胆囊癌p53、p73和p21~(WAF1)蛋白的表达

目的 探讨p53、p73和p21WAF1基因在胆囊癌中的表达.方法 应用免疫组化SP法检测48例胆囊癌、32例癌旁组织、20例正常胆囊组织p53、p73和p21WAF1蛋白的表达,分析p73和p21WAF1相互关系.结果 48例胆囊癌中,p53、p73和p21WAF1蛋白阳性表达率分别为56.2%、52.1%和43.8%,均高于癌旁组织和正常组织(P<0.01).胆囊癌中p73蛋白的表达与Nevin分期有关(P<0.05),p21WAF1蛋白的表达与淋巴结转移、Nevin分期有关(P<0.05).结论 p53、p73和p21WAF1基因在胆囊癌高表达,提示三者在胆囊癌发生发展中起重要作用.胆囊癌中p73与p21WAF1表达无相关性.     

转录因子与顺铂耐药关系的研究进展

顺铂是治疗实体肿瘤的常用药物之一,但肿瘤细胞对顺铂的耐药是目前肿瘤治疗中遇到的一大难题。近年来,随着顺铂耐药分子机制研究的深入,已发现一些转录因子如p53/p73、c-Myc、YB-1等与顺铂耐药相关。本文综述了转录因子与顺铂耐药的研究进展。     

抑癌基因p53、p63、p73在大肠癌中的表达及意义

目的 研究p53、p63、p73蛋白表达与大肠癌发生风险的关系.方法 采用免疫组织化学方法检测炎症性肠病、大肠癌及癌旁正常组织中p53、p63、p73蛋白的表达情况.结果 p53、p63、p73蛋白在大肠癌中的表达与炎症性肠病、癌旁正常组织对照,差异有统计学意义.p53、p63、p73蛋白表达与大肠癌的细胞分化程度有关,与黏膜浸润深度、淋巴结转移情况无关.结论 p53、p63、p73蛋白表达增加与大肠癌有关,p53、p63、p73蛋白表达增加与大肠癌的恶性度有一定的关系.     

p73基因与鼻咽癌关系的研究现状

p53基因家族目前包括p53、p63、p73,共3个基因。p53基因是一个研究较为深入的肿瘤抑制基因,与人类肿瘤相关性极高,其在人类肿瘤中突变率较高,且突变型具有致癌作用。p73基因作为p53家族的另一成员,与p53基因在基因及蛋白水平上具有高度的同源性。但是在许多方面与p53基因也存在着显著差异。本文就p73基因的表达类型、结构和功能及其与鼻咽癌的相关性作一综述。     

p73与p53在卵巢上皮性肿瘤中的表达及其相关性的研究

目的：研究抑癌基因p73及突变型p53蛋白在人上皮性卵巢肿瘤组织中的表达及其临床意义,进一步探讨卵巢上皮性肿瘤的发生发展机制。方法：检测102例卵巢上皮性肿瘤组织中p73及p53蛋白的表达情况,应用SPSS11．5统计软件进行检验,综合患者的手术病理分期、组织类型、病理分级以及预后等重要的相关因素来分析每种蛋白表达的差异及其相关性。结果：①p73蛋白在良性肿瘤中无表达,而在交界性肿瘤和卵巢癌中均有表达,与组织分化有关,与临床分期无明显相关性。②p53蛋白在良性肿瘤中无表达,而在交界性肿瘤和卵巢癌中均有表达,与临床分期、病理分级及有无腹水和淋巴结转移相关。③p73表达与p53表达呈显著正相关。④p53蛋白累积与生存预后呈显著负相关,而p73表达与生存时间无关。结论：①p73基因异常表达可能参与了卵巢上皮性肿瘤的发生发展。②在卵巢上皮性恶性肿瘤中,p73过表达与p53表达状况明显相关。     

膀胱癌组织mdm2，p53基因蛋白的表达及意义

检测膀胱癌组织中mdm2基因蛋白和p53基因蛋白表达并探讨二者与肿瘤分期、分级、复发的关系。方法 采用免疫组织化学技术(ABC法)对60例膀胱移行细胞癌(TCC)组织中mdm2基因蛋白和p53基因蛋白的表达进行了检测。结果 mdm2基因蛋白表达主要见于中、高分化的肿瘤细胞,并随肿瘤临床分期的增高,表达率逐渐下降,初发者比复发者表达率高(P<0.05),而p53基因的表达则与其相反。两者异常表达呈负相关(γ=-0.4737,P<0.05),均与肿瘤生长方式、年龄、性别无关。结论 mdm2基因蛋白与p53基因蛋白的异常表达与膀胱癌的临床分期、病理学分级及肿瘤复发有密切关系。     

紫杉醇耐药机制的研究进展

耐药是临床治疗肿瘤失败的重要原因,肿瘤细胞对紫杉醇耐药又是一个多途径的过程,本文分别从多药耐药、微管蛋白同型的改变、微管蛋白的突变以及促凋亡基因Bax和p53等方面阐述紫杉醇的耐药作用机制。     

p53、p63和p73蛋白在血管瘤组织中表达的相关性分析

为探讨 p5 3、p63和 p73蛋白在血管瘤中表达及与血管瘤发生发展机制的研究 ,采用免疫组织化学方法 ( S-P法 )检测人皮肤血管瘤增生期、退化期及正常组织中 p5 3、p63和 p73蛋白的表达水平及进行图像分析。结果显示 ,发现 p5 3、p63和 p73蛋白在血管瘤增生期的表达高于退化期 ,差异有显著性意义 ( P<0 .0 1) ,提示 p5 3、p63和 p73蛋白与血管瘤的发生、发展及退化密切相关。     

恶性肿瘤患者血清及胸水p53的表达及意义

p53基因是一种肿瘤抑制基因,正常功能是调控细胞增殖。肺癌、乳癌和直肠癌等肿瘤中均有p53蛋白的突变和缺失。研究表明,突变型p53蛋白不仅失去正常的肿瘤抑制基因作用,而且部分出现癌基因的促细胞增生作用。恶性胸水是肿瘤细胞胸腔浸润和转移的结果。本文对30例伴胸水的恶性肿瘤患者同时进行血清和胸水p53含量的检测,并与正常人血清及结核性胸水对照。旨在研究p53在血清及胸水中的表达水平与肿瘤生长、侵袭、转移的关系。     

p16与p53蛋白及增殖细胞核抗原在肝细胞癌中的表达

为探讨 p1 6、p53蛋白及增殖细胞核抗原在肝细胞肝癌发生发展中的作用及临床意义 ,用免疫组织化学方法检测 30例肝细胞癌组织中 p1 6、p53蛋白及增殖细胞核抗原的表达。结果 ,p1 6、p53蛋白及增殖细胞核抗原在肝细胞癌组织中阳性表达率分别为 36.67%、56.67%、83.33% ,且与肝细胞癌组织的分化程度及有无肿瘤包膜受侵有关。p1 6蛋白与 p53蛋白和增殖细胞核抗原阳性表达无明显相关 (P >0 .0 5) ,而 p53蛋白与增殖细胞核抗原阳性表达明显相关 (P <0 .0 5)。提示 p1 6基因失活、p53基因突变和细胞增殖活性增强在肝细胞癌发生发展过程中起重要作用 ,p1 6、p53蛋白及增殖细胞核抗原的表达对肝细胞癌的分级及预后判断有一定意义 ,有助于早期诊断及治疗     

One, two, three—p53, p63, p73 and chemosensitivity

Molecular links between apoptosis, tumorigenesis and drug resistance provide starting points for new therapeutic approaches and for a targeted cancer therapy. The discovery of the p53-related genes p63 and p73 raised the possibility that they may be cancer-associated genes and as a consequence that p53 is not the only component in predicting prognosis and response to chemotherapy, but instead the status of a network that contains p53, p73 and p63. This review focuses on the status and interrelationship of the p53 family members in human cancer as critical elements for tumor progression and response to therapy. Literature up to December 2006 is reviewed. p63 and p73--as well as p53--each use multiple promoters and alternative splicing to generate an array of isoforms, including full-length isoforms with a transactivation (TA-) domain homologous to that of full-length p53, and amino-terminally truncated (DeltaN-) isoforms. Whereas the full-length TA isoforms of p63 and p73 can activate downstream target genes and induce apoptosis, the DeltaN isoforms which lack the transactivation domain can act as dominant inhibitors of the full-length forms of p53, p63 and p73, inhibiting transactivation of target genes and induction of apoptosis. Deregulated dominant negative p63 and p73 isoforms play an oncogenic role in human cancer and contribute to chemoresistance. Thus, therapeutic modulation of TAp63/DeltaNp63, TAp73/DeltaNp73 and mutant p53 levels might be used to target the large percentage of human tumors that harbor p53 mutations and/or overexpress DeltaNp63 or DeltaNp73. Interfering with the expression or function of DeltaNp63 and/or DeltaNp73 and/or mutant p53 in tumor cells may render such tumors more responsive to therapy and reduce their aggressiveness and metastatic capacity.     

The p53-mediated cytotoxicity of photodynamic therapy of cancer: recent advances

Photodynamic therapy (PDT) is a promising modality for the treatment of both pre-malignant and malignant lesions. The mechanism of action converges mainly on the generation of reactive oxygen species which damage cancer cells directly as well as indirectly acting on tumor vasculature. The exact mechanism of PDT action is not fully understood, which is a formidable barrier to its successful clinical application. Elucidation of the mechanisms of cancer cell elimination by PDT might help in establishing highly specific, non-genotoxic anti-cancer treatment of tomorrow. One of the candidate PDT targets is the well-known tumor suppressor p53 protein recognized as the guardian of the genome. Together with its family members, p73 and p63 proteins, p53 is involved in apoptosis induction upon stress stimuli. The wild-type and mutant p53-targeting chemotherapeutics are currently extensively investigated as a promising strategy for highly specific anti-cancer therapy. In photodynamic therapy porphyrinogenic sensitizers are the most widely used compounds due to their potent biophysical and biochemical properties. Recent data suggest that the p53 tumor suppressor protein might play a significant role in porphyrin-PDT-mediated cell death by direct interaction with the drug which leads to its accumulation and induction of p53-dependent cell death both in the dark and upon irradiation. In this review we describe the available evidence on the role of p53 in PDT.     

简析p53基因与肿瘤多药耐药

在过去的数十年内对p53基因及其产物的研究取得了重大进展,而肿瘤的多药耐药已经成为现今肿瘤治疗的重大障碍。考虑到p53基因作为抑癌基因的重要意义,整理归纳了p53及其产物在抑癌方面的主要机制,肿瘤多药耐药基因之间的相互作用关系以及在神经系统中p53基因突变的反常保护机制,以期为逆转抗肿瘤药的多药耐药提供新思路。     

Expression of p53-family members and associated target molecules in breast cancer cell lines in response to vincristine treatment

As the antimitotic agent vincristine (VCR) has been reported to induce a weak p53 response in some studies, we hypothesised that p73 and p63, the recently described p53 homologues, may replace p53 in triggering apoptosis or cell cycle arrest effectors in VCR-treated cell lines. To address this issue, we measured p53, p73 and p63 mRNA and protein levels in two VCR-treated breast cancer cell lines, one p53-proficient (MCF7) and the other p53-deficient (MDA-MB157). We found an increase of p53 mRNA and protein levels in VCR-treated MCF7 cells, while, as expected, no p53 protein was detected in VCR-treated MDA-MB157 cells. Surprisingly, the p73 mRNA and protein expression levels decreased in both cell lines during VCR treatment, whereas p63 protein levels remained unchanged. In both cell lines, up-regulations of the canonical p53-target genes, such as p21 and GADD45, were consistently observed. We conclude that, in response to VCR treatment: (1) p53 is markedly induced in MCF7 cells, with the same extent than after DNA damaging drugs treatments; and (2) p63 is not involved, while p73 expression is down-regulated regardless of the p53 status of the cell lines. Our results therefore suggest the involvement of a fourth member of the p53 gene family, or the use of another pathway able to trigger canonical p53-target genes in response to VCR in p53-deficient cells.     

p73 as a pharmaceutical target for cancer therapy

About half of all human tumors contain an inactivating mutation of p53, while in the remaining tumors, the p53 pathway is frequently abrogated by alterations of other components of its signaling pathway. In humans, the p53 tumor suppressor is part of a small gene family that includes two other members, p73 and p63, structurally and functionally related to p53. Accumulating evidences indicate that all p53-family proteins function as molecular hubs of a highly interconnected signaling network that coordinates cell proliferation, differentiation and death in response to physiological inputs and oncogenic stress. Therefore, not only the p53-pathway but the entire "p53-family pathway" is a primary target for cancer drug development. In particular, the p53-related protein p73 has a crucial role in determining cellular responses to chemotherapy, and can vicariate p53 functions in triggering cell death after DNA damage in multiple experimental models. The biology and regulation of p73 is complex, since the TP73 gene incorporates both tumor-suppressive and proto-oncogenic functions. However, the p73 gene is rarely mutated in tumors, so appropriate pharmacological manipulation of the p73 pathway is a very promising approach for cancer therapy. Here we provide an overview of the principal mechanism of p73 regulation, and describe several examples of pharmacological tools that can induce p73 accumulation and function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. A better understanding of how the p73 pathway works is mandatory to discover additional players intervening in this pathway and has important implications for the improvement of cancer treatment with the development of new molecules or with the reposition of currently available drugs.     

Therapeutic targeting of the p53 pathway in cancer stem cells

Introduction: Cancer stem cells (CSCs) are a high profile drug target for cancer therapeutics due to their indispensable role in cancer progression, maintenance and therapeutic resistance. Restoring wild-type (WT) p53 function is an attractive new therapeutic approach for the treatment of cancer due to the well-described powerful tumor suppressor function of p53. As emerging evidence intimately links p53 and stem cell biology, this approach also provides an opportunity to target CSCs.

Areas covered: This review covers the therapeutic approaches to restore the function of WT p53, cancer and normal stem cell biology in relation to p53 and the downstream effects of p53 on CSCs.

Expert opinion: The restoration of WT p53 function by targeting p53 directly, its interacting proteins or its family members holds promise as a new class of cancer therapies. This review examines the impact that such therapies may have on normal and CSCs based on the current evidence linking p53 signaling with these populations.