结直肠癌肿瘤干细胞标志物的研究进展

CD44+、CD24+、CD166+、CD29+等参与结直肠癌的发生、侵袭和复发,表达越高预后越差,可作为结直肠癌肿瘤干细胞标志物,与其相关的信号传导通路和蛋白酶通过调节内环境也参与肿瘤的形成。通过研究肿瘤干细胞标志物可以早期诊断结直肠癌,减少肿瘤的复发,寻找治疗靶点,为结直肠癌的诊治提供突破点。     

人结直肠癌生物标记物概况

结直肠癌是全球最常见的肿瘤之一,其发病与社会环境、饮食习惯、遗传等多种因素有关。对结直肠癌患者,我们能做出较为准确的诊断,并进行相应的治疗,但目前我们缺少可以监测其治疗效果、预后水平等各方面的特异性指标。因此,研究者们对多种生物分子进行了大量实验,探究其作为结直肠癌特异性生物标记物的可行性。本文对目前各种结直肠癌生物标记物的研究进展进行综述。     

FAT10基因表达与结直肠癌患者临床病理因素及预后的关系

目的:探讨结直肠癌(CCT)组织中FAT10(Diubiquitin,双泛素)的基因表达与其病理因素及预后的关系。方法:收集我院2000～2003年73例有5年以上完整随访资料的结直肠癌术后患者,采用RT-PCR方法检测FAT10 mRNA在CCT、癌旁组织(TCT)和正常结直肠组织(NCT)中的表达情况,并分析临床病理因素对FAT10阳性表达率和相对表达量的影响,以及FAT10表达与预后的关系。结果:FAT10 mRNA在CCT阳性表达率为52.24%(35/67),且在CCT的相对表达量(0.735±0.034)明显高于TCT(0.561±0.044)和NCT(0.397±0.028)(P<0.05);FAT10 mRNA的阳性表达率及相对表达量受临床进展、淋巴结转移和TNM分级的影响较明显(P<0.05),而患者年龄、肿瘤大小、肿瘤分化程度等对其无明显影响(P>0.05);Log-Rank检验显示CCT患者中,FAT10表达阳性者生存率明显低于FAT10表达阴性者(P<0.01)。结论:FAT10在CCT的表达状况与CCT转移及预后关系密切,可以作为反映生物学行为和判断预后的有效指标。     

生物标记物在结直肠癌早期诊断及预后评估中的研究进展

近年来基因诊断在结直肠癌中的应用越来越广泛,该文综述生物标记物在结直肠癌早期诊断及预后评估中的研究进展.目前,早期诊断和预后评估为结直肠癌生物标记物探索的新方向,有望成为提高结直肠癌诊治效率的新检查方法.     

结直肠癌干细胞表面标志物和信号通路研究进展

肠道干细胞分为两种,一个是表达Lgr5基底柱状干细胞,其表达与疾病分期有关,调控着细胞周期不断更替;另一个是+4干细胞,与肿瘤异质性有关,表达Bmi1使细胞周期停滞,此外还包括Msi1。多项研究表明在结直肠癌中以上标志物是高表达的,并可作用于Notch和经典Wnt信号通路促进肿瘤的发生和进展。     

甲状腺癌组织中趋化因子4受体和趋化因子7受体的表达情况及临床病理意义

目的 研究甲状腺癌组织中趋化因子4受体(CXCR4)和趋化因子7受体(CXCR7)的表达情况及临床病理恿义.方法 选取2012年5月至2014年6月期间在本院进行外科手术的83例甲状腺癌患者及2014年45例甲状腺腺瘤患者,采用免疫组织化学染色方法检测甲状腺腺瘤及甲状腺癌中CXCR4和CXCR7的表达.结果 CXCR4和CXCR7在甲状腺癌中的表达阳性率均明显高于甲状腺腺瘤(P＜0.05).CXCR4和CXCR7在临床分期为Ⅲ～Ⅳ期的甲状腺癌患者中的表达阳性率均明显高于临床分期为Ⅰ～Ⅱ期者(P ＜0.05);CXCR7在有淋巴结转移的甲状腺癌患者中的表达阳性率明显高于无淋巴结转移者(P＜0.05),而CXCR4的表达阳性率与甲状腺癌患者有无淋巴结转移无关(P＞0.05);CXCR4和CXCR7在甲状腺癌组织中的表达阳性率与甲状腺癌患者性别无关(P＞0.05).在甲状腺癌患者中,CXCR4阳性表达和CXCR7阳性表达呈正相关(r =0.49,P＜0.01);在甲状腺腺瘤患者中,CXCR4阳性表达和CXCR7阳性表达不相关(r=0.14,P=0.21).结论 CXCR4和CXCR7参与了甲状腺癌的进展,并为临床上甲状腺癌诊断及靶向治疗提供理论基础.     

趋化因子CXCL14在结直肠癌组织中的表达及其临床相关性研究

 目的:分析趋化因子CXCL14在结直肠癌组织中的表达,并探讨其表达的临床意义。方法:采用实时荧光定量PCR和免疫组化对40例结直肠癌及癌旁正常组织CXCL14的表达进行检测。Kaplan-Meier生存曲线和Cox回归模型评估CXCL14在结直肠癌组织中表达的临床意义。结果:CXCL14 mRNA和蛋白水平在结直肠癌组织中的表达较正常组织明显降低（P＜0.05）。临床相关性分析表明,CXCL14表达的下调与肿瘤淋巴结转移、发生部位以及临床病理分期有关（P＜0.05）。Kaplan-Meier生存分析显示,不同CXCL14蛋白表达水平的患者,生存时间具有显著差异（P＜0.01)。结论:CXCL14可能参与结直肠癌的发生、发展过程。     

肿瘤标志物及血管新生因子与结直肠癌患者临床分期及肿瘤转移相关

目的探讨肿瘤标志物及血管新生因子与结直肠癌临床分期及肿瘤转移的关系。方法用电化学发光法及酶联免疫吸附法检测结直肠癌患者及同期来医院健康体检者各100例静脉血肿瘤标志物与血管新生因子水平,并分析其与肿瘤不同TNM分期及肿瘤转移之间的关系。结果癌患者CEA、CA19-9、Ang-2、VEGF及IGF-1水平均显著高于对照组(P0. 05);不同TNM分期间CEA、CA19-9、Ang-2、VEGF及IGF-1水平有明显差异(P0. 05),随着肿瘤进展,CA19-9、Ang-2及IGF-1水平均显著升高(P0. 05),Ⅳ期CEA及VEGF水平较Ⅰ、Ⅱ与Ⅲ期显著升高(P0. 05);肿瘤转移组患者的CEA、CA19-9、Ang-2、VEGF及IGF-1水平均显著高于无转移(P0. 05)。结论结直肠癌患者存在肿瘤标志物及血管新生因子水平异常升高,其指标水平检测对评估肿瘤分期及转移预测具有重要临床价值。     

FAK基因表达对人结直肠癌细胞增殖及运动的影响

目的:探讨黏着斑激酶(FAK)表达水平对结直肠癌细胞增殖及运动的影响.方法:针对FAK基因不同靶点设计siRNA序列, 构建siRNA重组子, 转染Caco-2细胞, 以RT-PCR和免疫细胞化学方法检测FAK mRNA和蛋白表达变化及时间效应, 同时检测FAK基因敲低对Caco-2细胞的凋亡、增殖及迁移的影响.结果:FAK siRNA导入Caco-2细胞后, FAK mRNA和蛋白表达水平明显下调, 细胞增殖及迁移能力受抑, 呈时间依赖关系, FAK mRNA水平下调在转染后48 h达到最大.结论:FAK siRNA可有效抑制靶基因表达, FAK表达水平下调后Caco-2细胞的增殖及运动明显受抑制.     

5-FU通过靶向Wnt/β-catenin信号通路对结直肠癌干细胞活性的影响

目的 基于Wnt/β-catenin信号通路探讨5-氟尿嘧啶（5-FU）对结直肠癌干细胞（CRC-CSC）活性的影响。方法 流式细胞术分选CD133标记的CRC-CSC,以不同浓度5-FU(6.25、12.50、25.00μmol/L)处理细胞,对照组以等体积培养液处理。药物作用48 h后,CCK-8法检测细胞增殖,划痕实验检测细胞迁移,流式细胞术检测细胞凋亡,平板克隆实验和球形成实验检测细胞克隆能力及悬浮球形成能力,蛋白免疫印迹法检测Wnt/β-catenin信号通路表达。结果 与对照组比较,高剂量5-FU处理后CRC-CSC细胞增殖能力（24 h、48 h两组分别为0.31±0.03vs. 0.53±0.05;0.37±0.03 vs. 0.61±0.05）和迁移能力（24 h、48 h两组分别为9.63±0.72 vs. 38.69±0.88;16.21±1.17 vs.58.69±1.32）显著增加（P<0.05）,细胞凋亡率（24 h、48 h两组分别为46.91±0.94 vs. 18.46±0.88;55.22±1.24 vs. 28.42±1.18）显著降低（P&...     

The role of CXC chemokine ligand 16 in physiological and pathological pregnancies

The survival and development of a semi‐allogeneic fetus during pregnancy require the involvement of a series of cytokines and immune cells. Chemokines are a type of special cytokine those were originally described as having a role in leukocyte trafficking. CXC chemokine ligand (CXCL) 16 is a member of the chemokine family, and CXC chemokine receptor (CXCR) 6 is its sole receptor. Emerging evidence has shown that CXCL16/CXCR6 is expressed at the maternal‐fetal interface, by cell types that include trophoblast cells, decidual stroma cells, and decidual immune cells (eg, monocytes, γδT cells, and natural killer T (NKT) cells). The regulation of expression of CXCL16 is quite complex, and this process involves a multitude of factors. CXCL16 exerts a critical role in the establishment of a successful pregnancy through a series of molecular interactions at the maternal‐fetal interface. However, an abnormal expression of CXCL16 is associated with certain pathological states associated with pregnancy, including recurrent miscarriage, pre‐eclampsia, and gestational diabetes mellitus (GDM). In the present review, the expression and pleiotropic roles of CXCL16 under conditions of physiological and pathological pregnancy are systematically discussed.     

CXCL12-G801A polymorphism modulates risk of colorectal cancer in Taiwan

Introduction

The chemokine CXCL12, designated stromal cell-derived factor-1 (SDF-1), plays a significant role in many cancer metastases. Previous studies have shown that CXCL12-G801A, a single nucleotide polymorphism (SNP) in the 3’ untranslated region, correlates with breast and lung cancer in Iran. The aim of this study was to evaluate the association of the gene variant CXCL12-G801A with colorectal cancer (CRC) in a Taiwanese cohort.

Material and methods

In this study, we used a denaturing high performance liquid chromatography (DHPLC) method to analyze the frequencies of CXCL12-G801A polymorphic variants between CRC patients (n = 258) and healthy controls (n = 300) in Taiwan.

Results

The SNP distribution was higher in CRC patients with TNM stage II (117/258) than healthy controls (52/300). We observed a significant increase in the G/A plus A/A genotype of the CXCL12-G801A polymorphism in CRC patients (45.35%) compared with healthy controls (17.33%). The analysis of allelic frequencies in both groups revealed that CRC patients have a higher frequency of A allele (23.45%) than healthy controls (8.67%). Furthermore, among older CRC patients, the frequency of the CXCL12-G801A genotype was significantly increased (p = 0.0148).

Conclusions

Our observations suggest that the CXCL12-G801A genotype may be associated with some clinical manifestations in CRC patients in Taiwan.     

痛风患者CXCL16血清水平的变化及临床意义

目的: 探讨慢性痛风患者血清C-X-C趋化因子配体16(CXCL16)水平变化与肾功能损伤状况之间的关系及其临床价值。方法: 收集20例并伴有慢性肾病的痛风患者、22个无其它并发症的痛风患者和22个慢性肾病患者作为实验观察对象, 同时随机抽取体检人群中年龄和性别相匹配的20个正常人群作为对照组。计算肌酐清除率和估计肾小球滤过率,并采用ELISA方法对各临床病例和对照人群的血清CXCL16水平进行测定,同时采用实时定量PCR检测CXCL16 mRNA表达水平。对患者的临床各相关指标进行分析,两组数据之间采用t检验、多组数据之间采用One-way ANOVA检验、多元逐步回归分析。结果: 痛风患者的血清CXCL16水平显著高于相应的正常对照者以及年龄性别相匹配的慢性肾病患者(P<0.05);伴有慢性肾病的痛风患者血清CXCL16水平明显高于无并发症的痛风患者(P<0.05)。此外,与正常对照者相比较,痛风患者的外周血单个核细胞(PBMC) CXCL16 mRNA分子表达水平也有显著的上升(P<0.05)。多重逐步回归分析表明血清CXCL16水平与患者24 h尿蛋白、肌酐清除率和C反应蛋白独立相关(P<0.05)。结论: 痛风患者的血清CXCL16水平变化与患者肾脏功能改变密切相关,但其具体的发病机制有待于进一步研究。     

Expression of CC and CXC chemokines and chemokine receptors in human leprosy skin lesions

We have investigated the expression of chemokines and their receptors in leprosy skin lesions using immunohistochemistry. Skin biopsies from 25 leprosy patients across the leprosy spectrum, 11 patients undergoing type I reversal reactions and four normal donors were immunostained by ABC peroxidase method using antibodies against CC and CXC chemokines and their receptors. Using an in situ hybridization technique we have also studied the expression of monocyte chemoattractant protein 1 (MCP-1), RANTES and interleukin (IL)-8 chemokines mRNA in leprosy skin lesions. Chemokines and receptor expression was detected in all leprosy skin biopsies. Expression of CC chemokines MCP-1 (P < 0.01) and RANTES (P < 0.01) were elevated significantly in borderline tuberculoid leprosy in reversal reaction compared to non-reactional borderline tuberculoid leprosy, but there was no difference in the expression of IL-8 chemokine. Surprisingly, there was no significant difference in the expression of CC (CCR2 and CCR5) and CXC (CXCR2) chemokine receptors across the leprosy spectrum. Similarly, there was no significant difference in the expression of mRNA for MCP-1, regulated upon activation normal T cell expressed and secreted (RANTES) and IL-8 chemokines. Here, the presence of a neutrophil chemoattractant IL-8 in leprosy lesions, which do not contain neutrophils, suggests strongly a role of IL-8 as a monocyte and lymphocyte recruiter in leprosy lesions. These results suggest that the chemokines and their receptors, which are known to chemoattract T lymphocytes and macrophages, are involved in assembling the cellular infiltrate found in lesions across the leprosy spectrum.     

CXCL12 chemokine expression suppresses human breast cancer growth and metastasis in vitro and in vivo

Chemokine receptors are now known to play an important role in cancer growth and metastasis. However, there is little information regarding chemokine expression in breast cancer. The aim of this study was to evaluate CXCL12 expression in breast cancer and to investigate the question of whether reduced expression of CXCL12 may have any pathological significance in breast cancer development or progression. In this study, we performed western blotting and immunohistochemistry to evaluate the expression of CXCL12 and relevance with clinicopathological factors in the invasive ductal carcinoma. Reduction of CXCL12 was significantly correlated with tumor size, lymph node metastasis, TNM stage and Her-2 expression in breast cancer. Patients with negative CXCL12 expression had significantly lower cumulative postoperative 5 year survival rate than those with positive CXCL12 expression. In addition, we demonstrated that upregulation of CXCL12 expression by infection with an adenovirus containing a CXCL12 vector significantly inhibited cell growth and reduced the migration of breast cancer cells. Furthermore, animal studies revealed that nude mice injected with the Ad-CXCL12 cell lines featured a lighter weight than the control cell lines. These data suggest that CXCL12 plays an important role in cell growth and invasion in human breast cancer and it appears to be a potential prognostic marker for patients with breast cancer.     

结直肠癌中ZHX2蛋白表达的检测及其临床病理意义

目的检测结直肠癌中ZHX2蛋白的表达情况,探讨ZHX2与结直肠癌的关系。方法利用免疫组化法分别检测73例结直肠癌组织及其对应的癌旁正常组织中的ZHX2蛋白的表达情况。结果 73例结直肠癌组织中ZHX2蛋白的阳性率为82.2%(60/73),癌旁正常组织中ZHX2蛋白的阳性率为94.5%(69/73),差异具有统计学意义(P<0.05)。在结直肠癌组织中,ZHX2蛋白的阳性表达与肿瘤的发生部位及分化程度有关(P<0.05),与性别、年龄、肿瘤大小、浸润深度、淋巴结转移及Dukes分期无关(P>0.05)。ZHX2(+)组患者的生存时间长于ZHX2(-)组(P<0.05)。结论 ZHX2作为一种转录抑制因子,可能参与结直肠癌的发生与演进,并有助于患者预后的判断。     

肝癌组织RUNX3mRNA和蛋白表达及其与临床病理的相关性研究

目的 探讨肝癌组织及其癌旁组织中RUNX3mRNA和蛋白表达情况,并分析其与临床病理因素的相关性.方法 采用RT-PCR（逆转录-聚合酶链反应）和IHC（免疫组织化学）分别检测肝癌组织及其癌旁组织中RUNX3mRNA和蛋白表达水平,并分析与临床病理因素的相关性.结果在51例肝癌组织中RUNX3mRNA表达量相对值为：0.4509±0.0963;在51例相对应的癌旁组织中RUNX3mRNA表达量相对值为：0.9147 ±0.0222;两者间差异有统计学意义（t=33.6087,P＜0.001）.在51例肝癌组织中RUNX3蛋白表达阳性率为49.02％（ 25/51）;而在51例相对应的癌旁组织中RUNX3蛋白表达阳性率为82.35％ （42/51）;两者间差异有统计学意义（x2=12.5706,P＜0.005）.RUNX3mRNA和蛋白表达水平均在分化程度、门静脉癌栓、肝内转移等病理因素差异有统计学意义（P＜0.05）,而在性别、肿瘤直径、肿瘤部位、癌肿出血坏死、组织分型的差异均无统计学意义（P＞0.05）.结论 RUNX3基因在肝癌组织中mRNA和蛋白表达水平均显著低于在癌旁组织中的表达水平,RUNX3mRNA和蛋白表达下调可能在肝癌的发生、发展过程中起着重要作用;RUNX3基因可能是肝癌的一种抑癌基因.     

dbCPCO: a database of genetic markers tested for their predictive and prognostic value in colorectal cancer

Colorectal cancer is the third most common cancer with a 5‐year survival rate of 30–65%. A portion of the interpatient variability in its clinical outcome is attributed to inherited and somatic genetic factors. Although numerous research articles have investigated these factors in colorectal cancer, there has not been a central resource, such as a public database, that compiles these findings. Here we describe the dbCPCO, a database of genetic variations tested for association with colorectal cancer prognosis and clinical outcome. dbCPCO curates the results of research articles on colorectal cancer that investigate the possible correlation of genetic factors with various patient and tumor characteristics. Literature reports are retrieved from PubMed. The data that meet the inclusion criteria are compiled in a relational database and posted in a dedicated Website. The genetic factors include inherited genetic polymorphisms, and somatic and germline mutations in both nuclear and mitochondrial DNA. As of March 2010, the dbCPCO Website posts 778 scientific findings on 456 polymorphisms, somatic and germline mutations from 189 genes, and genetic loci tested for correlation with clinicopathological features and/or clinical outcome in colorectal cancer. The dbCPCO is periodically updated and freely available for the scientific and medical community at http://www.med.mun.ca/cpco. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.