细胞自噬及其在肿瘤发生过程中的作用

细胞自噬性死亡是一种非凋亡性的程序性细胞死亡,其特征是在垂死细胞中利用自噬小体对细胞内容物进行降解。现对自噬的病理形态特征、生化改变、发生机制、分子调控、与凋亡的联系进行综述,以利于加深对细胞死亡方式的进一步认识,并介绍自噬在肿瘤发生过程中作用的研究进展。     

自噬在肿瘤发生中的作用机制及临床价值研究

随着对肿瘤研究的不断深入,人们发现肿瘤的发生、发展与紊乱的程序性细胞死亡密切相关.近年来的研究发现自噬性细胞死亡是程序性细胞死亡的一种新的存在形式.在多种通路的调控下,自噬和肿瘤可以进行双向调节.不仅如此,自噬可以通过不同的机制对肿瘤进行双重调节.由于自噬与肿瘤之间存在大量调节通路,所以将自噬与肿瘤免疫治疗相结合是一种新型有效并具有一定可行性的多模式治疗策略.本文总结了自噬与肿瘤研究的相关内容,并且着重讨论了自噬与肿瘤发生、发展的相关机制以及自噬在新型多模式治疗中的应用价值.     

自噬在肿瘤发生发展及治疗中的作用

自噬是真核细胞生长分化、功能发挥及死亡的重要调控机制,自噬异常与肿瘤等多种人类疾病的发生发展有关。在分子水平,自噬与细胞的凋亡、增殖信号相互作用,共同影响肿瘤细胞的存活与死亡。由于自噬主要起维持细胞生存的功能,抑制自噬就成为辅助肿瘤治疗的一个新方向;然而,抑制自噬后的肿瘤细胞又具有逃避死亡的潜在危险,而限制了这一疗法的应用。自噬与肿瘤的复杂关系正日益受到关注,揭示其分子机制必将对肿瘤治疗产生深刻的影响。     

细胞自噬在肿瘤中的作用

自噬为一种细胞的自我消耗过程,其具有潜在的抗肿瘤生物学活性,亦与肿瘤耐药有关.该文从自噬的调节机制入手,综述自噬参与肿瘤发生的机制,自噬在肿瘤治疗中的作用及应用,以期为自噬在临床上的应用提供依据.     

自噬的表观遗传修饰在肿瘤发生发展中的作用

细胞自噬是一种进化上的保守过程,可降解胞质成分从而促进细胞存活和组织平衡,它的激活与生物学功能受到多种自噬相关基因和信号通路的调节。其中表观遗传修饰广泛参与细胞自噬过程,调节细胞凋亡和自噬,成为癌症的另一种标志,在肿瘤的发生、发展中发挥了重要作用。为了更深入了解自噬的表观遗传修饰与肿瘤发生、发展的关系,本文将近期相关的研究进展做一综述。     

自噬在肿瘤发生与发展中的调控机制

自噬是一个多步骤的动态过程,包括诱导、成核、延伸、自噬体形成、自噬溶酶体形成,细胞将自身胞浆蛋白或细胞器包裹形成囊泡并在溶酶体中降解,在维持细胞内稳态中发挥重要的作用。多种肿瘤细胞中存在自噬活性的改变,参与细胞恶变及肿瘤细胞生长。在肿瘤发生早期,细胞利用自噬清除细胞内折叠异常的蛋白质和功能异常的细胞器如线粒体,抑制细胞应激反应,防止基因损伤从而抑制肿瘤发生。在肿瘤发展过程中,肿瘤细胞利用自噬作用帮助自身在营养缺乏和低氧状况下得以存活。研究自噬在肿瘤发生发展中的调控机制将为肿瘤治疗提供新策略。     

细胞自噬在肝癌发生发展中的作用

细胞自噬是细胞内高度保守的细胞自我消化和分解代谢过程,是维持细胞内稳态的重要机制之一。在肝癌发生发展的不同阶段,细胞自噬起着不同作用。在肝癌的起始阶段,经常存在自噬缺陷,这也可说明细胞自噬的正常运转可抑制肝癌的发生;但是在肝癌的发展过程中,随着肿瘤微环境的变化,肝癌细胞也会利用自噬来保护自己。故自噬所扮演的角色也在改变,起着保护肝癌细胞的作用。另外,自噬与肝癌细胞的转移及耐药也密切相关。     

自噬及其与肿瘤关系的研究进展

自噬是真核细胞特有的普遍生命现象,在维持细胞自我稳态、促进细胞生存方面起重要作用,广泛参与多种生理和病理过程.自噬与肿瘤细胞的存话与死亡密切相关,预示着自噬将成为肿瘤研究中的一个新热点.本文对自噬的概念及生物学特性以及与肿瘤的关系作一概述.     

自噬及其与肿瘤关系的研究进展

自噬是真核细胞特有的普遍生命现象,在维持细胞自我稳态、促进细胞生存方面起重要作用,广泛参与多种生理和病理过程.自噬与肿瘤细胞的存话与死亡密切相关,预示着自噬将成为肿瘤研究中的一个新热点.本文对自噬的概念及生物学特性以及与肿瘤的关系作一概述.     

自噬在肿瘤发生、发展、治疗及预后中的作用

自噬在肿瘤细胞存活中扮演一把双刃剑的作用,它既可以促进细胞生存,也可以导致肿瘤细胞发生自噬性细胞死亡。最近研究表明,自噬在肿瘤的发生、发展、治疗及预后中均扮演重要角色,并有可能成为肿瘤治疗的新途径。     

Autophagy regulation and its role in cancer

The modulation of macroautophagy is now recognized as one of the hallmarks of cancer cells. There is accumulating evidence that autophagy plays a role in the various stages of tumorigenesis. Depending on the type of cancer and the context, macroautophagy can be tumor suppressor or it can help cancer cells to overcome metabolic stress and the cytotoxicity of chemotherapy. Recent studies have shed light on the role of macroautophagy in tumor-initiating cells, in tumor immune response cross-talk with the microenvironment. This review is intended to provide an up-date on these aspects, and to discuss them with regard to the role of the major signaling sub-networks involved in tumor progression (Beclin 1, MTOR, p53 and RAS) and in regulating autophagy.     

自噬及其与结直肠癌的发生和治疗

自噬是细胞通过降解自身的蛋白质及细胞器并循环利用降解产物以维持细胞生存的,过度自噬可导致细胞自噬性死亡.近年来研究发现,自噬在结直肠癌发生、发展及治疗中有重要作用,但其作用机制和对放化疗疗效的影响仍存在争议.     

Human neurotropic polyomavirus,JCV, and its role in carcinogenesis

A number of recent studies have reported the detection of the ubiquitous human polyomavirus, JC virus (JCV), in samples derived from several types of neural as well as non-neural human tumors. The human neurotropic JCV was first identified as the etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually occurs in individuals with defects in cell-mediated immunity, including AIDS. However, upon mounting evidence of the oncogenic potential of the viral regulatory protein, T-antigen, and JCV's oncogenecity in a broad range of animal models, studies were initiated to determine its potential involvement in human carcinogenesis. Initially, the most frequently observed tumors in rodent models, including medulloblastoma, astrocytoma, glioblastoma, and other neural-origin tumors were analysed. These studies were followed by analysis of non-neural tumors such as colorectal carcinomas. In a subset of each tumor type examined, JC viral genomic DNA sequences could be detected by PCR and confirmed by Southern blot hybridization or direct sequencing. In a smaller subset of the tumors, the expression of T-antigen was observed by immunohistochemical analysis. Owing to the established functions of T-antigen including its ability to interact with tumor suppressor proteins such as Rb and p53, and its ability to influence chromosomal stability, potential mechanisms of JCV T-antigen-mediated cellular dysregulation are discussed. Further, as increasing evidence suggests that T-antigen is not required for maintenance of a transformed phenotype, a hit-and-run model for T-antigen-induced transformation is proposed.     

Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis

MicroRNAs (miR) are a class of small ( approximately 21 nucleotide) noncoding RNAs that, in general, negatively regulate gene expression. Some miRs harboring CGIs undergo methylation-mediated silencing, a characteristic of many tumor suppressor genes. To identify such miRs in liver cancer, the miRNA expression profile was analyzed in hepatocellular carcinoma (HCC) cell lines treated with 5-azacytidine (DNA hypomethylating agent) and/or trichostatin A (histone deacetylase inhibitor). The results showed that these epigenetic drugs differentially regulate expression of a few miRs, particularly miR-1-1, in HCC cells. The CGI spanning exon 1 and intron 1 of miR-1-1 was methylated in HCC cell lines and in primary human HCCs but not in matching liver tissues. The miR-1-1 gene was hypomethylated and activated in DNMT1-/- HCT 116 cells but not in DNMT3B null cells, indicating a key role for DNMT1 in its methylation. miR-1 expression was also markedly reduced in primary human hepatocellular carcinomas compared with matching normal liver tissues. Ectopic expression of miR-1 in HCC cells inhibited cell growth and reduced replication potential and clonogenic survival. The expression of FoxP1 and MET harboring three and two miR-1 cognate sites, respectively, in their respective 3'-untranslated regions, was markedly reduced by ectopic miR-1. Up-regulation of several miR-1 targets including FoxP1, MET, and HDAC4 in primary human HCCs and down-regulation of their expression in 5-AzaC-treated HCC cells suggest their role in hepatocarcinogenesis. The inhibition of cell cycle progression and induction of apoptosis after re-expression of miR-1 are some of the mechanisms by which DNA hypomethylating agents suppress hepatocarcinoma cell growth.     

Expression of IGF-1R in colorectal polyps and its role in colorectal carcinogenesis

Insulin-like Growth Factor Receptor 1 (IGF-1R) may play a role in the neoplastic progression of colorectal cancer because it is related to both cellular proliferation and differentiation. The aim of this study was to further elucidate the role of IGF-1R in colorectal carcinogenesis by evaluating IGF-1R expression in different types of precancerous colorectal polyps and comparing its expression to normal mucosa and colorectal carcinoma. A total of 47 colorectal polyps and their respective adjacent normal mucosa were collected from 32 patients. In addition, 20 colorectal adenocarcinoma tissues were obtained from patients undergoing colorectal resection, and 12 normal non-malignant colorectal mucosal tissues collected from outpatients served as the control group. The pit patterns of polyps were classified by the Kudo classification scheme through magnifying chromoendoscopy. Immunohistochemistry and quantitative real-time RT-PCR were utilized for expression analysis of IGF-1R in colorectal mucosa, polyps, and adenocarcinoma tissue. The results of immunohistochemistry showed no significant differences in IGF-1R expression in inflammatory polyps compared with their surrounding normal mucosa by the Mann-Whitney U test (p=0.251); however, tubular adenoma and villous adenoma tissues exhibited significantly higher levels of IGF-1R expression (p=0.000). The results of real-time RT-PCR showed that IGF-1R was transcribed at a high level in colorectal adenomatous polyps and adenocarcinoma compared with their respective paired normal mucosa. Spearman's rank correlation two-variable analysis was used to demonstrate a significant correlation between the expression of IGF-1R and neoplastic progression from normal mucosa to adenomatous polyps and finally to colorectal cancer (r=0.574, p=0.000). This study suggests that the expression of IGF-1R correlates with the degree of carcinogenesis. In addition, these results demonstrated that there is a significant correlation between the level of IGF-1R expression and pit patterns of polyps (r=0.432, p=0.002). Thus, IGF-1R might be a factor in the morphological change of colorectal mucosal crypts, and it may play an important role in the growth and malignant transformation of precancerous polyps. These results suggest that IGF-1R can be considered a biomarker for the stage and risk of carcinogenesis during neoplastic initiation and progression along the colorectal normal mucosa-polyp-cancer sequence. Inhibitors of IGF-1R are not only a promising targeted anticancer strategy, but also a possible option for the chemoprevention of colorectal cancer.