星形细胞上调基因1（AEG －1）介导肿瘤耐药的研究进展

星形细胞上调基因（Astrosyte elevated gene 1，AEG－1）具有促进癌症发生和发展的作用。AEG－1的过表达与血管生成、转移、及不同组织起源的癌细胞与各种化疗药物耐药有关。研究表明， AEG－1通过Ha－ras、myc、NF－κB及PI3K／Akt信号通路参与经典致癌途径。 AEG－1通过激活AMP激酶来促进自噬作用。另有研究指出， AEG －1调节耐药性是通过多药耐药基因（ Multidrug resistance ， MDR1） mRNA表达增加多聚核糖体的负载量，从而促进MDR1蛋白翻译。近来证明AEG－1作为一种RNA结合蛋白潜在影响药物的敏感性和耐药基因的表达。 AEG－1耐药性的多重功能显示，它作为抗肿瘤药物的靶点，为肿瘤靶向治疗提供新的途径是可行的。本文主要就AEG－1在化疗药物耐药方面的作用做一综述。     

Sirtuin 4和Sirtuin 5蛋白在代谢性疾病与肿瘤中的研究进展

沉默调节蛋白(Sirtuin,Sirt)是一类具有多种代谢调节酶活性的蛋白质家族,Sirtuin家族成员共有7个（Sirt 1~7）,其成员中Sirt 4蛋白具有NAD依赖的蛋白脂酰胺酶、ADP-核糖体转移酶和赖氨酸去酰基酶的活性,而Sirt 5蛋白具有NAD-依赖的赖氨酸去丙二酰酶、去琥珀酰酶和去戊二酰酶的活性。近年来研究发现,Sirt 4和Sirt 5广泛参与到细胞生存、衰老和代谢等生物学过程中,在生物体应激反应、炎症反应、肿瘤发生和能量代谢等众多生物学过程中扮演着重要角色,并在癌症、糖尿病、肥胖、帕金森和阿尔兹海默病等疾病的临床治疗方面具有一定潜力。本文归纳了Sirt 4和Sirt 5在代谢途径中的重要作用,并归纳了其与代谢性疾病及癌症的关系,希望能够为开发相关癌症的靶向药物、临床治疗提供新思路。     

细胞因子在实验性癌症恶病质中的作用

目的 探讨细胞因子TNF-α、IL－1、IL－6与癌症恶病质的关系,观察消炎痛对癌症恶病质的治疗效果。方法 且肺腺癌（LA795)接种T739小鼠建立癌症恶病质实验模型,测定荷瘤前后不同阶段小鼠血清IL－6、IL－1、TNF－α的水平及血糖、甘油三酯和总蛋白的变化及体重变化,并且观察消炎痛对癌症恶病质的治疗效果。结果 癌症恶病质小鼠的体重、血糖、血甘油三酯、血总蛋白显著低于非荷瘤组,而血清IL－6、TNF－α和IL－1水平显著高于非荷瘤组。消炎痛治疗后,恶病质小鼠的体重、摄食量、血糖、血甘油三酯和血总蛋白水平较生理盐水对照组显著提高且生存时间延长,同时IL－6、TNF－α、IL－1的血清水平显著低于生理盐水对照组。结论 IL－6、TNF-α、IL－1参与了本动物模型的癌症恶病质诱导。通过抑制IL-6、TNF-α、IL－1的升高,消炎痛具有改善癌症恶病质的作用。     

癌症中 IL －6信号通路研究进展

IL －6是一种多效细胞因子。IL －6在肿瘤患者外周血和肿瘤组织中均呈现高表达。IL －6与其相应受体结合,受体复合物结合 gp130后活化 STAT3和 Twist,导致 E －cadherin 表达下调,N －cadherin、Vi-mentin、Snail 等蛋白表达上调,诱发癌细胞发生上皮－间充质转化,从而增强癌细胞的侵袭力和远处转移能力。因此,对 IL －6／STAT3／Twist 信号通路的深入研究,可能为揭示癌症的发病机制研究开辟新的方向,为研发针对此信号通路来治疗癌症的特异性药物提供了理论基础。本文针对近期的研究进展作一综述。     

树突状细胞在肿瘤免疫和免疫治疗中的研究进展

树突状细胞（dendritic cells,DCs）是一类特殊的抗原呈递细胞,在先天和适应性免疫应答的启动和调节中起关键作用。了解DCs的功能以及肿瘤微环境对DCs的影响,有助于开发新的癌症治疗策略。通过调节DCs的功能改善肿瘤免疫治疗的疗效是目前研究的热点。大量研究表明,靶向肿瘤微环境中的DCs是癌症治疗极具前景的方法。本文重点讨论DCs在肿瘤免疫中的主要功能及靶向DCs在癌症中的治疗潜力。     

粪便菌群移植在癌症治疗中的研究进展

大量研究证明,肠道菌群失衡与人类癌症之间有密切的关系。肠道菌群不仅在维持肠道屏障和代谢营养方面发挥作用,更重要的是,这些微生物有助于调节局部和全身免疫功能,进而参与机体癌症的发病机制。粪便菌群移植(FMT)是一种调节肠道菌群的方法,它的有效机制主要基于有益微生物的增强、微生物组多样性的增加以及正常菌群的恢复。最近有研究表明,以病原体数量明显增加和有益细菌水平相对降低为特征的微生物改变与胃肠道和胃肠道外癌症的发展有关,提示调节肠道菌群是治疗人类癌症具有前景的手段之一。本文围绕FMT在治疗消化系统癌症、非消化系统癌症和癌症相关并发症上的作用展开论述,总结FMT在癌症治疗方面的最新进展。     

欧洲加强癌症协作研究

欧洲国家的癌症研究工作者为了身于积累必要的病人数．把临床的实验研究推向前进，而开展了协作研究。为了验证一个大家都感兴趣的新药，欧洲癌症研究与治疗机构（E－ORTC）的主席Kaye博士指出．该组织的临床研究协作网，即可承担此项工作。他还说他们正在鼓动建立完整的研究协     

肿瘤免疫检查点疗法的研究进展

经过多年研究,免疫检查点疗法终于成为许多癌症的治疗方法。免疫检查点分子主要包括两类：细胞相关蛋白4（CTLA－4）和程序性细胞死亡蛋白1（PD1）。靶向这两类分子的抗体已面世,并在临床取得不错疗效。在这篇综述中,我们主要介绍免疫检查点疗法,并讨论联合治疗的协同设计进展。     

PAK6对前列腺癌的双向调控作用

前列腺癌为一类男性患病率较高的癌症,对该癌症机制的认识以及治疗手段非常有限,在西欧和美洲男性中是一类致死率较高的癌症。随着科学研究的不断进展,p21活化激酶（PAK）蛋白家族在癌症中发挥的作用开始进入人们的视野。p21活化激酶6（PAK6）最初是以雄激素受体的配体结合域（LBD）上的氨基酸序列629～919,通过酵母双杂交识别出来的雄激素受体相关蛋白。而雄激素与雄激素受体在前列腺癌的发生与发展中发挥了十分重要的作用,因此 PAK6蛋白作为前列腺癌治疗的靶向蛋白被不断研究。本文主要介绍 PAK6在前列腺癌中的双向调节作用,包括通过磷酸化雄激素受体抑制雄激素受体向核内转移的抑癌作用,和通过抑制 BAD 凋亡通路、影响前列腺癌细胞生长周期以及促进前列腺癌细胞从细胞集落中脱离的促癌作用。同时 PAK6的表达水平和激酶活性的调节对 PAK6在前列腺癌中发挥作用具有十分重要的意义。激素与生长因素和内质网应激可能是提高 PAK6表达水平和激酶活性的两条途径。PAK6在前列腺癌中发挥的作用与其表达水平和激酶活性的调节机制对前列腺癌的治疗手段以及其治疗药物的靶向目标具有十分重要的意义。     

死亡相关蛋白激酶降解的研究

死亡相关蛋白激酶(DAPK)是钙离子/钙调素调节的丝氨酸/苏氨酸蛋白激酶,在细胞凋亡、自噬及增殖等过程中具有重要作用,其功能的缺失与癌症、中风、炎性反应、阿尔茨海默病和动脉粥样硬化等疾病密切相关.DAPK蛋白降解受到泛素-蛋白酶体途径(UPS)和溶酶体途径的双重调控.全面深入地了解DAPK蛋白降解,有利于对相关疾病的研究与治疗.     

Interferon regulatory factor 4 binding protein is a novel p53 target gene and suppresses cisplatin-induced apoptosis of breast cancer cells

ABSTRACT: BACKGROUND: Our previous work demonstrated that ectopic expression of interferon regulatory factor 4 binding protein (IBP) was correlated with the malignant behaviour of human breast cancer cells. The mechanisms controlling differential expression of IBP in breast cancer still remain unknown. RESULTS: To investigate the mechanism of IBP dysregulation in breast cancer, we identified IBP was a novel p53 target gene. IBP expression was negatively regulated by wild-type p53 and was p53 dependently suppressed by DNA damage agent cisplatin. Furthermore, high levels of IBP were found to decrease cisplatin-induced growth suppression and apoptotic cell death, which was associated with decreased p53 activity and imbalanced Bcl-2 family member expression. CONCLUSIONS: IBP is a novel p53 target gene which suppresses cisplatin-mediated apoptosis of breast cancer cells via negative feedback regulation of the p53 signalling pathway, suggesting IBP may serve as a target for pharmacologic intervention of breast cancer resistant to cisplatin therapy.     

Mechanisms for autophagy modulation by isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells

Multiple myeloma (MM) is characterized by the production of monoclonal protein (MP). We have shown previously that disruption of the isoprenoid biosynthetic pathway (IBP) causes a block in MP secretion through a disruption of Rab GTPase activity, leading to an enhanced unfolded protein response and subsequent apoptosis in MM cells. Autophagy is induced by cellular stressors including nutrient deprivation and ER stress. IBP inhibitors have been shown to have disparate effects on autophagy. Here we define the mechanisms underlying the differential effects of IBP inhibitors on autophagic flux in MM cells utilizing specific pharmacological inhibitors. We demonstrate that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition. IBP inhibitor-induced autophagy is a cellular defense mechanism as treatment with the autophagy inhibitor bafilomycin A1 enhances the cytotoxic effects of GGPP depletion, but not geranylgeranyl transferase inhibition. Immunofluorescence microscopy studies revealed that IBP inhibitors disrupt ER to Golgi trafficking of monoclonal light chain protein and that this protein is not a substrate for alternative degradative pathways such as aggresomes and autophagosomes. These studies support further development of specific GGTase II inhibitors as anti-myeloma agents.     

CLDN18.2蛋白在恶性肿瘤治疗中的研究进展

随着分子生物学研究的进展，靶向治疗已成为除手术、放疗、化疗之外恶性肿瘤治疗中的第四种有效手段。与传统化疗药物不同，分子靶向治疗药物具有特异性强、疗效明显、不良反应较小等优点。CLDN18.2蛋白是新发现的一种跨膜蛋白，具有高选择性特点，稳定地过表达于多种恶性肿瘤中，尤其是消化系统肿瘤及其转移瘤。近年来，其特异性抗体claudiximab（zolbetuximab/ IMAB362）在最新的临床试验中取得了显著的成功，CLDN18.2蛋白有望成为某些特定恶性肿瘤靶向治疗的分子靶点。      

铁调节蛋白2在恶性肿瘤中的研究进展

铁调节蛋白2（iron regulatory protein 2,IRP2）是继IRP1后被发现,存在于细胞胞浆中的一种RNA结合蛋白,由Irp2基因编码。IRP2主要通过与铁蛋白（Ferrintin,Fn）和转铁蛋白受体（transferrin receptor,TfR）的mRNA中的铁反应元件（iron-responsive elements,IREs）相结合来调节细胞内铁的利用和储存。IPR2是维持细胞内铁稳态必不可少的调节蛋白。近年来,越来越多的研究发现,IRP2在包括结肠癌、胰腺癌、肝癌和乳腺癌等多种恶性肿瘤中具有致癌作用,可通过调节铁、激活癌基因和抑制抑癌基因等方式影响恶性肿瘤的发生、发展和预后等,可能是恶性肿瘤中一个新的潜在治疗靶点。本文就IRP2在恶性肿瘤中的研究进展进行综述。     

Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells

Myeloma is characterized by the overproduction and secretion of monoclonal protein. Inhibitors of the isoprenoid biosynthetic pathway (IBP) have pleiotropic effects in myeloma cells. To investigate whether IBP inhibition interferes with monoclonal protein secretion, human myeloma cells were treated with specific inhibitors of the IBP or prenyltransferases. These studies demonstrate that agents that inhibit Rab geranylgeranylation disrupt light chain trafficking, lead to accumulation of light chain in the endoplasmic reticulum, activate the unfolded protein response pathway and induce apoptosis. These studies provide a novel mechanism of action for IBP inhibitors and suggest that further exploration of Rab-targeted agents in myeloma is warranted.     

Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response,chaperone regulation and apoptosis in myeloma cells

Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways.     

Clinical impact of assay of estrogen receptor beta cx in breast cancer

Since 1996 when estrogen receptor beta(ER beta) was discovered, much effort has been devoted to the question of the value of ER beta as a prognostic and/or predictive factor in breast cancer and its potential as a novel target for pharmacological intervention. When estrogen receptors are applied on sucrose gradients and quantified by ligand binding, we found that in contrast to ER alpha, which has a narrow tissue distribution, ER beta is expressed in many tissues including both normal and malignant breast tissue. Receptor protein levels in tissues can also be measured from the intensities of bands after Western blotting and can be quantified when purified and quantified receptor is used as a standard. With this technique, we found that there were some tumors which had over 600 fmol/mg of ER beta protein but no detectable estradiol binding. In such tumors, RT-PCR analysis revealed that ER beta cx is the only ER beta isoform present. ER beta cx is a splice variant which utilizes an alternative exon 8. This change in the C-terminus results in very poor binding to estradiol (E2) and has a dominant negative effect on ER alpha function. Immunohistochemical analysis with an ER beta cx specific antibody in 115 ER alpha-positive breast cancers revealed that about half of the samples expressed ER beta cx protein. Initial analysis of samples from patients with preoperative tamoxifen treatment revealed that ER alpha-positive tumors expressing ER beta cx and lacking PR seemed to be resistant to the anti-estrogen. We conclude that, in order to better characterize breast cancers and design appropriate therapy for individual patients, assays for ER beta cx must be made available to clinicians.     

m6A甲基化在妇科恶性肿瘤中的研究进展

近年来大量研究表明表观遗传现象m6A甲基化与恶性肿瘤的发生发展密切相关,其通过甲基转移酶、去甲基酶及m6A结合蛋白影响mRNA的剪切、翻译及稳定性从而调控肿瘤细胞的增殖、分化及耐药性。随着m6A甲基化在恶性肿瘤方面研究的不断深入,其在宫颈癌、子宫内膜癌和卵巢癌等妇科恶性肿瘤中的相关作用机制也逐渐被发现。本文将对近年来m6A甲基化在宫颈癌、子宫内膜癌和卵巢癌等发病率较高的妇科恶性肿瘤中的相关研究进展作一综述,介绍甲基转移酶、去甲基酶及m6A结合蛋白通过对mRNA的作用修饰而调控肿瘤发生发展的机制。其相关研究结果亦将为妇科恶性肿瘤的预防和治疗提供新的检测方法和作用靶点。     

Effective therapy of experimental human malignant melanomas with a targeted cytotoxic somatostatin analogue without induction of multi-drug resistance proteins

Malignant melanomas are characterized by a high intrinsic resistance to chemotherapy. Multiple drug resistance (MDR) can be mediated by transport proteins such as MDR-1, multidrug resistance-associated protein (MRP) or lung resistance protein (LRP). The cytotoxic analogue of somatostatin AN-238 consisting of 2-pyrrolinodoxorubicin (AN-201) linked to a somatostatin analogue RC-121 binds to receptors for somatostatin and is targeted to tumors expressing these receptors. We evaluated the expression of somatostatin receptors on human malignant melanoma tumor lines MRI-H255 and MRI-H187 and examined the effects of the targeted analogue AN-238 and its cytotoxic radical AN-201 on growth of these tumors in nude mice. We also studied the effects of AN-238 and AN-201 on the expression of MDR-1, MRP-1 and LRP by real-time PCR. AN-238 inhibited the growth of MRI-H255 and MRI-H187 tumors while AN-201 was ineffective. Blockade of somatostatin receptors by somatostatin analogue RC-121 abolished the effects of AN-238. Targeted therapy with AN-238 did not produce an induction of mRNA of MDR-1, MRP-1 or LRP. Our findings show that targeted chemotherapy with cytotoxic somatostatin analogue AN-238 inhibits the growth of malignant melanomas. AN-238 could provide a novel treatment approach for advanced malignant melanomas.     

嵌合抗原受体T细胞联合免疫检查点抑制剂治疗恶性肿瘤的研究进展

近年来,嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）治疗在恶性肿瘤治疗中取得了较多成果,尤其在血液肿瘤治疗方面有所突破,实体瘤治疗研究前景较为广阔,有望成为更多复发难治性肿瘤患者的选择。免疫检查点抑制剂疗法在肿瘤治疗中同样具有疗效,如肝癌、难治性霍奇金淋巴瘤等多种恶性肿瘤,为晚期肿瘤患者带来了希望。但是上述两种治疗方法均存在不同程度的局限性。CAR-T联合免疫检查点抑制剂会削弱肿瘤微环境的免疫抑制作用,提高CAR-T治疗的有效率,延长生存期。本文旨在对CAR-T细胞和免疫检查点抑制剂治疗及二者联合应用的研究进展予以综述。