胃癌血清肿瘤相关基因超甲基化检测及其意义

目的：探讨检测胃癌患者血清中肿瘤相关基因超甲基化的可行性及其意义。肿瘤患者的血清中游离DNA存在质或量的变化，是可能的肿瘤标志物。DNA甲基化不改变DNA序列和遗传密码，具有可逆性，被认为是基因转录调控的表观遗传机制之一。抑癌基因启动子超甲基化通常导致基因的转录失活，其功能的丧失，参与肿瘤的发生。方法：通过甲基化特异性PCR（MSP）检测52例胃癌组织和配对血清的hMLHl、E—cadherin、GSTPI、P15和P16基因的启动子超甲基化。20例健康体检者血清作为对照。结果：在胃癌组织中检测到hMLH1、E—cadherin、GSTP1、D15和p16基因的启动子超甲基化率分别为28名％、76．9％、23．1％、59．6％和69.2％；在患者血清中检测到hMLH1、E—cadherin、GSTP1、P15和P16基因的启动子超甲基化率分别为13．5％、38．5％、15．4％、25．0％和30．8％。84．7％的患者血清可以检测到异常甲基化．所有血清中检测到异常甲基化的患者，其肿瘤组织也能检测到相应基因的异常甲基化。对照组血清未检测到任何异常甲基化。结论：MSP检测血清异常甲基化是一种具有较高灵敏度和特异性的方法，可以在大部分胃癌患者血清中同时检测到多个肿瘤相关基因的异常甲基化，可以将其作为胃癌诊断的辅助手段。     

FHIT基因与肿瘤

脆性组氨酸三联体(FHIT)基因是一种定位于人类染色体3p14.2上的抑癌基因,在多种器官中都有表达,其包含的脆性位点FRA3B,是基因组中最脆弱的部分.FHIT可促进细胞凋亡,抑制细胞增殖和细胞癌变.FHIT基因高度甲基化、基因缺失、FRA3B脆性位点的改变以及蛋白合成过程中的异常,可导致FHIT基因功能缺失,促进多种肿瘤的发生与发展.将野生型FHIT导入FHIT表达降低或表达缺失的肿瘤细胞中可促进肿瘤细胞凋亡.FHIT基因与其他基因联合治疗可能为肿瘤的治疗提供新的方向.     

WIF-1启动子甲基化与肿瘤

WIF-1(Wnt Inhibitory Factor-1)是Wnt信号通路的一种拮抗物,能在胞外与Wnt蛋白结合而抑制Wnt信号转导。近年来的研究表明,多种肿瘤中均存在WIF-1基因启动子的异常甲基化。WIF-1启动子甲基化使WIF-1蛋白表达降低,从而降低了抑制Wnt信号转导的作用,使细胞发生增殖、分化,促进肿瘤的发生发展。检测组织中WIF-1甲基化程度,可作为肿瘤早期诊断和评估预后的生物学标志物;运用去甲基化剂如5-氮杂胞苷,可逆转WIF-1的甲基化状态,从而成为肿瘤治疗的一个新靶点。     

WIF-1启动子甲基化与肿瘤

WIF-1（Wnt Inhibitory Factor-1）是Wnt信号通路的一种拮抗物,能在胞外与Wnt蛋白结合而抑制Wnt信号转导。近年来的研究表明,多种肿瘤中均存在WIF-1基因启动子的异常甲基化。WIF-1启动子甲基化使WIF-1蛋白表达降低,从而降低了抑制Wnt信号转导的作用,使细胞发生增殖、分化,促进肿瘤的发生发展。检测组织中WIF-1甲基化程度,可作为肿瘤早期诊断和评估预后的生物学标志物;运用去甲基化剂如5-氮杂胞苷,可逆转WIF-1的甲基化状态,从而成为肿瘤治疗的一个新靶点。     

肿瘤表观遗传学研究的新视点-WIF-1基因的甲基化

肿瘤抑制基因的异常甲基化在肿瘤的发生、发展中扮演着重要角色,其甲基化状态可作为肿瘤早期诊断、评价转移和评估预后的重要分子标记,而且抑癌基因的去甲基化亦可为肿瘤提供一种新的治疗方法.候选的抑癌基因WIF-1是Wnt蛋白的内源性分泌型拮抗因子,研究发现其可在多种人类肿瘤中因基因过度甲基化而导致Wnt信号途径的异常激活,促进肿瘤的发生.     

S-腺苷甲硫氨酸、DNA甲基化与肿瘤

表观遗传学修饰是一个可逆的过程,影响基因表达但不引起基因序列改变。肿瘤组织中存在的DNA甲基化异常可以概括为广泛低甲基化伴局部高甲基化。研究证明DNA甲基化抑制剂通过诱导抑癌基因重新表达,从而达到治疗肿瘤的目的。但与此同时也可能导致促癌基因和肿瘤转移相关基因的表达。S-腺苷甲硫氨酸(S-Adenosylmethionine,SAM,AdoMet)是一种甲基基团供体,被认为是一种去甲基化抑制因子可能逆转低甲基化引起的促癌基因表达,SAM治疗人类多种疾病疗效显著,因此提出S-腺苷甲硫氨酸在晚期肿瘤治疗中的意义。     

Kallikrein 10的调控机制及其肿瘤临床应用的价值

人组织激肽释放酶10（Kallikrein10,KLK10）,是Kallikrein家族(KLK 1-15)的成员之一。KLK10编码激肽释放酶10（hK10）,hK10是一种分泌型丝氨酸蛋白酶,生理功能不明。KLK10与多种恶性肿瘤的发生、发展密切相关,KLK10异常表达受甲基化、激素受体等多种因素的调节,miRNA对KLK10的调控也成为新的热点。KLK10与KLK家族其他成员在部分肿瘤中平行表达,KLK10与其他KLKs可能存在共同的激素和miRNA调节通路。KLK10作为一种新的肿瘤生物学标志物,在卵巢癌、乳腺癌和胃结直肠癌等恶性肿瘤的早期诊断和预后评估及靶向治疗中的意义也日益显现。     

WIF-1与肿瘤关系的研究进展

WIF-1是Wnt/β-catenin信号通路的重要拮抗物之-.WIF-1作为-种抑癌基因,被发现在大多数肿瘤中表达降低,这与其启动子甲基化密切相关,而经去甲基化剂作用可恢复其表达.启动子甲基化导致的WIF-1抑癌作用的丧失可能主要通过异常激活Wnt/β-catenin信号通路而促进了肿瘤的发生.在不同肿瘤中,WIF-1表达降低与临床病理参数之间的关系有差异性.检测WIF-1表达及启动子甲基化水平可能为肿瘤早期诊断、治疗及判断预后提供帮助.     

MAGE-A基因亚家族及其在肿瘤临床上的应用前景

黑素瘤相关抗原（melanoma-associated antigen,MAGE）-A基因亚家族属于癌睾丸抗原家族,其定位于X染色体,包括MAGE-A1～MAGE-A12共12个成员。对MAGE-A在基因和蛋白水平的研究发现,其在正常组织中几乎不表达,而在多种肿瘤组织中均有较高水平的表达,并且往往表达一种以上的MAGE-A亚型。正常情况下,由于CpG岛高度甲基化,MAGE-A基因沉默表达。受辐射等因素影响时,基因组易发生去甲基化,促使MAGE-A基因表达。组蛋白的乙酰化也与MAGE-A的表达有关。MAGE-A作为肿瘤相关抗原,与肿瘤的发生、发展、耐药及较差的预后密切相关。由于MAGE-A特异性的表达于多种肿瘤,对MAGE-A亚型的检测尤其是多种亚型的联合检测有助于MAGE-A阳性肿瘤的诊断。此外,MAGE-A基因编码的抗原肽由MHCⅠ分子提呈至细胞毒性T细胞,从而发挥抗肿瘤活性。应用MAGE-A抗原肽的肿瘤疫苗已经投入临床试验,并取得了良好的治疗效果。     

Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in diffuse large B-cell lymphoma

Deletions in the short arm of chromosome 17 (17p) involving the tumor suppressor TP53 occur in up to 20% of diffuse large B-cell lymphomas (DLBCLs). Although inactivation of both alleles of a tumor suppressor gene is usually required for tumor development, the overlap between TP53 deletions and mutations is poorly understood in DLBCLs, suggesting the possible existence of additional tumor suppressor genes in 17p. Using a bacterial artificial chromosome (BAC) and Phage 1 artificial chromosome (PAC) contig, we here define a minimally deleted region in DLBCLs encompassing approximately 0.8 MB telomeric to the TP53 locus. This genomic region harbors the tumor suppressor Hypermethylated in Cancer 1 (HIC1). Methylation-specific PCR demonstrated hypermethylation of HIC1 exon 1a in a substantial subset of DLBCLs, which is accompanied by simultaneous HIC1 deletion of the second allele in 90% of cases. In contrast, HIC1 inactivation by hypermethylation was rarely encountered in DLBCLs without concomitant loss of the second allele. DLBCL patients with complete inactivation of both HIC1 and TP53 may be characterized by an even inferior clinical course than patients with inactivation of TP53 alone, suggesting a functional cooperation between these two proteins. These findings strongly imply HIC1 as a novel tumor suppressor in a subset of DLBCLs.     

Genetic and epigenetic analysis of the VHL gene in gastric cancers

The von Hippel-Lindau tumor suppressor gene (VHL), which is located on chromosome 3p25, plays an important role in tumorigenesis, particularly in tumor growth and vascularization. Mutations of the VHL gene have been observed in the hereditary VHL syndrome and a variety of other sporadic cancers. In this study, in order to investigate whether the VHL gene is involved in gastric carcinogenesis, we have examined the genetic alterations, including somatic mutations and allelic loss, with the two microsatellite markers, D3S1038 and D3S1110, as well as promoter hypermethylation of the VHL gene in 88 sporadic gastric adenocarcinomas. No mutation was detected in the coding region of the VHL gene. Allelic loss was found in 20 (33.9%) of 59 informative cancer cases at one or both markers. In addition, promoter hypermethylation was not detected in the gastric cancer samples. This is the first investigation of the genetic and epigenetic alterations of the VHL gene in gastric cancers. Our results suggest that genetic and epigenetic alterations of the VHL gene may be not involved in the development or progression of gastric cancers. The findings also provide evidence for the presence of another gastric cancer specific tumor suppressor gene at the 3p25 region.     

Targeted methylation of two tumor suppressor genes is sufficient to transform mesenchymal stem cells into cancer stem/initiating cells

Although DNA hypermethylation within promoter CpG islands is highly correlated with tumorigenesis, it has not been established whether DNA hypermethylation within a specific tumor suppressor gene (TSG) is sufficient to fully transform a somatic stem cell. In this study, we addressed this question using a novel targeted DNA methylation technique to methylate the promoters of HIC1 and RassF1A, two well-established TSGs, along with a two-component reporter system to visualize successful targeting of human bone marrow-derived mesenchymal stem cells (MSC) as a model cell system. MSCs harboring targeted promoter methylations of HIC1/RassF1A displayed several features of cancer stem/initiating cells including loss of anchorage dependence, increased colony formation capability, drug resistance, and pluripotency. Notably, inoculation of immunodeficient mice with low numbers of targeted MSC resulted in tumor formation, and subsequent serial xenotransplantation and immunohistochemistry confirmed the presence of stem cell markers and MSC lineage in tumor xenografts. Consistent with the expected mechanism of TSG hypermethylation, treatment of the targeted MSC with a DNA methyltransferase inhibitor reversed their tumorigenic phenotype. To our knowledge, this is the first direct demonstration that aberrant TSG hypermethylation is sufficient to transform a somatic stem cell into a fully malignant cell with cancer stem/initiating properties.     

Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis

The gene hypermethylated in cancer 1 (HIC1) is epigenetically inactivated, but not mutated, in cancer. Here we show that cooperative loss of Hic1 with p53, but not INK4a, yields distinct tumor phenotypes in mice. Germline deletion of one allele of each gene on the opposite chromosome yields breast and ovarian carcinomas and metastatic osteosarcomas with epigenetic inactivation of the wild-type Hic1 allele. Germline deletion of the two genes on the same chromosome results in earlier appearance and increased prevalence and aggressiveness of osteosarcomas with genetic deletion of both wild-type genes. In human osteosarcomas, hypermethylation of HIC1 is frequent only in tumors with p53 mutations. Our results indicate the importance of genes altered only through epigenetic mechanisms in cancer progression in conjunction with genetically modified tumor suppressor genes.     

TSLC1基因的研究进展

TSLC1基因是一种非小细胞肺癌中的抑癌基因,属于免疫球蛋白超家族细胞黏附分子成员,与细胞黏附有关。研究显示TSLC1基因通过启动子高甲基化而表达沉默与多种肿瘤的发生、发展有关,可作为新的肿瘤标志物,指导肿瘤的早期诊断及靶基因治疗。该基因的表达缺失或突变可导致鼠的精子成熟障碍而引起不育,运用基因治疗可能给不孕症患者带来新的治疗途径。