T型钙通道与乳腺癌

T型钙通道是激活电位低、失活速度快、单通道电导小的电压依赖性钙通道,具有高组织特异性、突出的生理功能及药理学选择性等特点。近年来的研究表明,T型钙通道通过独特的激活失活效应参与细胞内外钙流的振荡,影响肿瘤细胞的增殖过程。值得关注的是正常人乳腺上皮细胞中没有T型钙通道,而在不同分化阶段的乳腺癌细胞中该通道却有表达。实验证实,T型钙通道的表达影响乳腺癌细胞的增殖,通道拮抗剂能够显著地抑制乳腺癌细胞增殖。这一发现为乳腺癌的诊断及靶向治疗药物的研发提供了新的思路。本文概要介绍了近年来T型钙通道与乳腺癌关系的研究进展。     

T-钙粘附素在肿瘤发生发展中的作用

T-钙粘附素是钙粘附素家族中的一个特殊成员,缺乏跨膜区和胞浆区,是通过糖基磷脂酰肌醇附着于细胞膜上．T-钙粘附素的异常表达参与到多种肿瘤的发生发展过程中,如肿瘤细胞的凋亡、增殖、侵袭和转移等过程．T-钙粘附素还可能参与肿瘤新生血管的形成和胞内外的信号传导过程．本文就T 钙粘附素在肿瘤发生发展过程中的作用及分子机制作一综述,该蛋白有可能成为肿瘤治疗的新靶点.     

副交感神经M1受体促进前列腺癌转移并抵抗肿瘤细胞凋亡的研究

该文旨在探讨副交感神经M1受体(muscarinic acetylcholine M1 receptor,CHRM1)通过调节PI3K/AKT信号通路对前列腺癌增殖、转移以及肿瘤细胞凋亡影响的研究。选用Western blot、免疫荧光等方法检测CHRM1在前列腺癌细胞中表达情况。体外培养人前列腺癌细胞系PC-3、LNCaP、DU145,然后用CHRM1激动剂卡巴胆碱(CAR)及特异性抑制剂哌仑西平(PIN)处理细胞。用CHRM1 RNAi慢病毒感染细胞,构建前列腺癌CHRM1敲低的稳转株。选用CCK8细胞增殖实验、平板克隆实验、细胞迁移侵袭实验、流式细胞术检测及透射电镜观察等方法探究CHRM1在前列腺癌中增殖、转移和凋亡水平。最后,用Western blot方法检测敲低的CHRM1前列腺癌细胞中上皮间质标志物及PI3K/AKT信号表达水平。结果显示,CHRM1大量表达在前列腺癌各细胞系细胞中。CAR处理后细胞增殖能力、克隆形成水平、转移能力及抗凋亡能力提高,而PIN处理后其增殖能力、克隆形成能力、转移能力及抗凋亡能力降低。敲低CHRM1后,细胞的转移能力及抗凋亡能力降低,且电镜下出现凋亡小体。在细胞迁移与侵袭实验中发现其转移能力与肿瘤的上皮–间充质转化(EMT)有关。同时,CHRM1通过PI3K/AKT信号通路调控肿瘤细胞进程。该研究结果提示,CHRM1在前列腺癌细胞中调节PI3K/AKT信号通路促进,前列腺癌增殖、转移并抵抗肿瘤细胞凋亡。     

多柔比星诱导人前列腺癌细胞免疫原性死亡

钙网蛋白(calreticulin,CRT)是介导肿瘤细胞发生免疫原性死亡的关键性信号分子,在某些理化因素诱导肿瘤细胞发生凋亡的过程中,内质网上的CRT迅速转位到细胞膜上。作为一种特异的信号分子,凋亡肿瘤细胞膜上的CRT能介导吞噬细胞对凋亡肿瘤细胞的识别和吞噬。目前有关免疫原性肿瘤细胞死亡的实验数据大多由动物细胞和动物活体实验得到,人肿瘤细胞在发生免疫原性细胞死亡时,是否也具有CRT膜转位这样的分子事件还需要进一步探讨。研究分析了3种临床常用的肿瘤化疗药物(柔红霉素、长春新碱、顺铂)对人前列腺癌PC3细胞CRT亚细胞定位的影响,及其在介导肿瘤细胞免疫原性死亡中的作用。在对比分析的3种临床抗肿瘤药物中,柔红霉素和顺铂可诱导人前列腺癌PC3细胞发生凋亡,但仅柔红霉素处理的PC3细胞膜上CRT的表达量显著增加。膜上高表达CRT的PC3细胞能更有效地被吞噬细胞吞噬。结果表明,柔红霉素作为抗肿瘤药物,能诱导敏感人肿瘤细胞的免疫原性细胞死亡。     

受体调节钙通道有三种机制

几乎所有的组织都有受体调节的钙通道,它们参与多种细胞功能,第二信使诱导的电压门控性钙通道开放是近年来提出的一种较完善的机制,以解释受体调节的钙电导变化。1,4,5-三磷酸肌醇(InsP_3)作为第二信使,使细胞内贮存的钙释放到胞浆内,使细胞内钙浓度([Ca](?))升高,从而引起钙内流,也就是钙通道开放。这种机制已经在几个系统内得到证实,但是在乳腺细胞中却没有发现这种电压门控性钙通道,而乳腺细胞上肯定存在着受体调节的钙通道。最近 Kuno,Reuter 和 Irvine 分别提出了另外三种机制,解释受体介导的钙内流。     

白细胞介素-8与肿瘤免疫逃逸

IL-8是趋化因子CXC家族的一员,是一种多细胞来源的细胞因子,在细胞的多种炎症反应中起调节作用,并且在自身免疫性疾病中也发挥重要作用。IL-8通过与细胞膜上的CXC趋化因子受体CXCR1和CXCR2相互作用,激活偶联的G蛋白,由G蛋白进一步激活PLC、AC、PLD、PI3K、JAK2及Ras等信号分子,从而调控基因表达、细胞增殖和分化、细胞代谢、细胞运动及血管生成等多种细胞生命过程。IL-8在多种恶性肿瘤细胞中表达量升高,其高表达与肿瘤细胞增殖、迁移、侵袭、血管生成及上皮间充质转化有密切联系。肿瘤免疫逃逸是肿瘤细胞产生和转移过程中的主要特征之一,肿瘤细胞可以通过多种机制使得人体免疫系统无法对其进行正常的识别和攻击,从而导致肿瘤细胞在体内存活,并且不断增殖和转移,而肿瘤细胞、免疫细胞以及肿瘤微环境中其他相关组分均可以促进肿瘤免疫逃逸。IL-8作为一种炎性趋化因子,已被证明在肿瘤免疫逃逸中具有重要作用,其可通过诱导肿瘤细胞PD-L1表达、抑制肿瘤细胞凋亡、促进肿瘤细胞EMT进程、促进肿瘤微环境血管生成、招募免疫抑制性细胞等五个方面介导肿瘤免疫逃逸。IL-8中和抗体和CXCR1/2拮抗剂在抗肿瘤治疗方面已经显示出较好的治疗效果。     

酪丝亮肽对人肝癌BEL-7402细胞钙稳态影响的实验研究

目前寻找有效的药物仍是治疗肿瘤的关键环节之一. 酪丝亮肽为中国新近研发并具有自主知识产权的三肽化合物. 观察了酪丝亮肽的抗肝癌作用, 并研究了其对肿瘤细胞钙稳态的影响, 以初步探讨它的抗肿瘤作用机制. 结果发现, 酪丝亮肽能显著抑制人肝癌BEL-7402裸鼠移植瘤的生长, 160 mg/(kg·d)治疗组肿瘤生长抑制率可达41.34%, 电子显微镜观察发现酪丝亮肽可引起移植瘤细胞的坏死和凋亡, 细胞器线粒体和内质网损伤, 并出现钙沉积. 应用激光扫描共聚焦显微镜及流式细胞仪观察发现, 10 mg/mL酪丝亮肽在400 s内可引起体外培养BEL-7402细胞胞浆钙离子浓度迅速升高, 最高幅度可达239.13%; 持续作用1 h后BEL-7402胞浆钙离子维持在高水平, 作用2 h后胞浆钙离子浓度开始下降, 4和24 h时的胞浆钙离子水平均低于对照, 相同剂量的药物对人正常肝细胞株Chang氏肝无明显影响; 酪丝亮肽还可使体外培养的BEL-7402细胞线粒体跨膜电位明显下降, 提示其抗肝癌机制可能是通过影响肿瘤细胞的钙稳态, 诱导其发生坏死或凋亡.     

钙信号调节小鼠前体脂肪细胞分化和脂质蓄积的机制

本试验用醋酸钙、p38丝裂原激活蛋白激酶(p38MAPK)抑制剂SB203580及钙通道阻滞剂和激动剂刺激小鼠前体脂肪细胞。通过实时定量PCR技术检测前体脂肪细胞分化标志基因和钙信号相关受体基因表达水平,用油红O染色提取法和Fura-2/AM荧光法测定胞内脂质蓄积情况及胞浆游离Ca2+浓度([Ca2+]i)变化,以探讨钙信号调节前体脂肪细胞分化的潜在机制。结果表明:钙通道阻滞剂和激动剂显著改变了脂蛋白脂酶(LPL),过氧化物增殖激活受体γ(PPARγ)、脂肪酸合成酶(FAS)的表达水平,且影响细胞内的脂质蓄积。与降低外钙摄入相比,降低内钙释放能促进前体脂肪细胞分化(P<0.01),而提高外钙摄入与提高内钙释放相比,提高外钙摄入显著抑制前体脂肪细胞分化(P<0.01)。SB203580可降低胞浆[Ca2+]i浓度,促进前体细胞分化和脂质蓄积(P<0.01)。但钙信号并未影响维生素D受体(VDR)和细胞外钙敏感受体(CaSR)的表达水平。提示钙信号可能通过p38MAPK通路影响前体脂肪细胞分化和脂质蓄积。     

Procaspase-8失调与肿瘤细胞对TRAIL的耐受

肿瘤坏死因子相关凋亡诱导配体(TRAIL)可激活胱天蛋白酶（caspase）家族蛋白系列级联反应,最终诱导细胞凋亡. TRAIL选择性地诱导肿瘤细胞凋亡而不损伤正常细胞,使其成为治疗癌症的潜在药物靶点. 目前已知,细胞型FADD样白介素-1-β转换酶抑制蛋白(c FLIP)和凋亡抑制蛋白(IAPs)是肿瘤细胞对TRAIL耐受的主要原因.胱天蛋白酶原-8（procaspase-8）是TRAIL凋亡信号途径中的凋亡起始蛋白. 然而近年发现,在某些肿瘤细胞中procaspase-8功能失调常会阻碍凋亡信号传导,使肿瘤细胞对TRAIL诱导的凋亡产生耐受. 本文就其机制进行概述.     

TXNIP基因与肿瘤发生及转移

硫氧还蛋白结合蛋白（thioredoxin interacting protein, TXNIP）在细胞增殖、凋亡、分化的过程以及肿瘤、应激性疾病的发生中具有重要功能. 作为一个氧还反应的调节子,TXNIP能与硫氧还蛋白(thioredoxin, Trx)相结合,下调Trx的表达,而Trx则在DNA的损伤及细胞凋亡机制中有着关键的作用. 本文阐述了TXNIP基因的特征及其蛋白的生物学功能, 并简要总结TXNIP在人类肿瘤中低表达的研究成果. TXNIP基因是一个新的抑癌基因,它在人类乳腺癌、肝癌、肺癌等癌组织细胞中均表达下降, 并且与肿瘤的转移相关. TXNIP的缺失可以促使肿瘤细胞的增殖和抑制细胞凋亡的进程. 而在抗肿瘤机制中, TXNIP可通过参与细胞周期阻滞、低氧调节、影响NK细胞(natural killer cell, NK cell)发育等过程介导肿瘤的发生发展.     

Paxillin promotes breast tumor collective cell invasion through maintenance of adherens junction integrity

Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among different human cancers, but its role in tumor progression is unclear. Herein we utilize a newly generated PyMT mammary tumor mouse model with conditional paxillin ablation in breast tumor epithelial cells, combined with in vitro three-dimensional (3D) tumor organoids invasion analysis and 2D calcium switch assays, to assess the roles for paxillin in breast tumor cell invasion. Paxillin had little effect on primary tumor initiation and growth but is critical for the formation of distant lung metastasis. In paxillin-depleted 3D tumor organoids, collective cell invasion was substantially perturbed. The 2D cell culture revealed paxillin-dependent stabilization of adherens junctions (AJ). Mechanistically, paxillin is required for AJ assembly through facilitating E-cadherin endocytosis and recycling and HDAC6-mediated microtubule acetylation. Furthermore, Rho GTPase activity analysis and rescue experiments with a RhoA activator or Rac1 inhibitor suggest paxillin is potentially regulating the E-cadherin-dependent junction integrity and contractility through control of the balance of RhoA and Rac1 activities. Together, these data highlight new roles for paxillin in the regulation of cell–cell adhesion and collective tumor cell migration to promote the formation of distance organ metastases.     

Calcium signaling regulates fundamental processes involved in Neuroblastoma progression

Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor in children. Despite NB’s relative rarity, high-risk NB patients have a poor prognosis with survival rate less than 50%. This is even worse for patients with relapsed or refractory NB. Finding effective alternative treatment strategies is therefore a must.Calcium is an intracellular messenger that is unequivocally present in normal physiology mediating proliferation, growth, migration, cell division, angiogenesis and cell death, as well as pathophysiological processes such as those included in Weinberg’s hallmarks of cancer. Within the past 20 years, the molecular identity of most calcium channels has been revealed, however for some of these channels the precise gating mechanism and their role in normal physiology is still elusive.Here we review the recent findings of components of calcium signaling that are deregulating in the malignant progression of NB. We further integrate critical calcium signaling pathways using patient-derived expression analysis.Revealing the roles of these calcium pathways in tumor development, progression, microenvironment and importantly - protection against antineoplastic drugs may hopefully lead to novel treatment strategies in the future.     

Y-a-t-il des gènes du cancer du testicule?

The reply to this question depends on a precise definition of the question. Does one mean genes that cause tumor formation, genes that are responsible for susceptibility to testicular cancer or genes that are associated with tumor progression? There is little evidence to support gene mutation as a cause of testicular cancer. Cancer formation is probably the result of a complex interaction between environmental factors and gene variants that may give a susceptiblity to cancer. Testicular cancer susceptibility genes are now being mapped. Recently a locus on Xq has been defined that is associated with some familial cases of germ cell tumors. Most of these cases have a history of cryptorchidism, so the locus may be responsible for a susceptibility t undecended testis. Other chromosomal rearrangements are associated with testicular cancer. These include interstitial deletions of 5q and 12q, and isochromosome 12p. The relationship between these changes and tumor formation or progression has yet to be established. Increasing evidence suggests that the isochromosome 12p may play an important role in testicular cancer, because this chromosomal rearrangment can be detected in carcinoma in situ cells which are considered to be the common ancestor of all types of testicular cancer. Multiple copies of a gene on 12p may influence cancer formation or development. A candidate factor is cyclin D2. This cyclin plays a key role in the progression of the cell cycle. Dysregulation of the cell cycle caused by the presence of an increased dose of cyclin D2 may play an important contribution in testicular cancer.     

Tumor promoting effect of podoplanin-positive fibroblasts is mediated by enhanced RhoA activity

There is growing evidence that stromal fibroblasts can promote tumor progression via several mechanisms. We previously reported that podoplanin (PDPN) expressed on stromal fibroblasts is functionally protein responsible for the promotion of tumor formation in mouse subcutaneous tissue. The purpose of the present study was to reveal the molecular mechanism by which PDPN on stromal fibroblasts promotes tumor formation. The subcutaneous co-injection of the human lung adenocarcinoma cell line A549 and human fibroblasts (hFbs) overexpressing wild-type podoplanin (WT-PDPN) promoted subcutaneous tumor formation, compared with the co-injection of A549 and control hFbs (64% vs 21%). On the other hand, hFbs expressing PDPN mutant in which the cytoplasmic domain of PDPN was deleted (PDPN-Del.IC), resulted in a relatively lower level of tumor formation (33%). Since PDPN reportedly regulates RhoA activity through its cytoplasmic domain, we measured the activation state of RhoA in hFbs expressing WT-PDPN. RhoA activity was 2.7-fold higher in WT-PDPN expressing hFbs than in control hFbs. Furthermore, the subcutaneous co-injection of hFbs expressing constitutive active RhoA (G14VRhoA) and A549 cells enhanced tumor formation compared with the co-injection of the same cell line and control hFbs. These results indicate that enhanced RhoA activity in hFbs expressing PDPN may be one of the mechanisms resulting in the promotion of tumor formation, suggesting that biomechanical remodeling of the microenvironment by stromal fibroblasts may play important roles in tumor progression.     

Trop2 as an oncogene in gastric cancer by regulating PI3K/Akt signaling pathway

High Trop2 expression relates to aggressive tumor behavior and contributes to poor overall survival rates in gastric cancer (GC) patients. However, little is known about the molecular mechanism of Trop2 in the carcinogenesis of GC. We found that over-expressed Trop2 induced cell proliferation and clone formation, inhibited cell apoptosis and induced S cell cycle arrest in GC cell lines, meanwhile, knockdown Trop2 inhibited cell proliferation and clone formation, induced cell apoptosis and inhibits S cell cycle arrest in vitro. Moreover, Trop2 depletion inhibited tumor growth , the anti-tumor rate in this report being 22.53% in vivo. In addition, Trop2 activated the PI3K/Akt signaling pathway to promote GC malignant progression. These results indicated that Trop2 is a critical regulation factor in the progression of GC, which may help to lead a novel insight into understanding the mechanism of the Trop2 in the pathogenesis of GC.     

Calcium-mediated mechanisms of cystic expansion

In this review, we will discuss several well-accepted signaling pathways toward calcium-mediated mechanisms of cystic expansion. The second messenger calcium ion has contributed to a vast diversity of signal transduction pathways. We will dissect calcium signaling as a possible mechanism that contributes to renal cyst formation. Because cytosolic calcium also regulates an array of signaling pathways, we will first discuss cilia-induced calcium fluxes, followed by Wnt signaling that has attributed to much-discussed planar cell polarity. We will then look at the relationship between cytosolic calcium and cAMP as one of the most important aspects of cyst progression. The signaling of cAMP on MAPK and mTOR will also be discussed. We infer that while cilia-induced calcium fluxes may be the initial signaling messenger for various cellular pathways, no single signaling mediator or pathway is implicated exclusively in the progression of the cystic expansion. This article is part of a Special Issue entitled: Polycystic Kidney Disease.     

A critical role of Gbetagamma in tumorigenesis and metastasis of breast cancer

A growing body of evidence indicates that G protein-coupled receptors (GPCRs) are involved in breast tumor progression and that targeting GPCRs may be a novel adjuvant strategy in cancer treatment. However, due to the redundant role of multiple GPCRs in tumor development, it may be necessary to target a common signaling component downstream of these receptors to achieve maximum efficacy. GPCRs transmit signals through heterotrimeric G proteins composed of Gα and Gβγ subunits. Here we evaluated the role of Gβγ in breast tumor growth and metastasis both in vitro and in vivo. Our data show that blocking Gβγ signaling with Gα(t) or small molecule inhibitors blocked serum-induced breast tumor cell proliferation as well as tumor cell migration induced by various GPCRs in vitro. Moreover, induced expression of Gα(t) in MDA-MB-231 cells inhibited primary tumor formation and retarded growth of existing breast tumors in nude mice. Blocking Gβγ signaling also dramatically reduced the incidence of spontaneous lung metastasis from primary tumors and decreased tumor formation in the experimental lung metastasis model. Additional studies indicate that Gβγ signaling may also play a role in the generation of a tumor microenvironment permissive for tumor progression, because the inhibition of Gβγ signaling attenuated leukocyte infiltration and angiogenesis in primary breast tumors. Taken together, our data demonstrate a critical role of Gβγ signaling in promoting breast tumor growth and metastasis and suggest that targeting Gβγ may represent a novel therapeutic approach for breast cancer.     

活化T 细胞核因子在皮肤疾病发生与发展中的作用

活化T细胞核因子(nuclear factor of activated T cell,NFAT)作为细胞信号转导中的一类重要因子,最早被认为是一种能结合和上调T细胞中IL-2基因启动子的诱导性核因子,现发现它不仅在免疫系统中发挥功能,在肿瘤发生、发展中也起着关键性作用。近年来,越来越多的研究显示NFAT与人类皮肤疾病的发生、发展密切相关。在多种皮肤疾病患者真表皮成分中,NFAT异常表达,促进T细胞活化、表皮细胞增殖及自身免疫反应的形成,甚至促进肿瘤形成和浸润转移。本文旨在阐述研究发现的NFAT在皮肤疾病中发挥的重要作用,涉及T细胞活化、自身免疫反应形成、肿瘤形成及其浸润转移,以及NFAT在皮肤疾病中作用机制,预测这些研究结果对于皮肤病的治疗有着重要意义。