p53与人类肺癌关系研究的进展

p53基因是目前人类所发现的与肿瘤发病相关性最大的抑癌基因(tumorsuppressorgene,TSG)。p53基因的点突变、缺失及灭活在肺癌的发生和进展过程中起着关键性的作用。随着各项研究的不断进展以及高新检测技术的出现,p53在肺癌的早期诊断中的价值得到进一步的肯定。同时,利用p53进行基因治疗及评价肺癌患者预后的研究也逐渐开展起来并取得一定成效。因此深入探讨p53基因与人类肺癌的关系具有重大的意义。本文就p53与人类肺癌关系研究的进展作一论述。     

p53 and Follow-up of Colorectal Adenocarcinomas

Circulating p53 antibodies (ELISA method), p53genetic alterations (SSCP), and protein overexpression(immunohistochemistry) were studied in 41 patients withcolorectal adenocarcinomas and 10 control patients. Carcinoembryonic antigen (CEA) and carbohydrateantigen 19.9 (CA 19-9) were evaluated in parallel. Tenpatients with p53 antibodies and p53 overexpression wereselected. Tumor DNA extracts from these 10 patients were analyzed by SSCP. Of all 41patients, 10 (24%) showed significant levels of p53antibodies, and p53 accumulation was detected in 20(48%) patients. In six patients, p53 antibodieconcentrations decreased rapidly after surgery; in twopatients, these levels returned to normal values. Of the10 selected tumors, eight revealed TP53 gene mutations.Only two patients with high values of both CEA and CA 19-9 developed p53 antibodies. Inconclusion, beside classical tumor markers, circulatingp53 antibodies may be considered as additional markersfor the management of patients with colorectaladenocarcinomas.     

p53 allele deletion and protein accumulation occurs in the absence of p53 gene mutation in T-prolymphocytic leukaemia and Sezary syndrome

In a series of 24 patients with chronic T-lymphoid disorders [13 T-prolymphocytic leukaemia (T-PLL) and 11 Sezary syndrome] we have studied (i) chromosome 17p abnormalities and p53 allele deletion by fluorescence in situ hybridization; (ii) mutation in the exons of the p53 gene by direct DNA sequencing; and (iii) p53 protein expression by immunocytochemistry and, in some cases, also by flow cytometry with DO-1, a monoclonal antibody to the p53 protein. The study revealed p53 deletion and accumulation of p53 protein in the absence of mutation in the exons that included the hot-spots and differs from that described in B-prolymphocytic leukaemia. Seven T-PLL and five Sezary syndrome patients had p53 overexpression, and five T-PLL and nine Sezary syndrome patients showed p53 deletion. Although the majority of cases with p53 accumulation had p53 deletion, the proportion of cells with the deletion did not correlate with the proportion of cells positive for p53 expression. Two cases of T-PLL showed strong p53 expression in the absence of p53 deletion, and one case of Sezary syndrome with p53 deletion in 97% of cells did not express p53. These findings suggest that a non-mutational mechanism exists for the accumulation of p53 protein in these T-cell disorders. The oncogenic effect of the accumulating wild-type protein has been reported in other malignancies. Whether haploidy resulting from p53 deletion contributes to this mechanism has yet to be determined. Alternatively, the frequent loss of the p53 gene could be associated with the deletion of an adjacent gene, which could be involved in the pathogenesis of these diseases.     

p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function

The role of p53 family member, p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16^INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) >2, and in activated-B-cell–like DLBCL patients with wide-type TP53. The prognostic impact in germinal-center-B-cell–like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of ∆Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations.     

Molecular diagnosis and treatment for esophageal carcinoma with p53

We reviewed molecular diagnosis and molecular treatment using p53 as a target for esophageal squamous cell carcinoma (SCC). First, we analyzed serum p53 antibodies (s-p53 Abs) in patients with esophageal SCC. Positive rate was 31% in all patients analyzed (n = 292) and 23% in stage I patients (cTNM/UICC stages) (n = 48). Presence of s-p53 Abs was significantly associated with p53 protein overexpression in resected tumor specimens. Seropositive patients were more likely to be resistant to chemoradiation and had a worse prognosis than seronegative patients. Second, we performed a clinical study of p53 gene therapy in 10 patients with unresectable chemoradiation-resistant esophageal SCC. In 9 patients, stability of the local tumor was achieved. No serious adverse events related to Ad5CMV-p53 have occurred in these patients, and the trial was safely conducted. Thus, intratumoral injection of Ad5CMV-p53 is safe, feasible, and biologically active when administered in multiple doses to patients with esophageal cancer. Observations from these clinical studies indicate that p53 is a useful molecular target in the diagnosis and treatment of esophageal SCC. Proceeding of a symposium at the 60th annual meeting of the Japan Esophageal Society: “Clinical aspects of molecular biology for the diagnosis and treatment of esophageal carcinoma.”     

Clinical significance of p53 antigen and anti-p53 antibodies in the sera of hepatocellular carcinoma patients

Background. To analyze the clinical significance of serum p53 protein and anti-p53 antibodies as serological markers for hepatocellular carcinoma (HCC). Methods. We studied clinical data, i.e., age, sex, etiology, serum alpha-fetoprotein (AFP) level, TMN staging, and Okuda staging in 141 patients with HCC. The sera of these patients were analyzed for serum p53 protein and serum anti-p53 antibodies by enzyme-linked immunosorbent assay (ELISA). Results. Serum p53 antigen and serum anti-p53 antibodies were detected in the sera of 32 of the 141 (22.7%) patients and 26 of the 141 patients (18.4%), respectively. Of note, the HCC patients who were positive for p53 antigen (32/141) had no circulating anti-p53 antibodies. When both these groups of patients were combined as a serum p53 status-positive group, the total number in this group was 58 (41.1%). Positive status of p53 was not associated with age (P = 0.206), serum alpha-fetoprotein level (P = 0.851), Okuda staging (P = 0.243), or survival (P = 0.078), but was correlated significantly with TMN staging (P = 0.049). Interestingly, a shorter survival time (mean, 3.9 months) was noted in the serum p53 status-positive group, in comparison with the longer survival time (mean, 6.5 months) in the serum p53 status-negative group. Conclusions. Combination of the detection of serum p53 antigen and antibodies by ELISA may represent a suitable noninvasive investigation in assessing the clinical implications and prognoses of patients with HCC. Received: December 8, 2000 / Accepted: June 22, 2001     

Immunohistochemical Expression of p16, p53, and p63 in Colorectal Adenomas and Adenocarcinomas

Purpose The aim of this study was to investigate the immunohistochemical expression of p16, p53, and p63 proteins according to some pathologic parameters related to colorectal adenomas and adenocarcinomas such as grade of dysplasia and histologic type. Methods Immunohistochemistry with the antibodies p16, p53, and p63 was performed in tubular, tubular-villous, and villous adenomas (n = 30) and in well, moderately, and poorly differentiated adenocarcinomas (n = 30). The p63-positive cases were submitted to double immunolabeling with the cytokeratin 5 (CK5). Results The p16 and p53 labelings were observed in some adenomas and adenocarcinomas but without any association with p63 expression, histologic type, or grade of differentiation of the neoplasm. P63 expression was found mainly in the villous adenomas and in the poorly differentiated adenocarcinomas. The poorly differentiated adenocarcinomas also exhibited coexpression of CK5 and p63. Conclusions Despite both p16 and p53 having been detected in colorectal neoplasms, they were not related to the different histologic variables nor to the expression of p63. However, p63 expression was closely associated with villous adenomas and poorly differentiated adenocarcinomas. Thus, p63 may represent a marker of poor differentiation in colorectal neoplasms. The coexpression of p63 and CK5 observed in this study could be related to divergent differentiation during the development of colorectal cancer, although further studies are warranted to refine the understanding of this process.     

胃黏膜癌前病变中p53和增殖细胞核抗原的表达及其临床意义

目的探讨胃黏膜癌前病变中p53和增殖细胞核抗原（PCNA）的表达及其临床意义。方法顺序选择病理检查为肠上皮化生、不典型增生、肠上皮化生不典型增生共存的患者各20例（分别为A、B和C组）,另选20例正常者作为对照（D组）。免疫组化法检测其组织中p53和PCNA的表达。结果胃黏膜癌前病变中p53蛋白、PCNA表达水平均高于正常黏膜（P〈0．01）,表达水平从肠上皮化生、不典型增生到二者共存者呈递增趋势。结论p53和PCNA表达对评估胃黏膜癌前病变发展趋势有重要的临床价值,有助于早期发现胃癌。     

肿瘤抑制基因p53与肝炎病毒调节的研究

肝炎病毒包括甲、乙、丙、丁、戊型等肝炎病毒 ,而研究最多的是乙型肝炎病毒 (HBV)和丙型肝炎病毒(HCV)。p5 3是肿瘤抑制基因 ,编码p5 3蛋白直接诱导基因的表达并参与细胞周期的调节。肝炎病毒基因编码的蛋白也作用于肝细胞 ,引起肝脏的损害。肝炎病毒与p5 3互相作用 ,导致肝细胞病变 ,特别是肿瘤的发生。一、p5 3的结构和功能p5 3基因是肿瘤抑制基因 ,又称为基因组卫士 ,在DNA损害时 ,在修复过程中具有重要作用。在这种条件下 ,p5 3抑制细胞周期或诱导凋亡。p5 3蛋白的结构和功能分为 4个区 ,其中 2个区最重要 :序列特异DNA结合区、氨…     

胃癌组织FAT10与突变型p53表达及其相互关系

目的 检测FAT10与突变型p53在胃癌组织中的表达情况及相互间关系.方法 采用免疫组化和逆转录-聚合酶链反应(RT-PCR)方法检测FAT10和突变型p53在62例胃癌患者的胃癌组织、癌旁组织(距癌边缘2～5 cm)及正常胃组织(距癌边缘>5 cm)中的表达水平,统计分析两者表达间的关联性及FAT10与胃癌预后之间的关系.结果 FAT10蛋白和突变型p53蛋白在胃癌组织中的表达阳性率分别为51.61%(32/62)和45.16%(28/62),显著高于癌旁组织[12.90%(8/62)和14.51%(9/62),χ2值分别=21.26和20.69,P值均<0.01]及正常胃组织[6.45%(4/62)和9.68%(6/62),χ2值分别=13.91和19.61,P值均<0.01].胃癌FAT10蛋白及mRNA的表达上升主要与胃癌的淋巴转移及TNM分期密切相关(P值均<0.05).胃癌组织中FAT10表达在蛋白及基因水平均与突变型p53表达呈正相关性(r值分别=0.865和0.761,P值分别<0.05和0.01).FAT10蛋白阳性表达或mRNA表达水平高者,其累计生存时间显著低于FAT10阴性者(P值均<0.05).结论 FAT10与突变型p53在胃癌组织中表达上调且呈正相关性,两者可能共同参与胃癌的形成与发展,FAT10对评价胃癌的预后可能有较好的价值.     

胃癌组织中hPOT1和p53表达及其临床意义

目的探讨人端粒保护蛋白1（hPOT1）和p53在胃癌发生发展中的作用及机制。方法采用免疫组化SP法检测53份胃癌组织标本（观察组）及10份正常胃黏膜组织标本（对照组）hPOT1和p53蛋白表达;分析其与胃癌病理参数的关系。结果观察组hPOT1和p53蛋白阳性率均显著高于对照组P〈0.05;hPOT1表达与胃癌组织学分型、分化程度及浸润深度有关（P〈0.05）。p53表达与肿瘤浸润深度有关,P〈0.05;观察组hPOT1与p53蛋白表达呈正相关,P〈0.05。结论 hPOT1和p53参与了胃癌的发生、发展;联合检测hPOT1和p53蛋白表达有助于判断胃癌患者的预后。     

p53 gene mutations and expression of p53 and mdm2 proteins in invasive breast carcinoma

The aim of the study was to analyzep53 gene mutations and the expression of p53 and mdm2 proteins in 31 randomly selected invasive breast carcinomas. The results were then correlated with tumor grade, stage, estrogen receptor status, nodal status, and DNA ploidy. The expression of the proteins p53 and mdm2 was determined immunohistochemically using formalin-fixed, paraffin-embedded material. Screening for p53 mutation involved analysis of the highly conserved regions of thep53 gene (exons 5–9) by the polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) technique. PCR products with band shifts were directly sequenced. Immunohistochemical staining of p53 was positive in 9 cases (29.0%), only 2 of which showed ap53 gene mutation. These were identified as a CG transversion at the second position of codon 278 in exon 8 and an AG transition at the second position of codon 205 in exon 6. A third case with a mutation was observed (CT transition, position 1 of codon 250 in exon 7) that did not show p53 immunohistochemically. Of the 9 p53-positive tumors, 2 were moderately differentiated (grade II). The remaining tumors were poorly differentiated (7/9). By contrast, p53-negative carcinomas were well differentiated (grade I) in most cases (P=0.02). DNA cytometry in 8 of the 9 p53-positive carcinomas revealed an aneuploid stem line. The majority of the p53-negative tumors were diploid (P=0.01). Mdm2 oncoprotein was detected in 10 tumors (32.2%), 4 of which were p53-positive, including the 3 with mutations. The grading of the mdm2-positive tumors was moderate or poor, G1 carcinomas were always noted to be mdm2-negative (P=0.04). Overexpression of p53 protein is a complex mechanism and does not merely indicate the detection of mutations in thep53 gene. This study has shown that p53 expression correlates with tumor grade and DNA ploidy. Mdm2 expression was also associated with the tumor grade. Immunohistological demonstration of the p53 protein alone is insufficient as a basis for comment on the functional state of thep53 gene and gene product. The interrelation between recognition of the p53 protein and gene mutation needs more careful assessment to define their roles in the control of neoplasia.     

大肠小扁平腺瘤、息肉样腺瘤p53、p21表达的研究

目的:观察大肠小扁平腺瘤p53、p21基因的表达,探讨小扁平腺瘤与息肉样腺瘤生物学行为的不同及其与大肠癌的关系.方法:利用免疫组化法研究50例小扁平腺瘤(A组)和30例息肉样腺瘤(B组)以及20例正常大肠黏膜(C组)的p53、P21基因表达情况.结果:p53、p21 在A、B、C 三组中阳性率分别为58%、56%;33.3%、36.7%;5%、10%.P53阳性率三组间差异有显著性(P＜0.05).p21阳性率:A、B组分别与C组有差异显著性(P＜0.05);A组高于B组,但卡方检验P＞0.05,无统汁学差异;A组进一步与B组中直径＜1.0cm的腺瘤的p21阳性率(30%)比较,差异有显著性(P＜0.05).结论:大肠小扁平腺瘤p53、p21基因的异常表达提示小扁平腺瘤的生物学行为与息肉样腺瘤有差别,可能更易于恶变.     

p53基因网络与幽门螺杆菌致胃病关系的研究进展

H pylori与胃黏膜病变关系密切已被公认,H pylori感染可引起胃黏膜细胞增殖与凋亡的失衡,这与其致病致癌密切相关.p53基因这一复杂的网络系统在调控细胞凋亡与增殖的过程中,发挥重要的作用.就p53下游基因网络与H pylori、胃黏膜细胞增殖凋亡之间的关系作一综述.     

The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo

There are currently two distinct models proposed to explain why both MDM2 and MDMX are required in p53 control, with a key difference centered on whether these two p53 inhibitors work together or independently. To test these two competing models, we generated knockin mice expressing a point mutation MDMX mutant (C462A) that is defective in MDM2 binding. This approach allowed a targeted disassociation of the MDM2/MDMX heterocomplex without affecting the ability of MDMX to bind to p53, and while leaving the MDM2 protein itself completely untouched. Significantly, Mdmx(C462A/C462A) homozygous mice died at approximately day 9.5 of embryonic development, as the result of a combination of apoptosis and decreased cell proliferation, as shown by TUNEL and BrdU incorporation assays, respectively. Interestingly, even though the MDMX mutant protein abundance was found slightly elevated in the Mdmx(C462A/C462A) homozygous embryos, both the abundance and activity of p53 were markedly increased. A p53-dependent death was demonstrated by the finding that concomitant deletion of p53 completely rescued the embryonic lethality in Mdmx(C462A/C462A) homozygous mice. Our data demonstrate that MDM2 and MDMX function as an integral complex in p53 control, providing insights into the nonredundant nature of the function of MDM2 and MDMX.     

p53基因在食管癌组织中的高表达

本文利用免疫组化LSAB法检测了p53基因在35例食管癌组织中的表达情况。35例食管癌标本中，60％（21／35）的标本癌组织都存在有p53基因的高表达，其中18例标本同时存在有癌旁粘膜上皮p53基因在10例癌旁粘膜上皮中也存在高表达。p53的高表达主要位于核内，部分也有胞浆表达。p53基因的高表达与癌组织的分化程度有关，分化越差，阳性率越高（P＜0．0025）。p53基因的表达存在异质性，并与肿瘤细胞的浸润转移及细胞周期的不同有关。我们的结果表明，p53基因的高表达在食管癌的发生中是一个常见的基因改变，它在食管癌的发生发展中起着重要的作用。     

基质金属蛋白酶与p53及核因子κB在肿瘤侵袭转移中的研究进展

基质金属蛋白酶在肿瘤侵袭转移中起着非常重要的作用.而基质金属蛋白酶的分泌与p53突变及核因子κB信号传导通路激活相关.因此综述基质金属蛋白酶与p53及核因子κB之间的关系,有利于寻找更多的靶点,以控制肿瘤发生、浸润、转移.