细胞核因子-kB在肿瘤化疗耐药方面的研究进展

细胞核因子-kB(nuclear factor of kappa B．NF-kB)是一种重要的转录调节因子。1956年由Sen和Baltimore等从成熟的B淋巴细胞中提取的一种能与免疫球蛋白K轻链基因增强子特定KB部位结合的蛋白质。许多研究证实，NF-KB与免疫应激，细胞分化，细胞周期调控，细胞凋亡及恶性肿瘤有关。近年来，     

白血病细胞核因子-κB活化与化疗药物诱导凋亡的关系

目的 研究化疗药物诱导P388白病细胞核因子-κB(NF-κB)活化与凋亡的关系,以及长春新碱(VCR)对它们的影响。方法 采用电泳迁移率变动分析(EMSA)检测细胞NF-κB活化水平;采用TdF介导的dUTF缺口末端标记技术(TUNEL)和DNA电泳方法检测细胞凋亡。结果 化疗药物诱导P388白血病细胞NF-κB活化与化疗药物诱导细胞凋亡有明显关系,0．1μmol／L VCR不仅能显著抑制100μmol／L阿糖胞苷(Ara-C)或100μmol／L鬼臼乙叉甙(Vp-16)诱导的P388细胞NF-κB活化(抑制率分别为52％和63％),而且增强它们诱导P388细胞凋亡的作用(凋亡增加率分别为89%和123%)。P388细胞在接触化疗药物前,NF-κB亦有一定程度的活化。结论 化疗药物诱导P388白血病细胞凋亡的同时,可活化NF-κB;VCR可通过抑制NF-κB活化,增强化疗药物诱导白血病细胞凋亡的作用。     

NF-κB、IκB与肿瘤细胞凋亡

细胞核因子κＢ又称κ基因结合核因子(ｎｕｃｌｅａｒｆａｃｔｏｒκｇｅｎｅｂｉｎｄｉｎｇ,ＮＦκＢ),是1种广泛存在于细胞中的具有多向性调节作用的蛋白质分子,参与调控细胞激酶、趋化因子、生长因子、细胞粘附因子及早期反应的蛋白质分子基因的转录,其活性受到1个强抑制物ＩκＢ的抑制。近年来研究结果表明:ＮＦκＢ能介导广泛的生物学作用,参与多种疾病的发生发展过程。ＮＦκＢ在细胞凋亡中有一定的作用。1　ＮＦκＢ和ＩκＢＮＦκＢ是1种转录因子,有着广泛的生物学作用。1986年Ｓｅｎ等[1]最初发现ＮＦκＢ是1种与免疫球蛋白κ轻链…     

NF-κB信号通路在恶性肿瘤化疗耐药中的作用

恶性肿瘤已然成为影响人们健康的最主要原因,化疗是应用最广泛最有效的抗肿瘤治疗手段之一。然而,随着化疗药物的使用,肿瘤细胞会产生耐药性,成为影响化疗效果的主要原因。耐药的产生可能涉及众多机制,包括细胞周期调控异常、凋亡信号通路受阻、耐药基因的异常表达等。近年来的研究表明,细胞存活信号通路在肿瘤化疗耐药中有着重要作用。核转录因子κB(Nuclear factor kappa B,NF-κB)信号通路的异常是恶性肿瘤耐药的主要机制之一。因此,NF-κB信号通路也可能成为克服恶性肿瘤耐药的有效靶点。本综述简要归纳NF-κB信号通路在恶性肿瘤化疗耐药中的作用和研究进展。     

细胞核因子κB与肿瘤治疗

以前认为肿瘤坏死因子（ＴＮＦ）是一种很有希望杀死肿瘤细胞的物质,有实验证明可缩小肿瘤组织。近几年来研究证明,ＴＮＦ不能直接杀死肿瘤细胞,确切地说ＴＮＦ不能单独对肿瘤细胞有杀伤作用,而是通过抑制细胞核因子κＢ（ＮＦκＢ）使肿瘤细胞死亡。ＮＦκＢ是一种ｐ５０和ｐ６５组成的异源双体,其活性还受到强抑制物ＩκＢ的控制。ＮＦκＢ在维持组织细胞的生死平衡、炎症反应和肿瘤治疗中的细胞凋亡起到调控作用,肿瘤治疗中的细胞因子、放疗和化疗药物都需通过ＮＦκＢ才能起作用,故认为其对肿瘤的治疗有潜在作用     

NF-κB在肿瘤中的研究进展

核因子kappaB(NF-B)因其在人体免疫,炎症,肿瘤的发生,发展,侵袭,转移等方面的重要作用而成为近来国际研究的热点.本文就其结构、功能、作用机制、与肿瘤的关系和未来研究方向等做一介绍.     

NF-κB与PCNA在人脑星形细胞瘤中的表达

目的:探讨NF-κB与PCNA在人脑星形细胞瘤以及正常脑组织中的表达情况及其与病理分级之间的相互关系。方法:SP免疫组织化学方法检测77例不同级别的星形细胞瘤及正常脑组织标本NF-κB p65与PCNA的表达情况。结果:除了在星形细胞瘤Ⅲ、Ⅳ级之间无显著性差异外(P>0.05),PCNA在其余各级别星形细胞瘤中的表达有显著性差异(P<0.05),其阳性率随着肿瘤级别的增高而升高。尽管NF-κB的表达总体差异有显著性(P<0.01),但NF-κB在星形细胞瘤相邻各级别之间的表达无显著性差异(P>0.05),然而高度恶性组(Ⅲ～Ⅳ级)阳性率显著高于低度恶性组(Ⅰ～Ⅱ级)阳性率,二者有显著性差异(P<0.01)。结论:NF-κB异常表达可能通过PCNA影响肿瘤细胞增殖活性,免疫组织化学方法联合检测NF-κB与PCNA的表达情况能客观反映星形细胞瘤的增殖恶性程度及预后。     

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.     

核转录因子NF-κB与胃癌关系的研究进展

核转录因子（nuclear factor kappa B，NF—κB）是1种分布和作用均十分广泛的真核细胞转录因子，属于NF—κB／Rel蛋白家族成员，由Sen等于1986年首先在B淋巴细胞中发现，它能够与B淋巴细胞免疫球蛋白κ轻链基因的增强子κB序列（GGGACTITCC）特异地结合。随后对NF—κB进行了广泛的研究，发现它能与多种细胞基因的启动子和增强子发生特异性结合，并促进相关基因的转录和表达，参与炎症反应、损伤应激、免疫防御、细胞增殖和凋亡等过程。研究证实，     

miR-155参与缺氧诱导的乳腺癌化疗耐药

摘 要：［目的］ 探讨miR-155在缺氧诱导的乳腺癌化疗耐药中的作用。［方法］ 以0、50、100、150、200μmol/L不同浓度CoCl2处理4T1细胞,建立缺氧模型。实时定量PCR检测缺氧条件下miR-155的表达与耐药基因BCRP的表达。通过慢病毒载体转染使miR-155过表达,通过caspase 3/9分光光度法探讨miR-155在缺氧环境下乳腺癌化疗耐药中的作用。［结果］ 随缺氧程度的增加,miR-155及BCRP基因表达增加,过表达miR-155可抑制阿霉素诱导的4T1细胞的凋亡。［结论］ 随着乳腺癌缺氧程度加重,miR-155表达逐渐增加,miR-155表达与乳腺癌化疗耐药相关。     

ERK通路在胰腺癌细胞株SW1990吉西他滨化疗耐药中的作用

目的:探讨细胞外信号调节激酶(ERK1/2)通路、多药耐药基因(mdr-1)、核糖核苷还原酶M1(RRM1),在胰腺癌细胞株SW1990吉西他滨(GEM)化疗耐药中的相互关系及作用.方法:通过浓度梯度递增法,诱导建立耐各种浓度GEM的胰腺癌细胞株.应用免疫组化图像分析方法,半定量检测各耐药细胞株中ERK1/2蛋白的表达;RT-PCR的方法检测mdr-1、RRMl mRNA表达,条带图使用Band凝胶分析软件进行半定量分析;MTT法测定0D492光密度值.计算IC50值.结果:建立的耐药细胞株可以在GEM终浓度分别为0、30、60、100、150、200nmol/L的培养液中稳定生长并传代.ERK1/2、mdr-1、RRMl的表达均随着耐GEM浓度的增加而升高,细胞耐GEM的浓度分别与mdr-1、RRM1基因表达呈现出高度正相关(r=0.960,P=0.002和r=0.966,P=0.002);ERK1/2灰度值也与mdr-1、RRM1基因的表达存在相关性(r=0.943,P=0.005和r=-0.883,P=0.02).耐GEM 200nmol/L的细胞株,ERK1/2灰度值、mdr-1/β-actin、RRM1/β-actin分别为164.22±13.17、1.41±0.04、1.45±0.18;经阻断剂U0126作用后三者的表达均呈现同步降低,分别为186.85±13.14、0.23±0.02、0.21±0.03;而激活剂EGF作用后,其表达呈现升高趋势,分别为106.55±16.45、1.50±0.07、1.52±0.12.耐GEM Onmol/L和200nmol/L浓度的细胞株,其IC50值分别为4.104和10.20,经阻断剂U0126处理后.IC50值下降到3.26和4.50;而经EGF处理后,IC50值则分别上升到8.89和17.17.结论:ERK通路可能参与调控mdr-1、RRM1基因表达,从而介导胰腺癌细胞株SWl990吉西他滨化疗抵抗.     

Sox2对膀胱癌细胞化疗耐药的影响及其分子机制的探讨

摘 要：［目的］ 探讨Sox2对膀胱癌细胞化疗耐药的影响及其分子机制。［方法］ 选用T24人膀胱癌细胞系,采用浓度递增方式建立顺铂耐药细胞系T24/DDP,慢病毒载体转染对应细胞,进行Sox2基因过表达或敲除,得到T24-Sox2细胞和T24/DDP-shSox2细胞系。qRT-PCR和Western blot检测各组细胞中Sox2与多药耐药相关蛋白（MRP）表达水平。MTT实验检测各组细胞在不同浓度顺铂作用下的吸光度值并计算IC50,绘制耐药曲线。流式细胞术检测各组细胞凋亡率,并使用qRT-PCR和Western blot检测凋亡相关蛋白的表达水平。［结果］ qRT-PCR和Western blot结果证实Sox2和MRP在膀胱癌顺铂耐药细胞系中高表达,耐药曲线提示Sox2与膀胱癌的顺铂耐药存在一定关联,耐药细胞系的IC50为(15.24±1.12)μg/ml,而非耐药细胞系的IC50为(4.88±0.72) μg/ml,P<0.05。Sox2表达上调能够抑制膀胱癌细胞凋亡,凋亡率从74.62%下降到25.84%,P<0.05。Bax和Caspase-3在Sox2高表达的细胞中呈低表达,而Bcl-2则呈高表达。［结论］ Sox2基因在顺铂耐药膀胱癌细胞系中表达水平显著高于正常非耐药膀胱癌细胞,且Sox2可能是通过抑制细胞凋亡来实现对化疗敏感性的调控。     

癌症登记在肿瘤防治研究中的应用

全文介绍了癌症登记的现状与发展；讨论了癌症登记的方法与作用；以启东的工作为例，简述了癌症登记资料的应用，并总结了启东开展癌症登记报告工作的体会。     

卵巢上皮癌组织中hMSH2的表达及其与化疗耐药的关系

目的 检测不同化疗敏感程度的卵巢上皮癌组织中hMSH2基因的表达,分析其与化疗耐药及预后的关系。方法 80例新鲜卵巢上皮癌组织均由手术中取得,采用ATP-TCA技术检测卵巢癌组织对八种药物：紫杉醇、卡铂、拓泊替康、多西他赛、吉西他滨、环磷酰胺体内代谢产物、依托泊苷及博来霉素的体外敏感性。采用Real-time PCR及Western blot法分别检测80例卵巢上皮癌组织中hMSH2 基因mRNA和蛋白水平的表达情况。结果 对紫杉醇耐药的卵巢上皮癌组中,hMSH2基因在mRNA及蛋白水平的表达均明显高于敏感组（P<0.01）,在对卡铂、拓泊替康、多西他赛耐药组中hMSH2表达水平也明显高于敏感组（P<0.05）;hMSH2基因的相对表达值与卡铂、拓泊替康、多西他赛的敏感度系数有显著相关性（P≤0.05）。早期卵巢癌患者组织的hMSH2表达水平明显低于晚期卵巢癌组织（P<0.05）。高、中分化卵巢癌组织hMSH2蛋白表达水平明显低于低分化卵巢癌组织（P=0.000）。原发卵巢癌患者组织的hMSH2表达水平明显低于复发卵巢癌患者组织（P<0.01）。结论 hMSH2基因的高表达与卵巢癌化疗耐药及预后相关,化疗可能诱导hMSH2基因的高表达;下调hMSH2基因的表达或许是逆转肿瘤耐药的新途径。     

KIF14 Promotes AKT Phosphorylation and Contributes to Chemoresistance in Triple-Negative Breast Cancer

Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor–negative/progesterone receptor–negative/human epidermal growth factor receptor 2-negative, “triple-negative” breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.Abbreviations: TNBC, triple-negative breast cancerestrogen-receptor negative/progesterone-receptor negative/Her2 negative; siRNA, small-interfering RNA; LC₅₀, median lethal concentration     

Ginsenoside Rh2 differentially Mediates microRNA Expression to Prevent Chemoresistance of Breast Cancer

Chemoresistance is the most common cause of chemotherapy failure during breast cancer (BCA) treatment.It is generally known that the mechanisms of chemoresistance in tumors involve multiple genes and multiplesignaling pathways,; if appropriate drugs are used to regulate the mechanisms at the gene level, it should bepossible to effectively reverse chemoresistance in BCA cells. It has been confirmed that chemoresistance in BCAcells could be reversed by ginsenoside Rh2 (G-Rh2). Preliminary studies of our group identified some drugresistancespecific miRNA. Accordingly, we proposed that G-Rh2 could mediate drug-resistance specific miRNAand corresponding target genes through the gene regulatory network; this could cut off the drug-resistanceprocess in tumors and enhance treatment effects. G-Rh2 and breast cancer cells were used in our study. Throughpharmaceutical interventions, we could explore how G-Rh2 could inhibit chemotherapy resistance in BCA,and analyze its impact on related miRNA and target genes. Finally, we will reveal the anti-resistance molecularmechanisms of G-Rh2 from a different angle in miRNA-mediated chemoresistance signals among cells.     

Chemoresistance in rat ovarian tumours

In a cisplatin resistant subline (O-342/DPP) of an intraperitoneally growing transplantable rat ovarian tumour (O-342), intracellular glutathione (GSH) was approximately doubled (mean [S.E.] 1.5 [0.26] vs. 0.8 [0.2] nmol/10⁶ cells). GSH reductase activity was higher (30.64 [4.07] vs. 20 [0.92] nmol/min per mg protein), although no difference was found for GSH-S-transferase. 24 h after exposure to cisplatin, formation of DNA interstrand cross-links was at a maximum in both lines and significantly higher in O-342 (162 [23] vs. 88 [22] rad eq). Combination treatment of O-342/DDP with buthionine sulphoximine plus cisplatin resulted in a marginal increase in survival compared with cisplatin treatment; treatment of this line with 3-aminobenzamide plus cisplatin was also superior to cisplatin alone. In the sensitive line both combinations were likewise superior to cisplatin alone. In vitro, at equimolar concentration, a new platinum complex (CTDP) was at least as active as cisplatin in both lines, which suggests a superior therapeutic index because its LD₅₀ in mice is threefold higher than that of cisplatin. A ruthenium complex (ICR) had a higher activity in the resistant line. A titanium complex (budotitane) was not active.     

Deptor Enhances Triple-Negative Breast Cancer Metastasis and Chemoresistance through Coupling to Survivin Expression

Transforming growth factor–β (TGF-β) functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs). Precisely how TGF-β acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR) inhibitor, Dep domain–containing mTOR-interacting protein (Deptor), in coupling TGF-β to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1) inversely correlated with the metastatic ability of human (MCF10A) and mouse (4T1) TNBC progression series and 2) robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor α–negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1) organoid growth in vitro, 2) pulmonary outgrowth in mice, and 3) resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli.Abbreviations: Deptor, Dep domain–containing mTOR-interacting protein, EMT, epithelial-mesenchymal transition, ER, estrogen receptor, MEC, mammary epithelial cell, mTOR, mammalian target of rapamycin, NMuMG, normal murine mammary gland cell, PyMT, polyoma middle T antigen, S6K, S6 kinase, TβR-I, TGF-β type I receptor, TGF-β, transforming growth factor–β, TNBC, triple-negative breast cancer