宫颈癌放疗敏感性相关因子研究现状

宫颈癌放疗的敏感性与放疗疗效密切相关。目前研究的与宫颈癌放疗敏感性相关因子包括细胞间黏附分子-3、缺氧诱导因子-1α、血管内皮生长因子、Ki67、p53等。寻找能在宫颈癌放疗前预测放射敏感性的指标,对于制定个体化的治疗方案、合理进行综合治疗具有重要意义。     

p53基因改变对人体鼻咽癌放射敏感性的影响

很久以来,肿瘤的病理类型、分化程度、乏氧等在临床上被看作是影响肿瘤放射敏感性的重要因素。近来一些文献报道细胞内某些癌基因(如ras、myc、raf等)的改变至少对肿瘤细胞的放射敏感性有影响。作者对既往在中国医科院肿瘤医院接受过放疗的部分鼻咽癌治疗前标本中p53基因的表达情况进行了检测,以了解p53基因改变对体内肿瘤放射敏感性的影响。1　材料和方法　　随机调取154例鼻咽癌患者治疗前活检的福尔马林固定、石蜡包埋标本,采用p53单克隆抗体DO-1(鼠抗人)和免疫组化染色试剂盒LSAB(日本DAKO公司)检测肿瘤组织中p53基因过量表达。其中…     

缺氧诱导因子-1α与宫颈癌放射敏感性的研究进展

缺氧诱导因子(HIF-1α)是人体内的调节蛋白,与宫颈癌的发生发展有密切联系,是影响宫颈癌放射敏感性的重要因素。在HIF-1α调节放射敏感性的过程中有很多基因和蛋白的参与,这些基因和蛋白都在直接或者间接地影响着宫颈癌放疗效果。目前很多研究正在进行,现就影响宫颈癌放射敏感性的HIF-1α蛋白及其相关基因和蛋白的最新研究进展作一综述。     

E2F基因与肿瘤放射敏感性研究进展

目的 肿瘤放射敏感性是影响肿瘤放射治疗效果的重要原因.在众多影响放射敏感性的因素中,细胞周期、细胞凋亡和DNA损伤修复发挥重要作用.E2F基因家族通过编码E2Fs转录因子家族,调控细胞周期、细胞凋亡等生命活动.本研究旨在总结E2F基因与肿瘤细胞放射敏感性的关系的研究进展.方法 应用PubMed、CNKI等数据库,以“E2F,放疗敏感性,辐射敏感性”等为关键词,检索1990-12-2017-05的中英文文献,共检索到英文文献1 560篇,中文文献634篇.纳入标准:(1)E2F的结构其对细胞周期,细胞凋亡,DNA损伤调控的相关研究;(2)肿瘤细胞辐射敏感性影响因素的临床、基础研究;(3)E2F基因与肿瘤放射敏感性关系的基础研究.排除标准:(1)讨论与辐射敏感性因素关系不紧密的研究;(2)探究不与E2F基因相互作用的基因和细胞因子的研究.符合分析的文献126篇,72篇纳入分析.结果 E2F基因通过PRb/E2F通路调控G1/S期转变,进而调控细胞周期进程.细胞DNA损伤后,E2F1通过p53依赖型和非p53依赖型方式诱导细胞凋亡,成为肿瘤放射治疗的潜在靶点.结论 探究E2F基因与肿瘤放射敏感性的关系将可能成为未来提高肿瘤放射敏感性的重要思路.     

p53基因增加肿瘤放射治疗敏感性的机制

在肿瘤放疗过程中,p53基因的正常功能对肿瘤细胞的凋亡和提高放射敏感性起了关键性作用。野生型p53基因通过激活或抑制一系列基因,使肿瘤细胞周期阻滞,抑制肿瘤细胞放射损伤的修复,促进肿瘤细胞的凋亡,以及在乏氧环境中对促进肿瘤细胞凋亡至关重要,增强了肿瘤细胞对放疗的敏感性。     

p21/WAF-1/CIP-1与宫颈癌放射敏感性的关系

已知凋亡受多种基因调控，其中p21／WAF-1／CIP-1是近年来研究较多的基因，又简称p21。它通过作用于周期蛋白．周期蛋白依赖性激酶(cyclin-CDK)复合物及增殖细胞核抗原(proliferating cell nuclear antigen，PCNA)引起肿瘤细胞生长抑制及调控细胞凋亡，从而影响肿瘤的放射敏感性。笔者搜集了30例宫颈癌病例，通过研究细胞凋亡与肿瘤放射敏感性以及p21与细胞凋亡的关系，探讨p21对宫颈癌放射敏感性的作用。     

p53基因增加肿瘤放射治疗敏感性的机制

在肿瘤放疗过程中,p53基因的正常功能对肿瘤细胞的凋亡和提高放射敏感性起了关键性作用。野生型p53基因通过激活或抑制一系列基因,使肿瘤细胞周期阻滞,抑制肿瘤细胞放射损伤的修复,促进肿瘤细胞的凋亡,以及在乏氧环境中对促进肿瘤细胞凋亡至关重要,增强了肿瘤细胞对放疗的敏感性。     

p53基因与放射敏感性

肿瘤放射敏感性是肿瘤放射治疗成败的关键,如何提高肿瘤细胞的放射敏感性,一直是放射肿瘤学家和放射生物学家关注的问题。传统的预测肿瘤放射敏感性的方法是在整体或细胞水平上进行测算与估计,但未能给临床治疗和评价预后提供足够的信息。近年来,开始在基因水平上研究预测和提高肿瘤放射敏感性及评价预后的方法。目前的研究发现与放射敏感性相关的基因很多,一些癌基因如ras、myc、raf等及抗癌基因RB、p53基因等均与放射敏感相关。p53基因是经广泛研究的抗癌基因,该基因突变与50%人类肿瘤相关。现就p53基因对肿瘤放射敏感性的影响综述如下。…     

食管癌放射敏感性相关基因及分子标志物研究进展

放疗是食管癌最主要的治疗手段之一,而放疗抵抗是食管癌放疗面临的最大困扰和障碍。放射敏感性是当今肿瘤放射生物学研究的重点和难点。多种基因可影响食管癌的放射敏感性,如果能筛选出放射敏感性的决定性基因,对于研究放射增敏、靶向治疗和预测放疗效果指导个体化治疗等具有重要意义。本文将从不同的信号转导通路入手就以往研究中食管癌放射敏感性相关的主要基因及重要分子标志物作一综述。     

p53/bcl-2与放疗诱导的宫颈癌细胞凋亡关系的研究

目的探讨宫颈癌放疗过程中,放疗诱导的细胞凋亡与p53、bcl-2的相关性.方法选择未经治疗的宫颈癌病人20例为实验对象,搜集分割放疗前后宫颈癌组织标本,用TDT-mediated dUTP-biotin nick end labeling(TUNEL)方法检测凋亡细胞;采用单克隆抗体免疫组化ABC法检测细胞凋亡相关基因p53、bcl-2的蛋白表达水平.结果(1)在宫颈癌放疗前后,细胞凋亡阳性率和平均凋亡指数分别为25%和0.11%、75%和2.8%,放疗前后有显著差异(P＜0.001);(2)放疗后p53蛋白表达显著减少,bcl-2蛋白无显著变化;(3)放疗前后,p53基因的表达与细胞凋亡呈有意义的相关性变化.结论放射治疗诱导了宫颈癌细胞凋亡的发生,并与凋亡调节基因p53及其表达呈间接有关.     

The effects of p53 status and human papillomavirus infection on the clinical outcome of patients with stage IIIB cervical carcinoma treated with radiation therapy alone

BACKGROUND: It has been suggested that the p53 tumor suppressor gene regulates the radiosensitivity in human malignancies after irradiation; however, in cervical carcinoma, the role of the p53 gene is still unclear because of inactivation of functional p53 by infection with human papillomavirus (HPV). The objective of this study was to clarify the effects of p53 status and HPV infection on the clinical outcome of patients with cervical carcinoma after undergoing radiation therapy. METHODS: Fifty-two patients with International Federation of Gynecology and Obstetrics Stage IIIB squamous cell carcinoma of the cervix who received radiation therapy alone were reviewed. The combination of external beam irradiation therapy and three sessions of intracavity brachytherapy irradiation was performed for all patients. Genomic DNA extracted from paraffin embedded tissues was examined for HPV types 16, 18 and 33 by the polymerase chain reaction (PCR) method and for p53 status by PCR-single-strand conformation polymorphism (PCR-SSCP) technique. The effects of HPV infection, p53 status, and other parameters on clinical outcome were investigated by univariate analysis. RESULTS: HPV-DNA was detected in 40 patients (76.9%), and 14 patients (26.9%) had mutations of the p53 gene in the study. There was a significant correlation between the existence of HPV and p53 status (P < 0.001). Mutations of the p53 gene were detected in 6 of 12 patients (50%) who had local recurrent tumors, whereas p53 were wild type in 32 of 40 patients (80%) who achieved local control. The p53 mutation had a significant correlations with local tumor recurrence. Furthermore, p53 status caused statistical significant differences in the curves of the recurrence free survival rate and local control rate as determined by the log rank test (P = 0.02 and P = 0.03, respectively). Conversely, no obvious correlation with any clinical outcome for patients with cervical carcinoma was found concerning HPV infection. CONCLUSIONS: It is possible that the p53 gene may be used as a predictive factor in radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix.     

Predictive value of p53, Bcl2 and bax in the radiotherapy of head and neck cancer

Radiation is known to induce DNA damage resulting in the onset of apoptosis. The apoptosis is modulated by p53, Bcl2 and Bax proteins. High level of wild type p53 is required for radiation induced apoptosis. The p53 status, therefore, may be a crucial determinant of radiosensitivity of tumor cells. Overexpression of Bcl2, however, inhibits apoptosis via hetero- and homodimeric interaction. Bax might function as a cell death effector molecule that is neutralized by Bcl2. The aim of the present study is to investigate the correlation between p53, Bcl2, Bax and c-myc levels and the clinical response of head and neck cancer patients to radiation. The base line and 30 GY gamma radiation induced values of p53, Bcl2, Bax and c-myc were estimated by Western blot in 40 biopsies of head and neck cancers. We found that the radiosensitivity of head and neck cancer patients depends on the ratio of p53, Bcl2 and Bax protein levels. High Bcl2 levels resulted in radioresistance of cancer patients. Overexpression of Bax and c-myc may ensure the radiosensitivity of head and neck cancer patients. Our studies indicate that prediction of radiation sensitivity of tumors could be based on the simultaneous evaluation of p53, Bax and Bcl2 levels.     

Prediction of tumor radiosensitivity in rectal carcinoma based on p53 and Ku70 expression

The identification of predictive indicators of radiosensitivity is extremely useful in selecting patients suited for preoperative radiotherapy and avoiding unnecessary preoperative treatment. In this study, we evaluated the possible role of the immunohistochemical expression pattern of p53 and Ku70 protein in determining tumor radiosensitivity in rectal cancer before preoperative irradiation. We examined pretreatment biopsy materials from 111 patients by immunohistochemistry. The expression pattern of p53 and Ku70 was evaluated for association with tumor radiosensitivity, which was defined according to the criteria of the Japanese Research Society for Cancer of the Colon and Rectum. There was a significant correlation between the expression pattern of p53 and tumor radiosensitivity (P = 0.045); Ku70 and tumor radiosensitivity (P < 0.001); and the combination of p53 and Ku70, and tumor radiosensitivity (P < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in both p53 and Ku70-positive cases for radioresistance were all superior to those of the group positive for p53 alone. In conclusion the examination of the combination of p53 and Ku70 may predict the radiosensitivity of rectal cancer before preoperative irradiation.     

吉西他滨联合X射线照射对肺癌细胞系放射增敏作用的初步研究

目的 探讨吉西他滨(GEM)是否对非小细胞肺癌具有放射增敏作用,并对GEM的放射增敏机制进行初步探讨.方法 用克隆形成分析法观察GEM对p53基因突变的人肺腺癌细胞系(973细胞)的放射增敏效应.流式细胞术观察照射前后973细胞周期分布和细胞凋亡,分析其与p53基因突变是否为放射增敏机制.结果 10 nmol/L GEM照前、照后给药均具有极轻微放射增敏作用;100 nmol/L GEM照前、照后给药时均具有明显放射增敏作用,且照前给药组的增敏作用明显强于照后给药组.p53基因突变影响细胞周期再分布及细胞凋亡,但与GEM的放射增敏作用无关.结论 100 nmol/L GEM具有明显放射增敏作用,p53基因突变、细胞周期再分布及细胞凋亡不是GEM放射增敏作用的主要机制.     

Relationship between p53 status and the bioeffect of ionizing radiation

Radiotherapy is widely used in the clinical treatment of cancer patients and it may be used alone or in combination with surgery or chemotherapy to inhibit tumor development. However, radiotherapy may at times not kill all cancer cells completely, as certain cells may develop radioresistance that counteracts the effects of radiation. The emergence of radioresistance is associated with the genetic background and epigenetic regulation of cells. p53 is an important tumor suppressor gene that is expressed at low levels in cells. However, when cells are subjected to stress-induced stimulation, the expression level of p53 increases, thereby preventing genomic disruption. This mechanism has important roles in maintaining cell stability and inhibiting carcinogenesis. However, mutation and deletion destroy the anticancer function of p53 and may induce carcinogenesis. In tumor radiotherapy, the status of p53 expression in cancer cells has a close relationship with radiotherapeutic efficacy. Therefore, understanding how p53 expression affects the cellular response to radiation is of great significance for solving the problem of radioresistance and improving radiotherapeutic outcomes. For the present review, the literature was searched for studies published between 1979 and 2021 using the PubMed database (https://pubmed.ncbi.nlm.nih.gov/) with the following key words: Wild-type p53, mutant-type p53, long non-coding RNA, microRNA, gene mutation, radioresistance and radiosensitivity. From the relevant studies retrieved, the association between different p53 mutants and cellular radiosensitivity, as well as the molecular mechanisms of p53 affecting the radiosensitivity of cells, were summarized. The aim of the present study was to provide useful information for understanding and resolving radioresistance, to help clinical researchers develop more accurate treatment strategies and to improve radiotherapeutic outcomes for cancer patients with p53 mutations.     

p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy.

Apoptosis is one of the causes of cell death in cervical cancer following radiotherapy. By studying the gene expression profile with cDNA apoptotic array, the p73 gene was found overexpressed in radiosensitive cervical cancers when compared with radioresistant ones. To investigate the role of the p73 gene in relation to clinical assessment of radiosensitivity in cervical cancer based on the findings of residual tumor cells in cervical biopsies after completion of radiotherapy, we studied the protein expression of p73 in 59 cervical cancers after radiotherapy and 68 normal cervices using immunohistochemistry. The expression of p73 was found to be significantly increased in cancer samples and, more importantly, in those samples sensitive to radiotherapy (P < 0.001). The overexpression of p73 actually predicted a better prognosis in cervical cancer patients (P < 0.001). To investigate the possible involvement of p73 downstream genes, the protein expressions of p21 and Bax were studied. The expression of p21, but not Bax, was found to be positively correlated with the expression of p73 (P = 0.001). Furthermore, the epigenetic regulation of p73 expression via DNA methylation was also investigated in 103 cervical cancers and 124 normals. Hypermethylation of p73 gene was observed in 38.8% of cervical cancers, and it was significantly associated with reduced or absent p73 expression (P < 0.001). Reactivation of p73 expression in two cervical cancer cell lines by demethylation treatment supported the role of methylation in the regulation of p73 expression. Our findings suggested that p73 expression was related to the radiosensitivity of cervical cancer cells and may play an important role in the regulation of cellular radiosensitivity.     

Radiosensitivity of human biliary tract cancer cell lines in vitro

The prognosis of biliary tract cancer is still poor. Although a number of clinical studies have suggested a role for radiation therapy in advanced biliary tract cancer, its value remains controversial. Moreover, the intrinsic radiosensitivity of bile duct cancer cell lines has not been described, and the molecular basis for the response of these tumors to ionizing radiation is poorly understood. The present study was designed to examine the intrinsic radiation sensitivity of human biliary tract cancer cells and its relationship to p53 status. Radiation response expressed by the parameters n, D-0, D-10, alpha, beta, (D) over bar (mean inactivation dose), and SF, of seven cell lines derived from gallbladder and bile duct cancers was determined. The results suggest that biliary tract cancer cell lines as a group are relatively radioresistant. The mean X-ray survival parameters for these seven cancer cell lines were D-0=2.13+/-0.29 Gy, D-10=5.73+/-0.59 Gy, (D) over bar=2.76+/-0.25 Gy, alpha=0.25+/-0.03, and SF2=0.54+/-0.05. One of the seven lines was more radiosensitive than the others (D-0=0.77+/-0.02 Gy, D-10=2.95+/-0.06 Gy, (D) over bar=1.57 Gy, alpha=0.35, SF2=0.35+/-0.03). Five of six lines examined expressed mutant p53 including the radiosensitive line; one radioresistant line expressed wild-type p53. Thus, although loss of wild-type p53 expression occurred frequently in these biliary cancer cell lines, radiosensitivity did not correlate with p53 status. In view of the intrinsic radioresistance of this type of tumor cell coupled with the poor tolerance of surrounding normal tissues, maximal surgical debulking and intraoperative radiation therapy may contribute to increased local control over resection and/or conventional fractionated radiotherapy.     

HPV分型及p53表达对宫颈癌放疗敏感性影响

目的 探讨宫颈癌患者中HPV分型及p53表达与放疗敏感性的相关性。方法 收集2014—2016年间宫颈癌患者80例,其中Ⅰ_B+Ⅱ_A期40例、Ⅱ_B+Ⅲ_A期40例。检测患者HPV的DNA的感染类型及p53的表达,采用单纯放疗方法对入选患者进行盆腔外和腔内照射,分析近期疗效与HPV分型及p53表达的相关性。χ²检验或Fisher's精确概率法检验,Spearman等级相关分析。结果Ⅰ_B+Ⅱ_A、Ⅱ_B+Ⅲ_A期放疗不敏感组(SD+PD)者p53阳性率分别为100%、100%,高于放疗敏感组(CR+PR)的80.0%、90.0(P=0.044、0.013)。p53的表达强度与放疗敏感性呈负相关(r=-0.427,P=0.000)。Ⅰ_B+Ⅱ_A、Ⅱ_B+Ⅲ_A期放疗不敏感组患者中HPV的DNA多重感染率多于单一亚型感染率,分别为65.0%、95.0%和35.0%、5.0%(P=0.004、0.003),放疗敏感性患者中HPV的DNA单一亚型感染率多于多重感染率,分别为85.0%、60.0%和15.0%、40.0%(P=0.004、0.003)。所有患者中HPV₁₆的检出率最高为66.3%,放疗不敏感组患者中HPV₁₈的检出率最高为60.0%。结论 p53高表达与宫颈癌放射抗拒有关,HPV的DNA多重感染的宫颈癌患者对放疗敏感性较差,HPV₁₆是双重感染中最常见亚型,放疗后未缓解患者中以HPV₁₈为主的多重感染检出率最高。     

miR-424-5p通过靶向抑制HMGA1表达提高宫颈癌放射敏感性

目的 探讨miR-424-5p对宫颈癌放射敏感性的影响及作用机制。方法 RT-qPCR检测miR-424-5p在宫颈癌组织和Hela细胞中表达;流式细胞术检测Hela细胞凋亡率;CCK-8检测Hela细胞增殖活性;蛋白印迹法检测Hela细胞中蛋白表达水平。结果 相较于正常组织和细胞,宫颈癌组织和Hela细胞中miR-424-5p表达量降低(1.03∶0.88,P<0.01;1.00∶0.75,P<0.001)。过表达miR-424-5p会抑制经放射处理后Hela细胞增殖活性(P<0.01),同时增加放射处理后Hela细胞凋亡率(24.82%∶49.94%,P<0.001)。过表达miR-424-5p会抑制HMGA1表达(1.01∶0.63,P<0.01),miR-424-5p会直接作用HMGA1进而影响宫颈癌放射敏感性。结论 miR-424-5p通过直接靶向HMGA1提高宫颈癌放射敏感性。