RASSF1A抑癌基因在肿瘤中的研究进展

肿瘤发生与不同的细胞机制有关,包括原癌基因的激活和抑癌基因的失活。RAS相关区域家族1A(RAS association domain family 1 A,RASSF1 A)是近年来新发现的一个候选肿瘤抑制基因(tumor suppressor gene,TSG),该基因的失活在多种人类肿瘤的发生发展过程中起重要作用。虽然基因缺失和点突变可引起基因的失活,但大量研究表明,该基因的失活与其启动子的高甲基化有关,此表观遗传学机制可使多种抑癌基因失活,并被证实为肿瘤发生发展的主要原因。论文就RASSF1A基因与肿瘤的研究进展予以综述。     

新型抑癌基因RASSF1与胃癌的关系

新近发现的RASSF1A基因位于染色体3p21．3区，是一种新型侯选肿瘤抑制基因，多项研究表明它可参与细胞凋亡和多种恶性肿瘤的发生。在多种肿瘤中失活。该基因的失活与其启动子区甲基化和杂合子缺失有关。另外发现一些病毒的感染可影响其甲基化状态。     

候选抑癌基因RIZ1

视网膜母细胞瘤蛋白质结合的锌指蛋白1( RIZ1)是一种甲基转移酶,其功能单位为特征性的PR锌指结构域.RIZ1能够通过PR结构域甲基化组蛋白3上第9位的赖氨酸,导致相应基因转录受抑,具有抑制肿瘤发生的作用.RIZ1在多种人类肿瘤中表达减低或缺失,其表达水平减低与肿瘤发生、进展等密切相关,被定义为一种候选抑癌基因.RIZ1在肿瘤中表达减低机制既涉及细胞遗传学又与表观遗传学改变密切相关.     

抑癌基因的研究进展

抑癌基因的研究进展上海市肿瘤研究所癌基因及相关基因国家重点实验室（２０００３２）顾健人一、抑癌基因的基本概念原癌基因是指一大类促进细胞分裂并有潜在致癌或促癌作用的基因群；抗癌基因或抑癌基因则是一大类可抑制细胞生长并能潜在抑制癌变作用的基因群。它们对细...     

癌基因与抑癌基因的表达研究进展

肿瘤的发生发展本质上是细胞原癌基因的激活和抑制基因的失活造成的。癌基因和抑癌基因的对探索肿瘤发病机制,寻找预防和治疗肿瘤的新措施具有重要意义。本文较全面地介绍了癌基因和抑癌基因的种类以及它们对细胞的调控作用和致癌、抑癌的分子机制,特别是总结了近年来癌基因及抑癌基因的研究进展。     

抑癌基因WWOX及其与恶性肿瘤的研究进展

WWOX(WW domain containing oxidoreductase)基因是2000年由Bednarek等[1]在染色体普通脆性位点(common frigal of sites,CFSs) FRA16D(16q23～32q24.1)区域克隆出的新基因.     

肝细胞癌中抑癌基因CDKN2A甲基化的研究进展

肝细胞癌（HCC）的发生是一个涉及多基因、多步骤的复杂过程，相关癌基因激活和抑癌基因失活的致癌模式逐渐为人们所认识。DNA甲基化是转录水平的DNA修饰方式之一，在调节基因表达及维持细胞正常分化中起着重要作用。其状态的改变是肝癌相关基因调控的一种方式，属于肝癌发生的早期事件。本文就抑癌基因CDKN2A（cyclin—dependent kinase inhibitor，CDKN2A）的结构与功能及其与肝癌的关系等方面的研究进展进行综述。     

RASSF1A基因与乳腺癌的研究进展

RASSF1是新发现的一种定位于染色体3p的肿瘤抑制基因。该基因存在多种不同的转录本,而RASSF1A是最重要最常见的转录本。它在多种实体肿瘤中如乳腺癌表达缺失,其主要原因是启动子甲基化。启动子甲基化作为肿瘤标记物在乳腺癌的诊断、治疗等方面有着广泛的研究前景和临床价值。     

抑癌基因PDCD4与肿瘤关系的研究进展

程序性细胞死亡4(programmed cell death 4,PDCD4)是近年来发现的与细胞凋亡相关的新肿瘤抑制基因。研究发现PDCD4在多种肿瘤中存在缺失或下调,并影响肿瘤细胞的生物学行为。本文从该基因的发现、与肿瘤发生、发展的关系以及作用机制进行了综述。     

新型肺癌候选抑癌基因RASSF1A研究进展

Ras相关区域家族1A(RASSF1A)是最近从3p21．3上发现的新型候选抑癌基因，在肺癌、乳腺癌和结肠癌等十几种恶性肿瘤中均出现高频率表达失活和异常高甲基化。将该基因转染入肺癌、肾癌等肿瘤细胞株中均可显著抑制癌细胞生长，逆转其恶性表型，提示该基因的失活可能在肺癌等多种肿瘤的发生发展中发挥重要作用。     

抑癌基因LKB1与乳腺癌他莫昔芬耐药性之间的关系

目的:研究抑癌基因LKB1对乳腺癌他莫昔芬耐药的影响及机制。方法:运用免疫组化技术对68例乳腺癌组织中LKB1、雌激素受体（ER）和孕激素受体（PR）的表达进行检测,并且利用GEPIA数据库验证实验结果;利用Kaplan-Meier Plotter数据库分析LKB1基因与ER/PR阳性的Luminal A/B亚型乳腺癌预后之间相关性;运用实时定量PCR、免疫印迹和免疫荧光技术分析LKB1在他莫昔芬耐药细胞系中的表达及定位;运用免疫印迹和免疫荧光技术分析他莫昔芬对LKB1表达及定位的影响。结果:在乳腺癌中LKB1与ER/PR的表达呈现显著的正相关性,ER/PR（+++）和ER/PR（+）两组间LKB1的表达差异具有显著的统计学意义（P＜0.001）;LKB1的表达量与乳腺癌预后呈现正相关性,在Luminal A/B亚型的乳腺癌中LKB1表达越低其预后越差;在他莫昔芬耐药细胞系及对照细胞中LKB1的mRNA和蛋白表达量差异无统计学意义,但是在耐药细胞中LKB1的定位发生了从细胞质向细胞核的移行;在体外他莫昔芬能够诱导LKB1表达并且促进LKB1从细胞质向细胞核的移行。结论:在Luminal A/B亚型的乳腺癌中,LKB1的低表达是一种不良预后的指标,并且该蛋白从细胞质向细胞核的移行与乳腺癌他莫昔芬耐药密切相关,而耐药与蛋白的表达量无关。     

肿瘤抑制基因ARHI的生物学功能及研究进展

肿瘤是一种基因病,抑癌基因在抵御肿瘤发生、发展中起着重要作用。ARHI(aplysia ras hom olog I)/NOEY2 是一个新发现的抑癌基因,是 ras/rap超家族成员之一,与 ras家族有50%~60%的同源性,位于人染色体1p31,属小GTP结合蛋白,是该家族第1个被报道的肿瘤抑制基因。ARHI基因编码的蛋白在人类多种组织表达,其中正常卵巢的ARHI表达最高。ARHI是一个印迹基因,印迹机制可能与其CpG岛的差异甲基化有关。ARHI 参与细胞周期调控可能作用于cyclin D1 ,使其不能与 CDK结合形成活性激酶,从而使细胞停止于 G1 期。AR HI可能通过依赖caspase和 calpain两条途径参与信号通路传导诱发细胞凋亡。该基因的异常表达跟多种肿瘤的发生、发展有关。ARHI基因参与了乳腺癌的发生和发展,该基因的表达缺失可能与乳腺癌的转移机制有关。卵巢癌、乳腺癌存在广泛的1p31缺失,其中 ARHI 基因是最常见的一个缺失区域。ARHI基因和蛋白在胰腺癌组织中有较高比例的缺失,提示该基因和蛋白在胰腺癌的发生中起一定作用。ARHI基因在膀胱癌、肝癌、前列腺癌等其他肿瘤中也有不同程度的表达异常。     

Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis

Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) has been demonstrated in several cancers, but its prognostic role is unknown. We aimed to investigate the risk associated with loss of ARID1A (ARID1A−) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS search from database inception until 01/31/2015 without language restriction was conducted, contacting authors for unpublished data. Eligible were prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of ARID1A (ARID1A+) vs. ARID1A−, assessed either via immunohistochemistry (loss of expression) or with genetic testing (presence of mutation). Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to ARID1A− adjusted for potential confounders. Of 136 hits, 25 studies with 5,651 participants (28 cohorts; ARID1A−: n = 1,701; ARID1A+: n = 3,950), with a mean follow-up period of 4.7 ± 1.8 years, were meta-analyzed. Compared to ARID1A+, ARID1A− significantly increased cancer-specific mortality (studies = 3; RR = 1.55, 95% confidence interval (CI) = 1.19–2.00, I² = 31%). Using HRs adjusted for potential confounders, ARID1A− was associated with a greater risk of cancer-specific mortality (studies = 2; HR = 2.55, 95%CI = 1.19–5.45, I² = 19%) and cancer recurrence (studies = 10; HR = 1.93, 95%CI = 1.22–3.05, I² = 76%). On the basis of these results, we have demonstrated that loss of ARID1A shortened time to cancer-specific mortality, and to recurrence of cancer when adjusting for potential confounders. For its role, this gene should be considered as an important potential target for personalized medicine in cancer treatment.     

UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation

Epigenetic changes play significant roles in cancer development. UHRF1, an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene (TSG) silencing in several cancers. In a previous study, we found that UHRF1 promoted gastric cancer (GC) invasion and metastasis. However, the role and underlying mechanism of UHRF1 in GC carcinogenesis remain largely unknown. In the present study, we investigated UHRF1 expression and function in GC proliferation and explored its downstream regulatory mechanism. The results demonstrated that UHRF1 overexpression was an independent and significant predictor of GC prognosis. Downregulation of UHRF1 suppressed GC proliferation and growth in vitro and in vivo, and UHRF1 upregulation showed opposite effects. Furthermore, downregulation of UHRF1 reactivated 7 TSGs, including CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML, via promoter demethylation. These results provide insight into the GC proliferation process, and suggest that targeting UHRF1 represents a new therapeutic approach to block GC development.     

Aberrant Methylation of the 1p36 Tumor Suppressor Gene RIZ1 in Renal Cell Carcinoma

Background: Retinoblastoma protein-interacting zinc finger gene 1(RIZ1) functions as a tumor suppressor.Hypermethylation-mediated RIZ1 silencing has been reported in several cancers, but not in renal cell carcinoma(RCC) yet. Materials and Methods: We examined the RIZ1 expression and methylation in a panel of RCC celllines and 50 primary tumors using semiquantitative/quantitative polymerase chain reaction (PCR), methylationspecific PCR, and bisulfite sequencing genomic. We also explored the relationship between methylation status ofRIZ1 and clinicopathological features in RCC patients. Results: RIZ1 expression was down-regulated or lost inOS-RC-2, 769-P, Caki-1, 786-O and A498 RCC cell lines. Restored expression of RIZ1 was detected after additionof 5-aza-2’-deoxycytidine with/without trichostatin A, suggesting that DNA methylation directly mediates itssilencing. The RIZ1 expression was significantly reduced in RCCs compared to adjacent non-malignant renalsamples (P<0.001). Aberrant methylation was detected in 15 of 50 (30%) RCCs and in 2 of 28 (7%) adjacent nonmalignantrenal samples (P=0.02). No statistically significant correlation between methylated and unmethylatedcases with regard to age, gender, pathological stage and grade was observed. Conclusions: RIZ1 expression isdown-regulated in human RCC, and this down-regulation is associated with methylation. RIZ1 methylation mayplay a role in renal carcinogenesis.     

抑癌基因RASSF1在胃癌组织中表达及其临床意义的研究

目的：探讨Ras相关区域家族1基因（RASSF1）两种不同转录本RASSF1A和RASSF1B在胃癌组织中的表达情况及与临床病理特征的关系。方法：采用RT-PCR方法，检测32例胃癌组织及相应的32例远隔病灶部位胃组织和51例胃良性病变中RASSF1A和RASSF1B mRNA的表达情况，并探讨RASSF1与临床病理因素之间的关系。结果：RASSF1A和RASSF1B在癌旁组织中表达缺失率均为6．25％（2／32），在胃癌组织中的表达缺失率分别为59．3％（19／32）和28．1％（9／32），两者表达RASSF1A的缺失率比较差异有统计学意义，P=0．008；RASSF1B的差异无统计学意义，P=0．078。RASSF1A和RASSF1B在浅表性胃炎组织中表达缺失率分别是10．0％（3／30）和6．7％（2／30）；在萎缩性胃炎组织中分别为28．6％（6／21）和14．3％（3／21），两组之间比较差异无统计学意义，P=0．060。RASSF1A和RASSF1B表达与胃癌高、中、低分化程度及肿瘤大小等均无相关性，P均〉0．05。结论：RASSF1A在胃癌组织中的表达缺失更明显。RASSF1A在癌旁正常组织到胃良性病变到胃癌中表达缺失率逐渐增加，表明RASSF1A是一种抑癌基因。检测RASSF1A在胃癌组织中的缺失率对临床判断肿瘤发生发展有指导意义。     

抑癌基因FASSF1在胃癌组织中表达及其临床意义的研究

目的:探讨Ras相关区域家族1基因(RASSF1)两种不同转录本RASSF1A和RASSF1B在胃癌组织中的表达情况及与临床病理特征的关系。方法:采用RT-PCR方法,检测32例胃癌组织及相应的32例远隔病灶部位胃组织和51例胃良性病变中RASSF1A和RASSF1B mRNA的表达情况,并探讨RASSF1与临床病理因素之间的关系。结果:RASSF1A和RASSF1B在癌旁组织中表达缺失率均为6.25%(2/32),在胃癌组织中的表达缺失率分别为59.3%(19/32)和28.1%(9/32),两者表达RASSF1A的缺失率比较差异有统计学意义,P=0.008;RASSF1B的差异无统计学意义,P=0.078。RASSF1A和RASSF1B在浅表性胃炎组织中表达缺失率分别是10.0%(3/30)和6.7%(2/30);在萎缩性胃炎组织中分别为28.6%(6/21)和14.3%(3/21),两组之间比较差异无统计学意义,P=0.060。RASSF1A和RASSF1B表达与胃癌高、中、低分化程度及肿瘤大小等均无相关性,P均>0.05。结论:RASSF1A在胃癌组织中的表达缺失更明显。RASSF1A在癌旁正常组织到胃良性病变到胃癌中表达缺失率逐渐增加,表明RASSF1A是一种抑癌基因。检测RASSF1A在胃癌组织中的缺失率对临床判断肿瘤发生发展有指导意义。