核心蛋白聚糖基因在肿瘤学中的研究进展

核心蛋白聚糖( Decorin,DCN)是富含亮氨酸小分子蛋白多糖家族成员之一,是公认的抑癌基因,可结合并灭活转化生长因子β( TGF-β)和抑制血管内皮生长因子( VEGF)表达,还可通过激活EG-FR/MAP激酶/p21信号通路介导的促细胞增殖信号通路等机制来抑制肿瘤细胞增殖与转移,在肿瘤的发展、血管形成、转移过程中具有重要作用. DCN在多种恶性肿瘤中表达,通过上调或下调DCN的表达,能够使DCN通过多种途径发挥其抗肿瘤活性,降低、延缓多种恶性肿瘤的发生、发展. DCN基因可能成为多种恶性肿瘤治疗的潜在靶点.     

p53及p21蛋白在胆囊癌及肝外胆管癌的表达

p21WAn（p21）是细胞周期蛋白依赖激酶（Cyclin-dependent kinases,CDks）抑制蛋白,为野生型p53基因下游激活产物。p53突变及p21蛋白异常表达在肿瘤的发生发展中起重要作用,见于多种人类恶性肿瘤。我们应用免疫组织化学的方法检测胆囊癌及肝外胆管癌组织中p53及p21的表达情况,探讨p53及p21蛋白表达的意义以及与临床病理指标的关系。     

PAK5调控的信号通路在癌症中的研究进展

小G蛋白Rho家族的下游靶蛋白-p21活化激酶(p21-activated kinases,PAKs),属丝氨酸/苏氨酸蛋白激酶,可与Rac1和Cdc42结合,在进化上高度保守,可被多种胞外信号活化.PAK5是PAKs家族中发现最晚、研究甚少的成员.PAK5在细胞骨架重组、细胞生长、增殖、分化、基因转录及细胞凋亡等功能中具有重要作用.研读文献可知,在神经源性肿瘤、胃肠道肿瘤及卵巢上皮癌等中均存在PAK5过表达.本文就PAK5与肿瘤的关系及其对细胞骨架调节、细胞增殖和抗凋亡等信号通路的调控机制做一综述.     

Gas6／Axl信号通路与肿瘤关系的研究进展

Axl为受体酪氨酸激酶家族成员之一,它与配体Gas6结合后激活自身酪氨酸激酶活性,通过激活下游信号转导途径,在细胞黏附、抗凋亡、增殖及迁移中发挥重要作用。近年来研究发现,在多种肿瘤组织中Gas6、Axl高表达,Gas6／Axl信号通路的激活在肿瘤细胞抗凋亡、增殖以及肿瘤血管生成、肿瘤侵袭和转移方面也有重要作用。目前针对拮抗Gas6／Axl信号通路的抗肿瘤实验研究也证实,Gas6／Axl信号通路在肿瘤治疗中有重要作用,因此Gas6／Axl信号通路可能会成为肿瘤治疗的新靶点。本文就Gas6／Axl信号通路与肿瘤的发生、发展及在抗肿瘤治疗中应用的进展作一综述。     

Bruton酪氨酸激酶在B细胞肿瘤中的研究进展

Bruton酪氨酸激酶（Btk）是非受体蛋白酪氨酸激酶Tec家族的成员之一,在B淋巴细胞的生长、增殖、分化和信号转导中起重要作用.当B细胞受体（BCR）受到各种因素激活后,Btk将被磷酸化而激活,激活的Btk引起下游信号分子的活化,BCR信号通路的活化在B细胞肿瘤的发生和维持中起重要作用.文章就近年来Btk在B细胞肿瘤中的研究进展作一综述.     

p21活化激酶4与肿瘤的研究进展

p21活化激酶4(PAK4)是最近发现的一种丝氨酸/苏氨酸蛋白激酶,在一系列细胞功能中发挥重要作用,如细胞周期、细胞增殖、细胞凋亡及细胞骨架重组等.近年研究发现,PAK4在许多肿瘤细胞中过表达,并通过多条信号通路参与肿瘤的发生及迁移浸润.     

靶向PI3K-Akt-mTOR信号通路抑制剂的研究进展

PI3K—Akt—mTOR信号通路控制着众多在肿瘤发生发展中至关重要的细胞生物学过程．包括细胞凋亡、转录、翻译、代谢、血管新生以及细胞周期的调控。遗传学上的改变和生化条件引起的激活经常发生在恶变早期和肿瘤进展期，同时，信号通路激活程度也是肿瘤患者预后的重要指标。因此抑制该信号通路成为肿瘤预防和肿瘤靶向治疗的热点。对于该信号通路的各个激酶，均有多种抑制剂处于临床前和临床研究阶段：     

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。     

Livin基因在恶性肿瘤诊断和治疗中的研究

Livin是凋亡抑制蛋白家族最新的成员,通过抑制半胱氨酸天冬氨酸蛋白酶、激活丝裂原激活蛋白激酶等途径参与细胞凋亡的调节.Livin在多种恶性肿瘤中高表达,并且在肿瘤的发生、发展中发挥重要作用,为肿瘤的诊断及治疗提供了新的研究方向.     

多途径丝裂原激活的蛋白激酶介导一氧化氮引起的肝癌细胞凋亡

目的研究非离子型的diazeniumdiolate类一氧化氮供体引起肝癌细胞凋亡的分子机制.方法利用免疫印迹、免疫沉淀、凝胶阻滞实验研究一氧化氮供体处理Hep3B肝癌细胞后,丝裂原激活的蛋白激酶、AP-1的激活以及和Hep3B肝癌细胞凋亡的关系.结果一氧化氮可引起细胞外信号调节蛋白激酶、c-jun N末端激酶和p38激酶的激活,特别是细胞外信号调节的蛋白激酶的持续激活,其中细胞外信号调节的蛋白激酶和c-jun N末端激酶的特异的阻断剂U0126和JNK抑制剂Ⅱ可阻断AP-1的激活和Hep3B细胞的凋亡,而p38激酶的阻断剂SB203580不能阻断AP-1的激活和Hep3B肝癌细胞的凋亡.结论一氧化氮通过激活细胞外信号调节蛋白激酶、c-jun N末端激酶,进而激活AP-1而引起Hep3B肝癌细胞的凋亡.     

P21-activated kinases in human cancer

A balance between proliferation, differentiation, migration and death of cells is critical for the normal development of an organism. Perturbations of this balance can contribute to cancer development. The p21-activated serine/threonine kinases (Paks) play an important role in a variety of cellular functions including cell morphogenesis, motility, survival, angiogenesis, and mitosis. Paks were initially identified as an effector molecules of RHO GTPases; however, recent evidence that they can be activated in both GTPase-dependent and -independent manners expands our understanding of their physiologic functions. Paks play an important role in growth factor signaling, leading to cytoskeletal reorganization that subsequently influences growth factor-mediated cell migration and metastasis functions. Recent findings that Paks play a role in mitosis, nuclear receptor-signaling and deregulation of Pak in cancer cells suggest that these kinases play an important role in both normal development and cancer progression. In this review, we summarize the results of recent advances into the role of Paks in tumorigenesis and metastasis.     

Src family kinases in tumor progression and metastasis

The Src family of non-receptor protein tyrosine kinases plays critical roles in a variety of cellular signal transduction pathways, regulating such diverse processes as cell division, motility, adhesion, angiogenesis, and survival. Constitutively activated variants of Src family kinases, including the viral oncoproteins v-Src and v-Yes, are capable of inducing malignant transformation of a variety of cell types. Src family kinases, most notably although not exclusively c-Src, are frequently overexpressed and/or aberrantly activated in a variety of epithelial and non-epithelial cancers. Activation is very common in colorectal and breast cancers, and somewhat less frequent in melanomas, ovarian cancer, gastric cancer, head and neck cancers, pancreatic cancer, lung cancer, brain cancers, and blood cancers. Further, the extent of increased Src family activity often correlates with malignant potential and patient survival. Activation of Src family kinases in human cancers may occur through a variety of mechanisms and is frequently a critical event in tumor progression. Exactly how Src family kinases contribute to individual tumors remains to be defined completely, however they appear to be important for multiple aspects of tumor progression, including proliferation, disruption of cell/cell contacts, migration, invasiveness, resistance to apoptosis, and angiogenesis. This review details the evidence for Src family activation in human tumors, and emphasizes possible consequences to tumor progression. Given the ability of Src and its family members to participate in so many aspects of tumor progression and metastasis, Src family kinases are attractive targets for future anti-cancer therapeutics.     

Src family kinases, key regulators of signal transduction

The Src family of protein tyrosine kinases (SFKs) plays key roles in regulating signal transduction by a diverse set of cell surface receptors in the context of a variety of cellular environments. SFKs have evolved many ingenious molecular strategies to couple receptors with the cytoplasmic signaling machinery. The contributions to this issue of ONCOGENE describe how this machinery regulates fundamental cellular processes, including cell growth, differentiation, cell shape, migration and survival, and specialized cell signals. The pleiotropic functions of Src and Src family members underscore the importance of these kinases and explain why many of the members of this family have been identified as cellular oncogenes. In this volume, we have attempted to provide the reader with an overview of the current understanding of the function of Src family kinases in the regulation of selected cellular signaling pathways.     

p38丝裂原活化蛋白激酶信号转导对肿瘤细胞凋亡的调控

p38丝裂原活化蛋白激酶(p38MAPK)信号通路是丝裂原活化蛋白激酶(MAPK)家族的一条重要途径,可被多种细胞外刺激而激活,近年来研究发现在细胞凋亡中发挥重要作用.p38MAPK可通过活化半胱天冬氨酸蛋白酶(caspase)家族成员、调节Bcl-2家族成员的活性、活化p53、参与Fas-FasL通路等多种途径介导肿瘤细胞的凋亡过程.     

JAK2抑制剂在肿瘤治疗中的应用价值

JAK家族是JAK-STAT信号传导通路中的非受体型酪氨酸蛋白激酶,JAK2-STAT3作为JAK-STAT通路中的一个重要信号轴,它在肿瘤中的持续性激活可以通过影响细胞的生长、凋亡、周期等起到促进肿瘤发生发展的作用.JAK2突变,尤其是JAK2V617F突变的发现引发了JAK2抑制剂的研究热潮,为肿瘤的治疗提供了新的方向.JAK2抑制剂能削弱肿瘤细胞的恶性生物学行为,在有JAK2V617F突变的血液系统肿瘤以及JAK2-STAT3信号异常的实体肿瘤中都具有一定的治疗价值.     

p21-activated kinases in cancer

The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of cancers. p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes for various oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility, but have recently also been shown to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, which results in tumour formation and cell invasiveness. Alterations in Pak expression have been detected in human tumours, which makes them an attractive new therapeutic target.     

An essential role of Pak1 phosphorylation of SHARP in Notch signaling

The p21-activated kinases (Paks), an evolutionarily conserved family of serine/threonine kinases, play an important role in cytoskeletal reorganization in mammalian cells. The Notch signaling pathway plays an important role in the determination of cell fate/differentiation in a number of organs. Notch signaling is a complex process, and the mechanism by which Notch regulates multiple cellular processes is intriguing. The expression of both Notch and Pak1 has been shown to be deregulated in several human cancers. Using yeast two-hybrid screening, we identified SHARP, one of the Notch signaling components, as a Pak1-interacting protein. We found that SHARP is a physiologic interacting substrate of Pak1, and that this interaction enhances SHARP-mediated repression of Notch target genes. Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and Thr3568 within the SHARP repression domain. Mutation of Pak1 phosphorylation sites in SHARP, inhibition of Pak1 functions by a Pak1-autoinhibitory fragment (amino acids 83-149), or expression of Pak1-specific siRNA interfered with SHARP-mediated repression of Notch target reporter gene activation. These results demonstrate that Pak1-SHARP interaction plays an essential role in enhancing the corepressor functions of SHARP, thereby modulating Notch signaling in human cancer cells.     

Jak family of kinases in cancer

The family of Jak kinases is composed from at least four different tyrosine kinases (Tyk2, Jak1, Jak2, Jak3) that share significant structural homology with each other. The members of this family of kinases associate constitutively with a variety of cytokine and hormone receptors. Upon binding of the specific ligands to their receptors, Jak kinases are rapidly activated and their kinase activities induced, to regulate tyrosine phosphorylation of various effectors and initiate activation of downstream signaling pathways. The discovery of this family of tyrosine kinases dates back in the early 1990s with the cloning of the Tyk-2 tyrosine kinase as a critical element of the Type I interferon signaling pathway. Extensive work over the last few years has provided evidence that Jak kinases play important roles in the generation of responses for interferons, which are cytokines that exhibit important antitumor activities. There is also accumulating evidence that constitutive activation of different Jaks and Stats mediates neoplastic transformation and promotes abnormal cell proliferation in various malignancies. This review summarizes the role of various Jak-kinase dependent pathways in malignancies and discusses the therapeutic implications of the recent advances in the field.     

Biological effects of TrkA and TrkB receptor signaling in neuroblastoma

The Trk family consists of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-NGF, BDNF, NT3 and NT4. Neurotrophins mediate their multiple effects through a number of distinct intracellular signaling cascades regulating such diverse biological responses as cell survival, proliferation and differentiation in normal and neoplastic neuronal cells. Expression of Trk receptors also plays an important role in the biology and clinical behavior of neuroblastomas. High expression of TrkA is present in neuroblastomas with favorable biological features and highly correlated with patient survival, whereas TrkB is mainly expressed on unfavorable, aggressive neuroblastomas. This short review discusses recent data on the biological roles of TrkA and TrkB signaling in neuroblastoma.