率为10．0％(3／30)。远处转移患者CK19检出率为8／8，良性病变患者为0／16，健康者为0／9。30例宫颈癌患者中有10例患者术后宫颈癌标本的免疫组化HPV E6和(或)原位杂交为阳性，均未检测到HPV16 mRNA(0／10)；8例远处转移患者的检出率为12．5％(1／8)，妇科良性病变患者和健康者的检出率分别为0／16和0／9。结论：CK19 mRNA作为宫颈癌患者外周血的检测标志物显示了较好的敏感性和特异性。HPV16 mRNA的检出率较低，临床价值有待进一步研究。     

Progestins initiate a luminal to myoepithelial switch in estrogen-dependent human breast tumors without altering growth

Although long-term clinical use of progestins is associated with an increased incidence of breast cancers, their role in established cancers is unclear. Estrogens are considered to be the main mitogens in the majority of breast cancers. Whether progesterone affects proliferation and/or differentiation is under debate. To assess the role of progesterone in established breast cancers, we used T47D human breast cancer cells that are estrogen receptor (ER) positive and either progesterone receptor (PR) negative or positive for PRA, PRB, or both. These cells were grown as strictly estrogen-dependent solid tumors in ovariectomized female nude mice. Progesterone or medroxyprogesterone acetate (MPA) alone did not support tumor growth, nor did progesterone or MPA given simultaneously with estrogen significantly alter estrogen-dependent tumor growth. However, treatment of mice bearing ER+PR+ but not ER+PR- tumors with either progesterone or MPA increased expression of the myoepithelial cytokeratins (CK) 5 and 6 in a subpopulation of tumor cells. These CK5+/CK6+ cells had decreased expression of luminal epithelial CK8, CK18, and CK19. We conclude that progestins exert differentiative effects on tumors characterized by transition of a cell subpopulation from luminal to myoepithelial. This may not be beneficial, however, because such a phenotype is associated with poor prognosis.     

Cytokeratins in different types of human lung cancer as monitored by chain-specific monoclonal antibodies

The expression of cytokeratins (CKs) in human lung cancer was studied using chain-specific monoclonal antibodies to CKs 4, 7, 8, 10, 13, 18, and 19. When applied to adenocarcinomas (ACs) of the lung, high levels of CKs 7, 8, 18, and 19 were detected in all tumors, while CK 4 was found in high concentrations in some ACs. CK 10 and 13 were completely absent, or only present in low numbers of cells. Small cell lung cancers (SCLCs) and lung carcinoids contained CK 18 and sometimes 8 and 19, but no CK 7 in most cases. Three out of four tumors, histologically classified as SCLC, and expressing CK 7 in a variable number of cells were found by electron microscopic studies to contain regions with AC and/or squamous cell carcinoma (SQC) differentiation. The monoclonal antibody specific for CK 7 can therefore possibly help to distinguish AC differentiation within SCLC. CKs 10 and 13 were completely absent in SCLCs and lung carcinoids, while few CK 4-positive cells were found in some SCLCs and in one lung carcinoid. Within SQCs the monoclonal antibodies revealed a pronounced heterogeneity in CK expression. CKs 4, 7, 8, 10, 13, 18, and 19 could be detected, although not evenly distributed among all tumor cells. Highly differentiated SQCs expressed high levels of the CKs specific for squamoid differentiation, i.e., CKs 4, 10, and 13 in variable numbers of cells. With decreasing histologically detectable SQC differentiation these markers were gradually lost, while the number of cells containing CKs 7, 8, 18, and 19 increased. Application of this panel of monoclonal antibodies can therefore distinguish not only the main subtypes of lung cancer, but can also indicate the degree of differentiation and the degree of heterogeneity. These findings can be used as a diagnostic aid in lung tumor pathology, which may have an impact on treatment and prognosis.     

Effects of altered expression and activity levels of CK1δ and ɛ on tumor growth and survival of colorectal cancer patients

Colorectal cancer (CRC) is the fourth leading cause of cancer related death worldwide due to high apoptotic resistance and metastatic potential. Because mutations as well as deregulation of CK1 isoforms contribute to tumor development and tumor progression, CK1 has become an interesting drug target. In this study we show that CK1 isoforms are differently expressed in colon tumor cell lines and that growth of these cell lines can be inhibited by CK1‐specific inhibitors. Furthermore, expression of CK1δ and ? is changed in colorectal tumors compared to normal bowel epithelium, and high CK1? expression levels significantly correlate with prolonged patients' survival. In addition to changes in CK1δ and ? expression, mutations within exon 3 of CK1δ were detected in colorectal tumors. These mutations influence ATP binding resulting in changes in kinetic parameters of CK1δ. Overexpression of these mutants in HT29 cells alters their ability to grow anchorage independently. Consistent with these results, these CK1δ mutants lead to differences in proliferation rate and tumor size in xenografts due to changes in gene expression, especially in genes involved in regulation of cell proliferation, cell cycle, and apoptosis. In summary, our results provide evidence that changes in the expression levels of CK1 isoforms in colorectal tumors correlate with patients' survival. Furthermore, CK1 mutants affect growth and proliferation of tumor cells and induce tumor growth in xenografts, leading to the assumption that CK1 isoforms provide interesting targets for the development of novel effective therapeutic concepts to treat colorectal cancer.