肿瘤发生发展中Mina53的作用机制

c-Myc的下游靶基因Myc-induced nuclear antigen with a molecular mass of 53 kDa（Mina53）在多种肿瘤组织中异常表达,且与肿瘤临床分期、淋巴结转移及临床预后之间关系密切。Mina53可通过调控细胞分化、增殖、凋亡等参与肿瘤发生发展,但其相关作用机制还不十分清楚。为此,本文拟通过综述Mina53在肿瘤发生发展中的机制研究进展,探讨其在肿瘤治疗中的意义和价值。     

Mina53与CBX8在肝细胞肝癌中的表达及其与临床病理特征和预后的关系

目的 探讨Mina53与CBX8在肝细胞肝癌中的表达,并分析两者与肝细胞肝癌患者临床病理特征及预后的关系。方法 收集121例肝细胞肝癌患者术后切除标本制作组织芯片,采用免疫组织化学PV6000法检测Mina53与CBX8在肝细胞肝癌及相应癌旁相对正常组织中的表达,应用SPSS23.0软件对数据进行统计分析。结果 Mina53、CBX8在肝细胞肝癌中的表达水平高于癌旁相对正常组织（均P<0.001）。Mina53表达与肿瘤大小、被膜侵犯、脉管侵犯、病理分级、TNM分期有关（均P<0.05）;CBX8表达与乙肝表面抗原（HBsAg）、肿瘤大小、被膜侵犯、TNM分期有关（均P<0.05）。肝细胞肝癌中Mina53与CBX8表达呈正相关（r=0.574, P<0.01）。Mina53与CBX8均高表达患者的OS和DFS较Mina53或CBX8高表达者和两者均低表达者更短（均P<0.001）。多因素分析显示,Mina53、CBX8的表达水平是肝细胞肝癌患者术后OS和DFS的独立预后影响因素（P<0 . 0 5 ） 。结论 Mina53及CBX8在肝细胞肝癌组织中高表达, 可能与肝细胞肝癌的发生发展和浸润转移有关,Mina53和CBX8高表达提示患者预后不良,联合检测Mina53和CBX8有助于肝细胞肝癌的预后判断。     

Mina53、Ki-67在中国人大肠癌中的表达及其与临床病理学之间的关系

目的 检测Mina53、Ki-67在大肠癌中的表达水平,研究其与临床病理学之间的关系,判断其表达对预后的意义,为大肠癌的早期诊断预防和治疗提供分子生物学依据。方法 收集长江大学附属第一医院,荆州市第一人民医院2004年12月—2006年12月大肠癌手术治疗的标本82例,应用免疫组化SP法检测组织切片中Mina53、Ki-67的表达,并与临床特征、病理分级等因素进行相关性分析。结果 82例大肠癌组织标本中,Mina53以及Ki-67均为核染色,Mina53阳性表达率为78.05%(64/82),Ki-67阳性表达率为80.49%(66/82);Spearman相关性检验显示,Mina53表达与Ki-67表达呈正相关(P=0.000),Mina53、Ki-67表达水平与分期相关,P值分别为0.029、0.037,Mina53、Ki-67表达水平越高,分期越晚。与年龄、肿块大小以及病理学分级无关;Cox回归分析显示,Mina53表达、术后分期与预后相关,P值分别为0.039、0.000,而Ki-67表达、病理分级、肿块大小与预后无关。结论 Mina53、Ki-67在大肠癌细胞中呈特异性高表达,且Mina53表达水平与Ki-67表达水平明显相关,两者的高表达提示肿瘤易出现淋巴结转移及远处转移,Mina53可能成为判断大肠癌预后的因素之一。     

细胞周期相关基因CDKN2A、TP53、RB1 和BRCA2在恶性肿瘤中的研究进展

CDKN2A、TP53、RB1和BRCA2是细胞周期相关基因，主要通过转录合成细胞周期相关蛋白，在细胞增殖和凋亡的调控方面发挥重要作用。并且CDKN2A、TP53、RB1和BRCA2基因在多种肿瘤的发生发展以及肿瘤的治疗和预后方面扮演重要角色。本文就近年来对CDKN2A、TP53、RB1和BRCA2在肿瘤中作用以及对患者治疗疗效和预后影响的研究进展进行综述。     

MTH1基因在肿瘤发生及治疗中的作用

MTH1蛋白能通过水解氧化的脱氧核糖核苷三磷酸修复活性氧造成的DNA损伤,其在肿瘤细胞中高表达,并维持肿瘤细胞存活.MTH1基因与微小RNA、RAS、p53等肿瘤相关基因关系密切,且MTH1抑制剂可以选择性地抑制肿瘤细胞增殖,是一个极具潜力的肿瘤治疗新靶点.     

p73基因与人类肿瘤的研究进展

p53基因家族新成员p73与其同源体p53在结构和功能上都具有高度相似性。p73基因过表达能够激活p53的靶基因从而诱导细胞凋亡,也能对异常的细胞增殖和一些DNA损伤事件产生反应性活化,同时因为p73在1p36的特殊定位,研究者认为p73基因或许像p53一样是一个肿瘤抑制基因。但是,p73基因敲除鼠并不发生自发性肿瘤,肿瘤中极少发现p73基因的突变,N末端转录活化区丢失的异构体ΔNp73具有与全长p73基因相反的功能,ΔTA p73更象一个癌基因起着促进肿瘤生长的作用。就p73及其异构体ΔTA p73在人类肿瘤中的矛盾表现及近期研究进展予以综述。     

P53蛋白的结构、功能和作用机制

近年来的研究显示,P53基因与多种人体肿瘤有关。P53基因是一个单拷贝基因,其基因产物是一种核蛋白。半衰期较短。最初的研究发现,P53蛋白能与多种DNA病毒蛋白结合,在肿瘤和转化细胞中常有高表达;P53基因具有使原代大鼠细胞永生化,和ras癌基因一起使大鼠成纤维细胞转化的能力,认为P53基因是典型的癌基因。但近几年的研究发现,起癌基因作用的是P53基因突变体,     

p73基因与人类肿瘤的研究进展

p53基因家族新成员p73与其同源体p53在结构和功能上都具有高度相似性。p73基因过表达能够激活p53的靶基因从而诱导细胞凋亡．也能对异常的细胞增殖和一些DNA损伤事件产生反应性活化，同时因为p73在1p36的特殊定位，研究者认为p73基因或许像p53一样是一个肿瘤抑制基因。但是．p73基因敲除鼠并不发生自发性肿瘤，肿瘤中极少发现p73基因的突变，N末端转录活化区丢失的异构体△Np73具有与全长p73基因相反的功能，△TA-p73更象一个癌基因起着促进肿瘤生长的作用。就p73及其异构体△TA-p73在人类肿瘤中的矛盾表现及近期研究进展予以综述。     

p73基因研究进展

p53基因的突变、失活及缺失与50%的人类肿瘤发生有关,因此p53基因被视为经典的抑癌基因。近年来,随着对p53基因广泛深入的研究,p53家族的其他成员不断被发现,其中p73基因是p53基因家族中被发现的第一个成员。p73基因编码的蛋白质,无论在结构上,还是在功能上均与p53蛋白相似,且与肿瘤的发生密切相关,可抑制细胞增殖,诱导凋亡。深入了解它们彼此的相似性、差异性,可对研究肿瘤的发生机制和对肿瘤的基因治疗提供帮助,为最终攻克癌症带来希望。     

p73基因研究进展

p53基因的突变、失活及缺失与50％的人类肿瘤发生有关，因此p53基因被视为经典的抑癌基因。近年来，随着对p53基因广泛深入的研究，p53家族的其他成员不断被发现，其中p73基因是p53基因家族中被发现的第一个成员。p73基因编码的蛋白质，无论在结构上，还是在功能上均与p53蛋白相似，且与肿瘤的发生密切相关，可抑制细胞增殖，诱导凋亡。深入了解它们彼此的相似性、差异性，可对研究肿瘤的发生机制和对肿瘤的基因治疗提供帮助，为最终攻克癌症带来希望。     

Mina53 as a potential prognostic factor for esophageal squamous cell carcinoma.

PURPOSE: We previously identified mina53, a novel Myc target gene. Here we investigated whether mina53 is related to esophageal squamous cell carcinoma (ESCC), a disease with poor prognosis. EXPERIMENTAL DESIGN: Mina53 expression was suppressed in ESCC cell lines by a RNA interference method to investigate whether Mina53 is involved in cell proliferation. Expression of Mina53 was investigated by Western blotting in tissue sections from patients with ESCC. Immunohistochemical analysis of Mina53 was carried out and compared with that using anti-Ki-67 antibody. Finally, the level of Mina53 expression was compared with the length of survival of patients with ESCC. RESULTS: Reduction of mina53 expression by RNA interference suppressed cell proliferation in ESCC cell lines. Western blot analysis of surgically resected ESCC specimens indicated that the expression of Mina53 in tumors was increased compared with that in adjacent nonneoplastic tissues in all four specimens examined. When formalin-fixed specimens from 52 patients with ESCC were stained immunohistochemically, it was found that Mina53 was highly expressed in 83% of specimens. Anti-Mina53 antibody stained tumors more efficiently than antibody against Ki-67, a cell proliferation biomarker, in some cancer specimens. Patients with high expression of Mina53 had shorter survival periods, whereas the expression level of Ki-67 in ESCC showed no relationship to patient outcome. CONCLUSIONS: Taken together, our results indicate that expression of Mina53 is a characteristic feature of ESCC and suggest that immunostaining by anti-Mina53 antibody may be useful as a potential prognostic indicator.     

Expression of Myc target gene mina53 in subtypes of human lymphoma

Mina53 (mina) was identified as a gene, which is directly induced by the oncogene c-myc. Elevated expression of Mina53 protein was found in >80% of colon cancer and esophageal squamous cell carcinoma (ESCC). Patients with high expression of Mina53 had shorter survival, suggesting the prognostic usefulness of Mina53. We studied Mina53 expression in lymphoma subtypes to examine its diagnostic significance and its possible role in lymphoma-genesis. Surgical cases of 28 lymphoma and 4 non-neoplastic tissues were stained immunochemically using anti-Mina53 monoclonal antibody. Mina53 expression correlated well with c-Myc expression in lymphoma, suggesting that c-Myc is a controlling factor for mina53 expression also in lymphomas. Although the expression of Mina53 as well as c-Myc was less frequent in lymphoma compared with those of colon and ESCC, increased expression of Mina53 was found in Burkitt-like lymphoma (1/1), Hodgkin's lymphoma (3/5), diffuse large B cell lymphoma (DLBCL) (5/13), lymphomas with a transition from follicular to DLBCL (1/2), with none in follicular (0/4) and T cell lymphoma (0/3). Analyses of the data suggested that Mina53 was frequently expressed in aggressive types of B cell lymphoma. To get more information about the expression of Mina53 in DLBCL, which most frequently occurs among lymphomas, we analyzed the expression of Mina53 in another 21 DLBCL specimens, which were in more advanced stages than those described above. The expression level of Mina53 correlated to the international prognostic index (IPI) values with statistical significance (r=0.477, P=0.0275). Notably, in this group, Mina53 expression did not correlate with c-Myc expression, suggesting that other factor(s) besides c-Myc largely affect the expression of Mina53 in advanced DLBCL. These results suggest that although Mina53 expression is not prominent in lymphoma in general, it may be related to tumor progression of B cell lymphoma.     

p53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma.

Anaplastic large-cell lymphoma (ALCL), as defined in the World Health Organization, is a heterogeneous category in which a subset of cases is associated with the t(2;5)(p23;q35) or variant translocations resulting in overexpression of anaplastic lymphoma kinase (ALK). p53 has not been assessed in currently defined subsets of ALCL tumors. In this study, we assessed ALK+ and ALK- ALCL tumors for p53 gene alterations using PCR, single-strand conformation polymorphism and direct sequencing methods. We also immunohistochemically assessed ALCL tumors for p53 expression. Three of 36 (8%) ALCL tumors (1/14 ALK+, 2/22 ALK-) with adequate DNA showed p53 gene mutations. By contrast, p53 was overexpressed in 36 of 55 (65%) ALCL tumors (16 ALK+, 20 ALK-). p21, a target of p53, was expressed in 15 of 31 (48%) ALCL tumors including seven of 15 (47%) p53-positive tumors. p21 expression in a subset of ALCL suggests the presence of functional p53 protein. Apoptotic rate was significantly higher in p53-positive than p53-negative tumors (mean 2.78 vs 0.91%, P = 0.0003). We conclude that the p53 gene is rarely mutated in ALK+ and ALK- ALCL tumors. Nevertheless, wild-type p53 gene product is commonly overexpressed in ALCL and may be functional in a subset of these tumors.     

Organ-specific susceptibility of p53 knockout mice to N-bis(2-hydroxypropyl)nitrosamine carcinogenesis

To elucidate which is the major determinant of susceptibility of p53 deficient mice, the carcinogen or the target organ, N-bis(2-hydroxypropyl)nitrosamine was administered to induce tumors in multi-organs. In a 15-week experiment, the incidences of both lung and hepatic vascular tumors were found to be significantly higher in p53 nullizygous (-/-) than in heterozygous (+/-) and wild-type (+/+) mice, indicating universal susceptibility of p53 (-/-) mice. In a 40-week experiment, p53 (+/-) mice showed increased susceptibility only with regard to vascular tumors, coinciding with significantly more frequent (60%) p53 gene mutations, in comparison with lung tumors with their low mutation rate (10.8%) (P<0.005). These results indicate that the target organ may be a more important factor than the carcinogen in determining susceptibility of p53 (+/-) mice.     

P21 gene expression as an indicator for the activity of adenovirus-p53 gene therapy in non-small cell lung cancer patients

Alterations in the tumor suppressor gene p53 lead to impaired cell cycle control, allowing for the development and growth of tumors. To restore a loss of p53 function, we performed a phase I study of intratumoral gene therapy with adenovirus expressing wild-type p53 in patients with non-small cell lung cancer carrying mutations in the p53 gene. Furthermore, in a phase II study, gene therapy was complemented with simultaneous cisplatin/vinorelbine treatment. Biopsies were obtained from all treated patients before and 24-48 hours after gene therapy to study changes in the expression of p53 target genes. We report here that in most of the cases, the target gene p21 was up-regulated, especially when injection of higher doses of p53-expressing adenovirus was combined with simultaneous chemotherapy, whereas Pig3, previously reported to be highly up-regulated by p53, generally did not show a clear increase. Interestingly, a clear p21 gene response was observed only in tumors showing stabilization or regression. We conclude that p21 appears to be up-regulated after adenovirus-mediated p53 gene transfer and is the most sensitive marker tested for biological response to gene therapy in the small cohort of non-small cell lung cancers that were studied.