缺氧诱导因子-1及其靶基因在肿瘤恶性进展中的作用

缺血缺氧的微环境是肿瘤形成和演进过程中普遍存在的现象.在缺氧条件下,肿瘤细胞改变代谢特点以保证存活并不断生长.缺氧诱导因子-1 (HIF-1)作为缺氧状态下细胞内重要的转录激活因子,可直接或间接调节100多个靶基因的转录激活,表达靶蛋白,使得肿瘤细胞能适应缺氧微环境,并且保持不断增殖、浸润和转移的能力.     

激活转录因子2表达与非小细胞肺癌患者预后不良的关系

目的:检测激活转录因子2（ATF2）/磷酸化激活转录因子2（p-ATF2）在非小细胞肺癌（NSCLC）中的表达,探讨其与NSCLC患者预后的关系。方法:采用逆转录RCR(RT-PCR)及蛋白质免疫印迹（Western blot）方法检测ATF2在NSCLC细胞系和新鲜肿瘤组织中的表达情况。免疫组织化学方法检测石蜡包埋的NSCLC及临近非肿瘤组织中ATF2和p-ATF2的表达情况。结果:与对照细胞相比,NSCLC细胞系中ATF2表达显著上调（P＜0.01）。与临近非肿瘤组织相比,NSCLC组织中ATF2表达显著上调（P＜0.01）。ATF2表达与患者TNM分期（P=0.002）、肿瘤大小（P=0.018）及转移（P=0.027）密切相关。69.8%（60/86）的NSCLC患者p-ATF2表达显著上调。Kaplan-Meier生存分析显示ATF2和p-ATF2表达上调NSCLC患者的总生存率显著低于低表达患者（P＜0.01,P＜0.05）。结论:NSCLC组织中ATF2和p-ATF2表达均上调,其过表达与NSCLC患者预后不良密切相关。     

活化转录因子4与肿瘤的发生发展及耐药

ATF4是活化转录因子即循环AMP反应元件结合蛋白家族成员之一.ATF4在肿瘤中受肿瘤微环境因素的诱导呈高表达,并进一步影响肿瘤的生长、凋亡、浸润、转移及耐药.因此,ATF4可能作为肿瘤治疗的潜在靶点.     

糖原合成激酶-3β与肿瘤的发生发展

近年来许多研究证实糖原合成激酶-3β(GSK-3β)在多种肿瘤的发生发展中起重要作用,它可通过多种机制调节肿瘤细胞的生长活性.在某些肿瘤中,GSK-3β的激活可抑制肿瘤细胞的生长;而在另一些肿瘤中,GSK-3β的激活可促进肿瘤细胞的生长,同时GSK-3β也能调节肿瘤细胞对化疗药物的敏感性.因此,GSK-3β有希望成为肿瘤治疗的新靶点.     

转录核因子-κB在肝炎病毒相关性肿瘤中的研究进展

转录核因子-κB(NF-κB)是炎症相关性肿瘤的重要调节基因,持续激活的NF-κB参与肝炎病毒相关性肿瘤(肝癌、胆管癌)的发生发展过程.抑制NF-κB的活性能有效延缓或阻碍肿瘤细胞的生长与转移,并能改善肿瘤对化疗的敏感性.因此,NF-κB有望在将来成为肝炎病毒相关性肿瘤治疗的有效靶点之一.     

Gli转录因子与肿瘤

Hedgehog（HH）信号通路参与胚胎发育、成人组织再生及修复,且在肿瘤细胞生长及转移过程中发挥重要作用。已有大量研究证实该信号通路的异常激活与多种肿瘤的发生发展密切相关。Gli是HH通路直接调控靶基因的转录因子,是该通路不同水平激活的最后共同通道,在致瘤过程中起着重要作用。Gli受多通路多因素调节,故抑制Gli靶向性治疗具有非常广阔的前景。本文对Hedgehog-Gli信号通路在恶性肿瘤发生发展中的作用、Gli转录活性的调控及致瘤作用、Gli转录因子的靶向治疗价值等方面的研究进展进行综述。      

缺氧诱导因子-1及其靶基因在肿瘤恶性进展中的作用

缺血缺氧的微环境是肿瘤形成和演进过程中普遍存在的现象。在缺氧条件下,肿瘤细胞改变代谢特点以保证存活并不断生长。缺氧诱导因子-1（HIF-1）作为缺氧状态下细胞内重要的转录激活因子,可直接或间接调节100多个靶基因的转录激活,表达靶蛋白,使得肿瘤细胞能适应缺氧微环境,并且保持不断增殖、浸润和转移的能力。     

c-myc对肿瘤细胞生长抑制基因的转录调控

c-myc基因在许多肿瘤的发生、发展过程中起着重要作用,它主要通过对靶基因的转录调控发挥作用。对c-myc如何调节肿瘤细胞周期生长抑制基因转录机制进行综述。c-myc对细胞周期的调控主要通过对生长抑制基因转录抑制实现,主要有2个不同机制一个通过myc/Max二聚体中c-myc蛋白的羧基端(C末端)与Mil-1形成复合物与生长抑制基因p15等启动子Inr区域结合,拮抗其他转录激活因子如Mil-1与Inr结构结合。另一机制c-myc及可能存在的抑制物与转录激活因子Sp1及SMad(smaandmadhomologue)等形成复合物干扰Sp1等对生长抑制基因的激活。造成细胞恶性转化及增殖。     

丝裂原激活的蛋白激酶(MAPK)信号转导通路与卵巢上皮癌

丝裂原激活的蛋白激酶（mitogen-activated protein kinase，MAPK）是一组可以被多种细胞外信号激活的丝／苏氨酸激酶，其参与细胞的多种生物学行为，包括基因的转录、细胞的分化及增殖、细胞周期调控、诱导细胞凋亡和维持细胞生存以及细胞的恶性化等。在信号转导过程中，3种MAPK（ERK、JNK和p38）信号通路所调节的细胞反应有所不同，持续活化的ERKI／2途径有助于肿瘤细胞的生长、增强抗凋亡能力；而JNK和p38的活化则可引起肿瘤抑制，诱导肿瘤细胞的凋亡。在卵巢癌细胞中MAPK级联可以被顺铂、TNF（肿瘤坏死因子）和GnRH促性腺激素释放激素等激活和调节。本文将对激素、生长因子和化疗药物作用于卵巢上皮细胞及肿瘤细胞后引起MAPK通路的变化情况作一综述。     

高迁移率族蛋白N在肿瘤中的研究进展

高迁移率族蛋白N(HMGN)是细胞内普遍存在的一类核蛋白,属于高迁移率族蛋白家族.它们能直接与DNA和核小体结合,诱导染色质纤维结构的改变,进而影响细胞内转录、细胞分化过程和细胞对受损DNA的修复能力.肿瘤的发生与累积突变导致的转录异常密切相关,转录异常促使肿瘤细胞得以逃脱细胞周期的严密调控.研究显示,HMGN可以通过参与细胞周期调节及影响肿瘤细胞的生物学行为等方式,在肿瘤发生发展中发挥重要作用.     

A hybrid protein comprising ATF domain of pro-UK and VAS, an angiogenesis inhibitor, is a potent candidate for targeted cancer therapy

Directional and controllable degradation of extracellular matrix mediated by the uPA-uPA receptor (uPAR) system is ubiquitously implicated in tumor establishment, invasion and metastasis. Targeting the excessive activation of this system as well as the proliferation of the tumor vascular endothelial cell would be expected to prevent tumor neovasculature and halt the tumor development. In this study, we created a fusion protein (ALV), comprising the aminoterminal fragment (ATF) of urokinase and VAS, the antiangiogenic functional domain of vasostatin. The antitumor activity of this hybrid molecule was evaluated with both in vitro and in vivo experiments. Cell adhesion and motility assays demonstrated that ALV, owing to its ATF moiety, could interact with uPAR on the tumor cell surface with high affinity and specificity, and thereby might competitively inhibit the plasmin activation by localized urokinase and contribute to the suppression of tumor invasion. These results and speculations were validated by zymography assay and Matrigel invasion assay. In addition, ALV exhibited an improved inhibitory efficacy against endothelial cell (EC) proliferation and capillary vessel formation in a 3D angiogenesis model, proving that ATF and VAS, when fused into a chimeric molecule, cooperatively inhibited angiogenesis by targeting both the interaction of uPA and uPAR on cell surface (by ATF) and EC proliferation (mainly by VAS). Animal model confirmed that, at the same molar dose, ALV produced significantly higher therapeutic benefit than VAS and ATF in terms of tumor growth delay and mice survival prolongation. Conclusively coupling VAS with the uPAR ligand ATF resulted in an improved antineoplastic activity, which may show a novel avenue for the design of tumor therapeutic drugs.     

Modulation of invasive properties of human glioblastoma cells stably expressing amino-terminal fragment of urokinase-type plasminogen activator

The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on the surface of tumor cells is involved in the activation of proteolytic cascades responsible for the invasiveness of those cells. The diffuse, extensive infiltration of glioblastomas into the surrounding normal brain tissue is believed to rely on modifications of the proteolysis of extracellular matrix components; blocking the interaction between uPA and uPAR might be a suitable approach for inhibiting glioma tumorigenesis. We assessed how expression of an amino-terminal fragment (ATF) of uPA that contains binding site to uPAR affects the invasiveness of SNB19 human glioblastoma cells. SNB19 cells were transfected with an expression plasmid (pcDNA3-ATF) containing a cDNA sequence of ATF-uPA. The resulting ATF-uPA-expressing clones showed markedly less cell adhesion, spreading, and clonogenicity than did control cells. Endogenous ATF expression also significantly decreased the invasive capacity of transfected glioblastoma cells in Matrigel and spheroid-rat brain cell aggregate models. ATF-uPA transfectants were also markedly less invasive than parental SNB19 cells after injection into the brains of nude mice, suggesting that competitive inhibition of the uPA-uPAR interaction on SNB19 cells by means of transfection with ATF cDNA could be a useful therapeutic strategy for inhibiting tumor progression.