肿瘤病毒诱导细胞异常增殖作用机制的研究进展

肿瘤是当前危害人类健康最严重的疾病,它以细胞增殖为主要病变特征.自从1911年Rous发现鸡肉瘤病毒可以使鸡发生白血病,人们就将病毒与肿瘤联系起来.本文就肿瘤病毒诱导细胞异常增殖作用机制方面分两部分进行阐述.     

人类肿瘤病毒介导缺氧信号致病机制的研究进展

病毒感染与多种肿瘤的发生发展密切相关,病毒入侵宿主细胞后常引发多个关键细胞信号通路的调控紊乱,其中对缺氧信号的调控尤为重要,日益受到关注。本文主要介绍各种常见人类肿瘤病毒如何通过编码毒蛋白篡改缺氧诱导因子(HIF)信号通路,以及在应答缺氧微环境时如何诱发肿瘤发生发展分子机制的研究进展,并概括肿瘤病毒介导HIF信号通路及其对缺氧应激反应的共有模式,提示肿瘤病毒调控缺氧信号诱发癌症的潜在治疗靶点和策略。     

肝再生磷酸酶PRL-3在肿瘤发生过程中的机制和靶向治疗

磷酸激酶因参与多种信号通路的异常激活导致肿瘤生成和发展而受到重视,但与磷酸激酶功能相对的磷酸酶却因与底物作用的瞬时性、缺乏底物特异性等多种原因较少得到深入研究。近年来,随着研究手段的不断进步,越来越多的结果显示,磷酸酶在疾病的发生发展中同样扮演了重要角色,如肝再生磷酸酶3(PRL-3),其异常高表达在实验动物、细胞培养和患者中均被证实与癌症发生、转移和预后密切相关。目前,关于其作用机制研究虽有一定进展,但仍有许多问题需要进一步解释。本文总结了迄今为止对PRL-3结构、功能和基因表达调控的研究进展,分析了PRL-3在癌症转移中的作用机制,并简要归纳了靶向PRL-3进行癌症治疗的一些最新现状。     

三基序蛋白27的生理意义及其在肿瘤发生发展中的作用

三基序蛋白27(tripartite motif 27,TRIM27)是一种E3泛素连接酶,在细胞核、胞质溶胶和内体中均有分布,广泛存在于多种细胞中。TRIM27还具有转录抑制活性以及SUMO E3连接酶活性。TRIM27参与调控机体多种正常的生理过程：例如作为转录调控蛋白质促进减数分裂过程,与生殖过程密切相关;通过增强胱天蛋白酶3(cysteine-containing aspartate-specific protease-3,caspase-3)活性诱导正常细胞凋亡过程的发生;不仅可以抑制由IκB激酶(IkappaB kinase, IKK)家族成员介导的NF-κB的激活,还能通过泛素化降解NF-κB抑制剂Iκbα,进而参与NF-κB信号通路,在先天免疫中发挥重要调控作用;通过激活STAT3信号通路参与多种炎症疾病的发生。最新研究表明,TRIM27还参与了癌症进程关键信号通路,例如PI3K/AKT,Wnt/β-catenin等,从而促进非小细胞肺癌,结直肠癌和肝癌等多种常见癌症细胞的增殖、侵袭和转移能力,抑制它们凋亡过程的发生以及抑制卵巢癌细胞的细胞周期停滞。同时,TRIM27作...     

乙肝病毒相关肝细胞癌小鼠模型的构建和前沿应用现状

病毒感染可引起世界范围内12％左右癌症的发生,每年约有130万例患者死亡.目前一个重要的瓶颈问题就是所有类型的肿瘤病毒均缺乏可广泛使用的体内研究模型.肝癌是全球第四大癌症相关死亡原因,其中肝细胞癌(hepatocellular carcinoma,HCC)占80％,是最常见的类型.乙型肝炎病毒(hepatitis B ...     

Twist1在肿瘤发生中的作用

Twist1作为bHLH转录因子起初被发现在胚胎发育中起关键作用. 最近10年研究证明,它在多种癌的发生、发展中发挥重要作用. 本文结合多种信号通路（如MAPK、STAT、NF κB）以及与其基因表达调控相关的转录因子、翻译后修饰、microRNA等综述Twist1表达调节. 同时,根据其参与癌的发展及作用方式,结合细胞间联系、肿瘤微环境、侵袭和迁移、化疗抗性、上皮 间质转化（EMT）、细胞衰老与程序性死亡、肿瘤干细胞等,概括Twist1在肿瘤发生中的作用.     

长非编码RNA的作用机制及在肿瘤发生发展中的意义

功能基因组学的飞速发展将越来越多的目光引向了对非编码转录产物功能的研究。在人的转录组中,存在着一类长度大于200nt,但并不具备编码蛋白质功能的基因转录产物,即长非编码RNA(long noncoding RNA,lncRNA)。相比于小分子RNA,它们仍是目前基因组转录产物中较为陌生的部分。在整个基因组转录产物中,lncRNA所占的比例远远超过编码RNA所占的比例。不同于编码RNA,lncRNA的保守性要差得多,然而在其分子内部,却含有较为保守的局部区段,且其表达具有时空特异性,这些现象都提示了lncRNA具有重要的生理生化功能。越来越多的研究表明,lncRNA在基因表达调控方面发挥着十分重要的作用,与物种进化、胚胎发育、物质代谢以及肿瘤发生等都有着紧密的联系,其功能的深入研究将使目前对细胞的结构网络和调控网络的认识带来革命性的变化,具有不可估量的科学和临床价值。该文将着重讨论lncRNA在不同层面上对基因表达的调控机制以及在肿瘤发生发展中的意义。     

Axin在肿瘤发生中的作用机制

阐明肿瘤发生机制的细胞信号转导途径的研究是当今生物医学领域研究的热点。Axin是一个肿瘤抑制因子,它以构架蛋白的形式在Wnt、JNK、p53、TGF-β、G蛋白信号转导途径等众多信号转导途径中参与细胞生长、增殖、分化、癌变和凋亡等多种重要细胞命运的调控过程。现从Axin的发现、Axin通过多种信号转导途径抑制肿瘤发生和AXIN1基因突变与肿瘤发生之间的关系这三个方面介绍肿瘤抑制因子Axin与肿瘤之间的研究进展。     

BPTF在肿瘤发生发展中的功能及相关分子机制研究

染色质重塑过程通过影响染色质开放状态参与基因的转录调控.作为染色质重塑复合物最大的亚基,含溴域和锌指结构的蛋白BPTF可通过多种途径调控基因表达,如参与染色质重塑过程,影响DNA可及性;作为独立的转录因子发挥作用;与其他转录因子、组蛋白或长链非编码RNA等协同发挥作用,并通过影响细胞增殖、迁移侵袭、干性维持、免疫应答等...     

VPS35在肿瘤发生与转移中的作用及机制研究

VPS35是Retromer复合体的重要组成部分,在内吞体蛋白分选转运过程中有重要作用.最近研究表明,VPS35作为一种新的致癌基因,在多种肿瘤中高表达,调控多种因子及通路,从而影响肿瘤的发生发展和转移.本文综述了目前VPS35调控肿瘤相关因子及通路进而促进肿瘤发生与转移的最新研究进展,总结讨论了VPS35在肿瘤发生与转移中的作用机制,为将来深入研究VPS35/Retromer组分在肿瘤发生转移中的作用及机制提供借鉴与参考.     

Oncolytic Immunotherapy: Can’t Start a Fire Without a Spark

Recent advances in cancer immunotherapy have renewed interest in oncolytic viruses (OVs) as a synergistic platform for the development of novel antitumor strategies. Cancer cells adopt multiple mechanisms to evade and suppress antitumor immune responses, essentially establishing a non-immunogenic (‘cold’) tumor microenvironment (TME), with poor T-cell infiltration and low mutational burden. Limitations to the efficacy of immunotherapy still exist, especially for a variety of solid tumors, where new approaches are necessary to overcome physical barriers in the TME and to mitigate adverse effects associated with current immunotherapeutics. OVs offer an attractive alternative by inducing direct oncolysis, immunogenic cell death, and immune stimulation. These multimodal mechanisms make OVs well suited to reprogram non-immunogenic tumors and TME into inflamed, immunogenic (‘hot’) tumors; enhanced release of tumor antigens by dying cancer cells is expected to augment T-cell infiltration, thereby eliciting potent antitumor immunity. Advances in virus engineering and understanding of tumor biology have allowed the optimization of OV-tumor selectivity, oncolytic potency, and immune stimulation. However, OV antitumor activity is likely to achieve its greatest potential as part of combinatorial strategies with other immune or cancer therapeutics.     

Identifiability of the joint distribution of age and tumor size at detection in the presence of screening

In recent years, a stochastic model of cancer development and detection allowing for arbitrary screening schedules has been developed and applied to analysis of screening trials and population-based cancer incidence and mortality data. The model is entirely mechanistic, builds on a minimal set of biologically plausible assumptions, and yields the joint distribution of tumor size and age of a patient at the time of diagnosis. Whether or not parameters of the model can be estimated from data generated by cohort studies depends on model identifiability. The present paper provides a proof of this important property of the model.     

Tumor suppressor microRNAs: A novel non-coding alliance against cancer

Tumor initiation and progression are the outcomes of a stepwise accumulation of genetic alterations. Among these, gene amplification and aberrant expression of oncogenic proteins, as well as deletion or inactivation of tumor suppressor genes, represent hallmark steps. Mounting evidence collected over the last few years has identified different populations of non-coding RNAs as major players in tumor suppression in almost all cancer types. Elucidating the diverse molecular mechanisms underlying the roles of non-coding RNAs in tumor progression might provide illuminating insights, potentially able to assist improved diagnosis, better staging and effective treatments of human cancers. Here we focus on several groups of tumor suppressor microRNAs, whose downregulation exerts a profound oncologic impact and might be harnessed for the benefit of cancer patients.     

Tumor interstitial fluid — A treasure trove of cancer biomarkers

Tumor interstitial fluid (TIF) is a proximal fluid that, in addition to the set of blood soluble phase-borne proteins, holds a subset of aberrantly externalized components, mainly proteins, released by tumor cells and tumor microenvironment through various mechanisms, which include classical secretion, non-classical secretion, secretion via exosomes and membrane protein shedding. Consequently, the interstitial aqueous phase of solid tumors is a highly promising resource for the discovery of molecules associated with pathological changes in tissues. Firstly, it allows one to delve deeper into the regulatory mechanisms and functions of secretion-related processes in tumor development. Secondly, the anomalous secretion of molecules that is innate to tumors and the tumor microenvironment, being associated with cancer progression, offers a valuable source for biomarker discovery and possible targets for therapeutic intervention. Here we provide an overview of the features of tumor-associated interstitial fluids, based on recent and updated information obtained mainly from our studies of breast cancer. Data from the study of interstitial fluids recovered from several other types of cancer are also discussed. This article is a part of a Special Issue entitled: The Updated Secretome.     

Identification and characterization of mouse SSX genes: a multigene family on the X chromosome with restricted cancer/testis expression

Human SSX was first identified as the gene involved in the t(X;18) translocation in synovial sarcoma. SSX is a multigene family, with 9 complete genes on chromosome Xp11. Normally expressed almost exclusively in testis, SSX mRNA is expressed in various human tumors, defining SSX as a cancer/testis antigen. We have now cloned the mouse ortholog of SSX. Mouse SSX genes can be divided into Ssxa and Ssxb subfamilies based on sequence homology. Ssxa has only one member, whereas 12 Ssxb genes, Ssxb1 to Ssxb12, were identified by cDNA cloning from mouse testis and mouse tumors. Both Ssxa and Ssxb are located on chromosome X and show tissue-restricted mRNA expression to testis among normal tissues. All putative human and mouse SSX proteins share conserved KRAB and SSX-RD domains. Mouse tumors were found to express some, but not all, Ssxb genes, similar to the SSX activation in human tumors.     

Dopamine: an old target in a new therapy

Dopamine, a molecule of joy and emotions, plays vital role in regulation cancer growth and tumor angiogenesis. Dopamine secrets from neural cells in brain and peripheral cells as well. Peripheral dopamine is associated with tumorigenic events. Recent publication [Sarkar et al. Int. J. Cancer: doi:10.1002/ijc.29414, 2014] suggests that dopamine can be an ideal substitute as an anti-vascular endothelial growth factor A (VEGF-A) agent for the treatment tumor angiogenesis as dopamine is less expensive, minimum side-effect and more sensitive than other drugs. The studies also found that dopamine prevent the 5FU-induced neutropenia in tumor-bearing mice. Collectively, these pre-clinical studies claim that dopamine could be a novel therapy for managing cancer growth and chemotherapy related disorder.     

自噬与肿瘤关系的研究与进展

自噬是一个高度发达而且十分保守的生物学分解代谢过程。自噬与肿瘤的关系十分密切,在肿瘤发生发展的过程中,自噬活性的改变却是一把双刃剑。自噬,它既能够使肿瘤细胞耐受不同的应激条件而使其获得更好的生存,也可以通过各种信号途径减轻许多不良应激条件下的细胞损伤,如慢性炎症、慢性细胞死亡及基因组损伤等,从而而减少肿瘤的发生。再者,一方面,某些肿瘤的发生和发展过程中也同样依赖于自噬,并且肿瘤细胞可以利用自噬来对抗抗癌药物的一定的细胞毒性。而另一方面,有些癌症却需要利用自噬的作用来杀死肿瘤细胞。虽然自噬与肿瘤的关系是十分复杂的,也存在不少的分歧,但总的来说自噬在癌症中的作用是至关重要的。结合近年来国内外研究的发展,我们这篇综述重点讨论的是自噬在癌症中的作用,并且探讨其潜在的作用机制,以及目前自噬在癌症治疗中的应用。     

Limitations of the cancer stem cell theory

Cancer stem cells (CSCs) can be operationally defined as a subset of neoplastic cells which are responsible for the growth and re-growth of primary and metastatic tumors. Although the existence of perpetually dividing cells is a logical necessity to explain the malignant properties of human tumors, experimental data supporting their existence have only recently been obtained. New knowledge in basic stem cell biology and the availability of several cell surface markers for the definition and isolation of small subsets of immature cells coupled to the use of the classical model of xenotransplantation in immune deficient mice has identified putative CSCs in several solid tumors such as mammary, colon, brain, pancreas, prostate, melanoma and others. However, the theory must be considered as still in its infancy, since tumors grown in mice only partially recapitulate the biology of human cells. In addition, whether the “transformed” cell is the neoplastic counterpart of a normal stem cell or whether complete malignant behaviour can occur in a more differentiated cell has still to be demonstrated. In spite of these difficulties, the CSC hypothesis could be of clinical relevance, especially in the definition of new ways to assay drug sensitivity of primary human tumors.     

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

Skin cancer is the most common cancer in the United States and is mainly caused by environmental UV radiation. Reducing skin cancer incidence is becoming an urgent issue. The stress-inducible protein Sestrin2 (Sesn2) plays an important role in maintaining redox and metabolic homeostasis and their related pathologies. However, the role of Sesn2 in cancer remains unclear. Here we show that UVB radiation induces Sesn2 expression in normal human keratinocytes, mouse skin, normal human melanocytes, and melanoma cells. In addition, Sesn2 promotes AKT activation through a PTEN-dependent mechanism. Sesn2 deletion or knockdown sensitizes squamous cell carcinoma (SCC) cells to 5-fluorouracil-induced apoptosis and melanoma cells to UVB- and vemurafenib-induced apoptosis. In mice Sesn2 knockdown suppresses tumor growth from injected human SCC and melanoma cells. Last, as compared with normal skin, Sesn2 is up-regulated in both human skin SCC and melanoma. Our findings demonstrate that Sesn2 promotes AKT activation and survival in response to UVB stress and chemotherapeutics and suggest that Sesn2 is oncogenic in skin SCC and melanoma.