VPS35在恶性肿瘤中的作用

囊泡分选蛋白35(vacuolar protein sorting 35,VPS35)是一种逆转运蛋白，负责货物蛋白的分选和运输，与阿尔茨海默病、帕金森病等神经退行性疾病有关。VPS35广泛参与多种信号通路，在细胞的生长、增殖、自噬和凋亡等方面具有重要的作用。VPS35在多种恶性肿瘤中高表达，并通过不同机制调节肿瘤细胞的增殖、迁移、侵袭能力。本文主要围绕VPS35的结构特征、参与的信号通路及VPS35在恶性肿瘤中发挥的作用进行综述，旨在为今后的临床研究提供理论依据。     

Hedgehog信号通路靶基因与肿瘤的关系之研究进展

Hedgehog（HH）蛋白属于分泌蛋白家族,广泛表达于哺乳动物,非哺乳动物等多个物种,参与调控多种肿瘤形成,器官成熟、血管生成,干细胞分化,免疫细胞以及胚胎发育。文章主要就近几年来国内外对hedgehog信号通道下游靶基因在肿瘤干细胞,肿瘤细胞的转移,增殖,凋亡及胚胎发育等方面的研究进展进行综述,重点阐述hedgehog信号通路下游靶基因与肿瘤及发育的关系,以期能为与hedgehog信号通道参与调控的相关疾病提供一些靶向性临床诊疗的新思路。     

天然提取物诱导人HepG2 细胞凋亡的研究进展

细胞凋亡是机体维持内环境稳定,更好的适应生存环境采取的一种死亡过程。细胞凋亡异常与肿瘤的发生、发展存在密切的关系。细胞凋亡的信号途径主要有死亡受体介导的外源性通路、线粒体介导内源性通路、内质网信号通路及MAPK信号通路。通过作用于凋亡信号通路上一些关键基因,诱导肿瘤细胞凋亡被认为是临床抗肿瘤治疗最有成效的治疗方法之一。研究已证实多种天然提取物作用于凋亡信号途径中一些重要因子可诱导细胞凋亡,并取得较好的抑制肿瘤增殖的效果。本文是关于细胞凋亡机制及各种天然提取物作用于凋亡通路上主要基因进行抗肿瘤治疗研究进展的综述。     

miR-365在肿瘤中的研究进展

在了解肿瘤信号通路方面虽已取得了实质性的进展,但由于肿瘤的致瘤通路、耐药性等方面的复杂性,导致仍然缺乏治疗肿瘤的有效手段。micro RNAs(mi RNAs)的发现为解决这个问题提供了新的希望。mi R-365作为mi RNAs中的重要一员,在肿瘤中频繁的异常表达已经证明其与肿瘤的发生发展及预后息息相关。因此深入研究mi R-365在肿瘤中的表达特点及与相关基因的调控关系将为了解肿瘤细胞周期、增殖、凋亡等生物学功能提供更有效的视点,为肿瘤的临床治疗提供潜在的治疗靶点。现就mi R-365在肿瘤中的表达及与信号通路之间的调控作一简要综述,以揭示mi R-365在肿瘤细胞内的表达调控情况。     

多胺代谢与肿瘤细胞信号转导

肿瘤细胞的快速增殖依赖于细胞内的多胺水平,耗竭细胞内多胺可抑制肿瘤细胞增殖并诱导其凋亡。与此同时,细胞内多胺含量的改变可以影响肿瘤细胞内多种信号通路的活性,依据受影响信号分子功能的差异,这些信号通路活性的改变具有增强或抑制耗竭多胺产生的抗肿瘤效应的功能,从而对肿瘤细胞的生长、分化、迁移和侵袭产生不同的影响。综述多胺对肿瘤相关信号通路的影响及其分子机制。     

Hippo-YAP信号通路在结直肠癌发生发展中的作用

结直肠癌是消化系统常见的恶性肿瘤,发生发展机制复杂。Hippo-YAP信号通路作为肿瘤抑制的一个重要信号通路,具有调节器官大小和维持细胞增殖与凋亡的动态平衡等功能。研究发现Hippo-YAP信号通路可以通过影响细胞的增殖、凋亡等从而参与结直肠癌的发生发展。本文就Hippo-YAP信号通路在结直肠癌中的作用及其机制进行综述。     

经典Wnt信号通路与非小细胞肺癌潜在治疗靶点的研究新进展

经典Wnt信号通路在人类非小细胞肺癌(non-small cell lung cancer,NSCLC)的发病和病程进展中具有重要的调控作用,它与肿瘤组织的增殖、生长、代谢、侵袭和转移有着紧密联系。在NSCLC发生发展中,经典Wnt信号通路的相关蛋白表达发生较复杂的改变,并影响疾病预后,因此,研究这些相关蛋白的表达情况有助于明确NSCLC发病机制以及研究潜在治疗方法。现对经典Wnt通路中NSCLC相关蛋白表达情况和作用以及潜在治疗靶点进行了归纳。     

Hippo-YAP/TAZ信号通路在干细胞增殖、分化及器官再生中的研究进展

Hippo-YAP/TAZ信号通路最初在果蝇中被发现,是器官发育和肿瘤生长过程中重要的调节者。通过调控细胞增殖、凋亡和分化等过程影响器官再生。近年来,对于Hippo-YAP/ TAZ信号通路在调节干细胞 (SC)增殖、自我更新及分化过程中的相关机制有了较大进展。本综述拟通过介绍Hippo-YAP/TAZ信号通路在SC增殖及多向分化过程中的作用、调控机制及器官再生方面的研究进展,为应用SC治疗疾病提供相关理论基础。     

Bmi-1在丁酸钠诱导肿瘤细胞凋亡过程中的作用机制

丁酸钠（Sodium butyrate,NaB）是一种组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitors,HDACi）,通过增加组蛋白的乙酰化,使染色质处于开放状态,便于基因转录与表达。多梳基因家族（Polycomb group genes,PcG）的成员Bmi-1蛋白可以对染色体组蛋白进行修饰,使一些抑癌基因如p14、P16和P21基因等表达沉默,同时Bmi-1蛋白通过Wnt信号通路激活原癌基因c-Myc,使Bmi-1、Wnt信号通路、c-Myc组成一个正反馈循环,还可以上调端粒酶的表达,导致肿瘤的发生。HDACi可以下调Bmi-1蛋白的表达,并通过上调p14、p16和p2l等的表达以及线粒体通路和Wnt信号通路抑制肿瘤细胞的增殖、分化,诱导肿瘤细胞凋亡。HDACi将可能为肿瘤的治疗提供一个广阔的前景,本研究将对Bmi-1在丁酸钠诱导肿瘤细胞凋亡过程中的作用机制作一综述。     

人参皂苷-Rh2诱导肿瘤细胞凋亡信号转导通路研究进展

人参皂苷-Rh2诱导肿瘤细胞凋亡机制复杂,且不同机制间相互联系。它主要通过调节细胞周期蛋白依赖性激酶复合物特异性信号传递引发细胞周期阻滞诱导细胞凋亡,或通过调控细胞信号转导通路,如ROS、Ca2+、PKC、JNK介导的线粒体信号通路和TRAIL-R1(DR4)介导的死亡受体信号通路等诱导肿瘤细胞凋亡。     

MAP17 and the double-edged sword of ROS

Reactive oxygen species, ROS, are beneficially involved in many signaling pathways that control development and maintain cellular homeostasis. In physiological conditions, a tightly regulated redox balance protects cells from injurious ROS activity, but if the balance is altered, it promotes various pathological conditions including cancer. Understanding the duality of ROS as cytotoxic molecules and key mediators in signaling cascades may provide novel opportunities for improved cancer therapy. MAP17 is a small 17-kDa non-glycosylated membrane protein that is overexpressed in many tumors of different origins, including carcinomas. Immunohistochemical analysis of MAP17 during cancer progression demonstrates that overexpression of the protein strongly correlates with the progression of most types of tumor. Tumor cells that overexpress MAP17 show an increased tumoral phenotype associated with an increase in ROS. However, in non-tumor cells MAP17 increases ROS, resulting in senescence or apoptosis. Therefore, in tumor cells, MAP17 could be a marker for increased oxidative stress and could define new therapeutic approaches. Here, we review the role of MAP17 as a putative oncogene, as well as its role in cancer and anticancer therapies.     

Escaping cell death: survival proteins in cancer

Defects in apoptosis signaling pathways are common in cancer cells. Such defects may play an important role in tumor initiation because apoptosis normally eliminates cells with damaged DNA or dysregulated cell cycle, i.e., cells with increased malignant potential. Moreover, impaired apoptosis may enhance tumor progression and promote metastasis by enabling tumor cells to survive the transit in the bloodstream and to grow in ectopic tissue sites lacking the otherwise required survival factors. Finally, raised apoptosis threshold may have deleterious consequences by rendering cancer cells resistant to various forms of therapy. The intensive apoptosis research during the past decade has resulted in the identification of several proteins which may promote tumorigenesis by inhibiting apoptosis. Of special relevance in human cancer are those commonly expressed in primary tumors and functioning at the common part of the signaling pathway leading to apoptosis. Proteins fulfilling these criteria include antiapoptotic members of the Bcl-2 protein family, heat shock proteins, Hsp70 and Hsp27, as well as survivin, the novel cancer-associated member of the inhibitor of apoptosis protein family. Understanding the molecular mechanisms of action of these proteins may offer novel modes of rationally and selectively manipulating the sensitivity of cancer cells to therapy.     

CMTM家族成员在肿瘤细胞中的分子机制及潜在临床价值

恶性肿瘤已成为危害人类健康的重要杀手,针对肿瘤的研究也成为当今医学界的热点.含有MARVEL跨膜结构域的趋化素样因子基因家族(CKLF-like MARVEL transmembrane domain containing family of genes,CMTM family),原名人类趋化素样因子超家族(chemo...     

神经前体细胞表达发育性下调蛋白4在消化系统肿瘤发生中的作用

神经前体细胞表达发育性下调蛋白4(neural precursor cell expressed,developmentally down-regulated protein 4,NEDD4-1,部分文章也称NEDD4)是近年来才备受关注的肿瘤相关基因,属于E3 HECT(homologous to E6 associated protein C terminus,E6蛋白c端同源基因)泛素连接酶NEDD4样家族成员。泛素连接酶,能够参与多种蛋白质的泛素化、溶酶体及蛋白酶体的降解、胞核-胞质转位等,间接影响不同恶性肿瘤的多种信号通路。随着大量NEDD4-1与肿瘤相关实验的不断深入,目前已发现其可通过调控细胞周期、癌细胞侵袭转移、拮抗耐药性等许多途径影响肿瘤的生物学行为。在消化系统肿瘤中,NEDD4-1主要通过PTEN/PI3K/AKT、TGF-β、Hippo、LDLRAD4等多条通路促进肝细胞癌的增殖、侵袭和迁移能力;在胰腺癌中发现,NEDD4-1在PI3K/AKT信号通路中发挥癌基因作用,但在与Myc-SIRT2所形成的信号环路中,却发挥抑癌基因的作用;在胃癌和结直肠癌中,NEDD4-1所参与的信号通路与其他消化系统肿瘤均不相同,NEDD4-1能独立于PTEN/PI3K/AKT通路而发挥促进胃癌恶化、转移(EGFR信号通路)和抑制结直肠癌肿瘤生长(WNT信号通路)的作用。NEDD4-1已经成为人们治愈肿瘤的热门研究方向。本文通过系统总结NEDD4-1在不同消化系统肿瘤中的功能、信号通路和潜在抑制剂等,进行探讨NEDD4-1与不同信号通路的关系,旨为临床在癌症治疗领域提供重要的参考数据。     

The perivascular niche microenvironment in brain tumor progression

Glioblastoma, the most frequent and aggressive malignant brain tumor, has a very poor prognosis of approximately 1-year. The associated aggressive phenotype and therapeutic resistance of glioblastoma is postulated to be due to putative brain tumor stem-like cells (BTSC). The best hope for improved therapy lies in the ability to understand the molecular biology that controls BTSC behavior. The tumor vascular microenvironment of brain tumors has emerged as important regulators of BTSC behavior. Emerging data have identified the vascular microenvironment as home to a multitude of cell types engaged in various signaling that work collectively to foster a supportive environment for BTSCs. Characterization of the signaling pathways and intercellular communication between resident cell types in the microvascular niche of brain tumors is critical to the identification of potential BTSC-specific targets for therapy.Key words: glioblastoma, perivascular niche, brain tumor, cancer stem-like cells, microenvironment     

Hypoxia inhibition of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Hypoxia is a common environmental stress. Particularly, the center of rapidly growing solid tumors is easily exposed to hypoxic conditions. Thus, tumor cell response to hypoxia plays an important role in tumor progression as well as tumor therapy. However, little is known about hypoxic effect on apoptotic cell death. To examine the effects of hypoxia on TRAIL-induced apoptosis, human lung carcinoma A549 cells were exposed to hypoxia and treated with TRAIL protein. Hypoxia significantly protected A549 cells from apoptosis induced by TRAIL. Western blotting analysis demonstrated that hypoxia increased expression of antiapoptotic proteins such as Bcl-2, Bcl-XL, and IAP family members. The increase of these antiapoptotic molecules is believed to play an hypoxia-mediated protective role in TRAIL-induced apoptosis. Our findings suggest that an increase of antiapoptotic proteins induced by hypoxia may regulate the therapeutic activity of TRAIL protein in cancer therapy.     

肿瘤中与survivin有关的信号通路及分子以及靶向survivin的治疗前景

Survivin在细胞内环境稳定和肿瘤的形成中起重要的作用,在肿瘤的治疗中,survivivin的靶向治疗调节与一些典型的信号通路和一系列生长因子有关。众所周知,survivin是一个小的凋亡蛋白抑制因子,也是一个主要的抗癌靶标,与细胞分裂和凋亡抑制有关,它在大部分正常组织中缺失但在大部分癌组织中过表达。Survivin是一个与众多细胞信号通路有关的节点蛋白,这些通路协调各种细胞因子、转录网络和修饰基因,通过调节癌细胞内环境稳定直接或间接促进细胞增殖。临床前研究数据表明,survivin的抑制可以降低细胞增殖促进凋亡,增加细胞对细胞毒药物和放疗的敏感性,其过表达与不良预后和治疗耐受有关。因此对于癌症治疗,survivin是一个潜在的靶标。     

赖氨酸乙酰转移酶5与肿瘤

赖氨酸乙酰转移酶5(KAT5)作为MYST家族中的一员,可通过乙酰化不同底物,参与转录、DNA修复、分化和信号转导等细胞过程。KAT5的作用不可被其他MYST家族成员替代,并且KAT5的敲除可直接导致细胞凋亡,说明KAT5可能位于细胞中生理信号通路的上游,发挥着极其重要且独一无二的作用。因此,KAT5表达量的变化极有可能导致肿瘤的发生发展。过去的研究发现,KAT5在乳腺癌、黑色素瘤、肺癌中表达降低,在这些肿瘤中被认为是抑癌因子。然而,近年来研究发现,KAT5在乳腺癌、肝癌、黑色素瘤、前列腺癌和肺癌等肿瘤中既可高表达又可低表达。在KAT5高表达前提下,KAT5可作为促癌因子发挥促癌作用,而在KAT5低表达的前提下,KAT5又可作为抑癌因子发挥抑癌作用,并随着KAT5进一步表达下降,抑癌作用减弱,从而导致肿瘤的发生发展。此外,KAT5还被发现在骨肉瘤、甲状腺癌、胶质母细胞瘤和结直肠癌等肿瘤中异常表达,且KAT5的异常表达与肿瘤细胞的增殖、转移、凋亡、药物和放疗抵抗性密切相关。因此,KAT5是具有潜力的肿瘤治疗靶点之一。本文根据近些年KAT5在肿瘤中的表达量和在相应表达量下参与的抑癌或促癌信号通路进行综述,希望为肿瘤的治疗与预后监测提供新的启示和参考。     

Semaphorins in cancer: Biological mechanisms and therapeutic approaches

The hallmarks of cancer include multiple alterations in the physiological processes occurring in normal tissues, such as cell proliferation, apoptosis, and restricted cell migration. These aberrant behaviors are due to genetic and epigenetic changes that affect signaling pathways controlling cancer cells, as well as the surrounding “normal” cells in the tumor microenvironment. Semaphorins and their receptors (mainly plexins and neuropilins) are aberrantly expressed in human tumors, and multiple family members are emerging as pivotal signals deregulated in cancer. Notably, different semaphorins can promote or inhibit tumor progression, depending on the implicated receptor complexes and responsive cell type. The important role of semaphorin signals in the regulation of tumor angiogenesis, invasion and metastasis has initiated multiple experimental approaches aimed at targeting these pathways to inhibit cancer.