食管鳞癌中NF-κB、p53的表达及其与新辅助化疗敏感性的关系

目的:研究食管鳞癌NF-κB和p53的表达情况与术前化疗敏感性的关系.方法:应用免疫组织化学技术EnVision法,检测60例新辅助化疗前胃镜活检食管鳞癌组织中NF-κB和p53蛋白的表达情况,并分析其与肿瘤对化疗反应的关系.结果:在60例食管癌中NF-κB和p53阳性表达率分别为61.6%(37/60) ,56.6%(34/60).NF-κB和p53表达与鳞癌分级及肿瘤侵犯深度无相关性( P>0.05),与淋巴结转移密切相关(P<0.05).60例食管鳞癌组织中NF-κB与p53的表达呈正相关(Rs =0.279,P<0 05);共阳性25例中22例对化疗反应无效,NF-κB与p53共阳性与化疗敏感性有相关性(P<0.01). 结论:NF-κB和p53在食管癌的发生发展中可能起协同作用,测定其表达情况可作为预测肿瘤对化疗敏感性的指标.     

核因子-κB及P糖蛋白在人骨肉瘤中的表达及意义

目的探讨核因子-κB(NF-κB)及P糖蛋白(P-gp)在骨肉瘤组织中的表达及其临床意义。方法选取2009年1月至2016年12月间武汉大学人民医院收治的经术前穿刺组织学病理诊断的26例骨肉瘤患者的肿瘤组织标本,采用免疫组化法(S-P法)及West Blot法测定NF-κB及P-gp在诱导化疗后骨肉瘤组织中的表达。比较化疗原发耐药组(6例)和化疗有效组(20例)中NF-κB及P-gp表达的差异,并分析其与化疗耐药的相关性。结果化疗耐药组骨肉瘤组织的p-gp阳性表达率为83.3%,显著高于化疗有效组p-gp的阳性表达率35.0%,差异有统计学意义(P<0.01)。化疗耐药组骨肉瘤组织NF-κB阳性表达率为83.3%,显著高于化疗有效组45.0%,差异有统计学意义(P<0.01)。相关因素分析表明,NF-κB及P-gp在骨肉瘤组织中的表达与其耐药有高度相关性,NF-κB P65的表达与P-gp表达呈正相关,差异有统计学意义(P<0.05)。结论 NF-κB及P-gp在骨肉瘤原发耐药组中高表达,可能是骨肉瘤原发耐药的发生机制之一。     

核因子-κB与肺癌化疗

核因子-κB(NF-κB)与肿瘤密切相关,许多研究证实抑制NF-κB的活性可以增强肺癌对放化疗的敏感性.对NF-κB的干预,可能是治疗肺癌的突破口.     

乳腺癌患者核基质结合区结合蛋白1和核因子相关蛋白κB的表达水平及其相关性分析

目的 研究特异性核基质结合区结合蛋白1(SATB1)和核转录因子kappaB p65(NF-κB p65)蛋白的表达,探讨其表达与乳腺癌发生、发展的相关性.方法 应用免疫组织化学染色法检测80例乳腺癌组织样本中的蛋白SATB1和NF-κB p65的表达,分析其相互关系,并探讨其与乳腺癌临床特征之间的关系.结果 80例乳腺癌组织样本中SATB1和NF-κB p65的阳性表达率分别为70.00%和56.25%.SATB1和NF-κB p65的表达与肿瘤大小、组织学分级、ER受体状态和淋巴结转移有关,与年龄和TNM分期无关.SATB1和NF-κB p65在乳腺组织中的表达呈明显正相关.结论 SATB1和NF-κB p65在乳腺癌组织中协同高表达,与乳腺癌患者的临床特征存在密切联系.     

细胞核因子-κB在肿瘤化疗耐药方面的研究进展

细胞核因子-κB(nuclear factor of kappa B,NF-κB)是一种重要的转录调节因子.1956年由Sen和Baltimore等[1]从成熟的B淋巴细胞中提取的一种能与免疫球蛋白κ轻链基因增强子特定κB部位结合的蛋白质.许多研究证实,NF-κB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,NF-κB研究涉及肿瘤发生、浸润、转移和耐药许多研究方面.以NF-κB作为靶点来探索解决肿瘤化学治疗中的耐药问题更是作为研究的热点.本文针对NF-κB在肿瘤化学治疗中耐药问题做一综述.     

结肠癌叉头框蛋白P3、促泛素结合衔接子p62及核因子-κB与癌旁肿瘤沉积形成相关性分析

目的 探究结肠癌患者叉头框蛋白P3(Foxp3)、促泛素结合衔接子(p62)及核因子κB(NF-κB)表达及与癌旁肿瘤沉积形成相关性。方法 选取河北北方学院附属第一医院普通外科2019年1月至2022年1月收治的结肠癌患者80例,根据其是否合并癌旁肿瘤沉积分为对照组(36例),沉积组(44例)。使用实时荧光定量PCR技术(qRT-PCR)检测患者Foxp3、p62、NF-κB mRNA表达,使用免疫组化检测患者Foxp3、p62、NF-κB阳性细胞表达,使用蛋白质印迹法检测两组患者病灶组织中Foxp3、p62、NF-κB mRNA相对蛋白表达量。并使用多因素Logistic回归分析以上指标与患者癌旁肿瘤沉积形成相关性。结果 比较两组基线资料,差异无统计学意义。沉积组Foxp3、p62、NF-κB mRNA表达显著高于对照组,差异具有统计学意义(P<0.05);沉积组Foxp3、p62、NF-κB免疫组化阳性细胞占比表达显著高于对照组,差异具有统计学意义(P<0.05);沉积组Foxp3、p62、NF-κB蛋白相对表达显著高于对照组,差异具有统计学意义(P<0.05);...     

甲状腺癌中NF-κB p50、NF-κB p65的表达及其与临床特征的关系

目的 探讨甲状腺癌组织中NF-κB p50、NF-κB p65的表达及其与临床特征的关系.方法 选取73例甲状腺癌患者作为研究对象.采用免疫组化SP法检测所有患者甲状腺癌组织的NF-κB p50、NF-κB p65表达情况,并分析其与临床特征的关系.结果 ①NF-κB p50表达阳性组与NF-κB p50表达阴性组之间性别、年龄、病理类型相比,差异无统计学意义(P>0.05);NF-κB p50表达阳性组肿瘤直径、淋巴结转移显著高于NF-κB p50表达阴性组,差异有统计学意义(P<0.05).②NF-κB p65表达阳性组与NF-κB p65表达阴性组之间性别、年龄、病理类型相比,差异无统计学意义(P>0.05);NF-κB p65表达阳性组肿瘤直径、淋巴结转移显著高于NF-κB p65表达阴性组,差异有统计学意义(P<0.05).③甲状腺癌组织表达NF-κB p50与NF-κB p65呈显著正相关(γs=0.653,P<0.05).结论 甲状腺癌组织表达NF-κB p50、NF-κB p65与肿瘤直径、淋巴结转移密切相关,两者可能在甲状腺癌发生发展、淋巴结转移过程中发挥协同作用.     

NF-κB、c-myc和survivin在非霍奇金淋巴瘤中的表达及临床意义

目的:探讨非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)中NF-κB、c-myc和survivin蛋白表达水平及其临床意义.方法:采用免疫组织化学PV-9000二步法检测62例NHL肿瘤组织及18例淋巴结反应性增生(reactive hyperplasia of lymph node, RH)组织中NF-κB、c-myc和survivin的表达情况,并分析蛋白表达与临床病理特征、化疗疗效及预后的相关性.结果:NF-κB、c-myc和survivin蛋白在NHL组织中的阳性表达率分别为61.29%、77.42%和72.58%,高于RH组织中的表达率16.67%、 22.22%和11.11%(P<0.01).NF-κB、c-myc和survivin的表达与NHL的恶性程度、临床分期均呈正相关(P<0.05),而与患者的年龄、全身症状、PS评分和淋巴结外病变数目均无相关性(P>0.05),其中NF-κB、c-myc在T细胞淋巴瘤中的阳性表达率高于B细胞淋巴瘤(P<0.05).NF-κB、c-myc和survivin在NHL组织中阳性表达率与其化疗疗效呈负相关(r=-0.362、r=-0.296和r=-0.273,P<0.05).NHL组织中NF-κB、c-myc和survivin表达之间均存在正相关关系(r=0.514、r=0.476和r=0.313,P<0.05),且NF-κB和c-myc在国际预后指数(international prognostic index,IPI)高危组中的表达均高于IPI低危组(P<0.05).结论:NF-κB、c-myc和survivin的表达状况与NHL患者恶性程度、临床分期及化疗疗效存在相关性,可作为评价NHL患者预后的生物学参考指标.     

核因子κB在胰腺癌中的表达及与VEGF和p53表达的相关性

目的探讨核因子κB(NF-κB,p65)在胰腺癌组织中的表达及其与VEGF、p53蛋白表达的相互关系。方法电泳迁移率变动分析(EMSA)测定45例胰腺癌及癌旁组织、8例慢性胰腺炎和9例正常胰腺组织中NF-κB的活性,Western印迹法检测NF-κB、IκB-a蛋白表达;免疫组织化学法检测胰腺癌中VEGF、p53、p65蛋白表达。结果NF-κB在肿瘤组织中被激活;NF-κB在胰腺癌、旁组织、慢性胰腺炎、正常胰腺组织中阳性表达率分别为71.0%、20.0%、12.5%、0(P<0.05);NF-κB基因表达与胰腺癌的分化程度、临床分期、肿瘤大小无关(P>0.05),与淋巴结转移和周围浸润有相关性(P<0.05);转移癌中NF-κB蛋白表达与VEGF、p53蛋白表达显著相关。结论核因子κB基因在胰腺癌中过度表达并与VEGF、p53一起参与胰腺癌的浸润、转移过程。     

核因子-κBp65、IκB-a在肝炎相关性肝细胞癌中的表达及临床意义

目的研究乙型(B)肝炎和(或)丙型(C)肝炎相关性肝细胞癌(HCC)中NF-κBp65、IκB-a的表达及意义.方法采用免疫组化方法检测48例B型肝炎相关性HCC,20例C型肝炎相关性HCC,15例BC混合型肝炎相关性HCC,21例癌旁组织以及9例正常肝脏组织中NF-κ Bp65、IκB-a的表达.结果 NF-κ Bp65在B、C、BC组中的阳性表达率分别为60.4%(29/48)、85.0%(17/20)和93.3%(14/15),C组、BC组均高于B组,差异均有显著性(P<0.05);IκB-a在肝炎相关性HCC及癌旁组织中的阳性表达率分别为21.7%(18/83)和57.1%(12/21),差异有显著性(P<0.05).NF-κ Bp65、IκB-a在9例正常肝脏组织中无表达.结论 NF-κ Bp65高表达而IκB-a低表达在肝炎相关性HCC的发生过程中可能起重要作用.     

Nuclear Factor-κB modulates cellular glutathione and prevents oxidative stress in cancer cells

The NF-κB is best known for its role in inflammation. Here we show that constitutive NF-κB activity in cancer cells promotes the biosynthesis of redox scavenger glutathione (GSH), which in turn confers resistance to oxidative stress. Inhibition of NF-κB significantly decreases GSH in several lines of human leukemia and prostate cancer cells possessing high or moderate NF-κB activities. Concomitantly, NF-κB inhibition by pharmacological and molecular means sensitizes “NF-κB positive” cancer cells to chemically-induced oxidative stress and death. We propose that inhibition of NF-κB can reduce intracellular GSH in “NF-κB-positive” cancers thereby improving the efficacy of oxidative stress-based anti-cancer therapy.     

GPCR-CARMA3-NF-kappaB Signaling Axis: A Novel Drug Target for Cancer Therapy

G protein-coupled receptors (GPCRs) play pivotal roles in regulating various cellular functions. It has been well established that GPCR activates NF-κB and aberrant regulation of GPCR-NF-κB signaling axis leads to cancers. However, how GPCRs induce NF-κB activation remains largely elusive. Recently, it has been shown that a novel scaffold protein, CARMA3, is indispensable in GPCR-induced NF-κB activation. In CARMA3-deficient mouse embryonic fibroblast cells, some GPCR ligand-, like lysophosphatidic acid (LPA), induced NF-κB activation is completely abolished. Mechanistically, upon GPCR activation, CARMA3 is linked to the membrane by β-arrestin 2 and phosphorylated by some PKC isoform. Phosphorylation of CARMA3 unfolds its steric structure and recruits its downstream effectors, which in turn activate the IKK complex and NF-κB. Interestingly, GPCR (LPA)-CARMA3-NF-κB signaling axis also exists in ovarian cancer cells, and knockdown of CARMA3 results in attenuation of ovarian cancer migration and invasion, suggesting a novel target for cancer therapy. In this review, we summarize the biology of CARMA3, discuss the GPCR (LPA)-CARMA3-NF-κB signaling axis in ovarian cancer and speculate its potential role in other types of cancers. With a strongly increasing tendency to identify more LPA-like ligands, such as endothelin-1 and angiotensin II, which also activate NF-κB through CARMA3 and contribute to myriad diseases, GPCR-CARMA3-NF-κB signaling axis is emerging as a novel drug target for various types of cancer and other myriad diseases.     

Insulin-like growth factor-binding protein-3 suppresses tumor growth via activation of caspase-dependent apoptosis and cross-talk with NF-κB signaling

Nuclear factor-kappaB (NF-κB) is constitutively activated in a variety of human cancers including prostate cancer and involved in tumorigenesis, tumor progression and chemo-resistance. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a potent tumor suppressor and is significantly suppressed in a variety of cancers. Diverse biological effects of IGFBP-3 have been reported to be both dependent and independent of the IGF/IGF-I receptor (IGF-IR) axis. The precise underlying mechanisms of IGF/IGF-IR-independent, antiproliferative actions of IGFBP-3 are yet to be elucidated. We found an inverse correlation between NF-κB activity and IGFBP-3 expression during prostate cancer progression using an in vitro prostate cancer progression model. Restoration of IGFBP-3 resulted in significant inhibition of constitutively elevated NF-κB activity in prostate cancer cells. IGFBP-3 further inhibited the expression of NF-κB-regulated angiogenic factors such as VEGF and IL-8, and cell adhesion molecules, ICAM-1 and VCAM-1. This inhibitory action of IGFBP-3 was IGF/IGF-IR-independent since IGFBP-3 mutant devoid of IGF binding affinity had a similar inhibitory effect. We identified that IGFBP-3 degrades the key NF-κB regulatory molecules-IκBα and p65-NF-κB proteins through activation of caspase-8 and -3/-7, thereby inhibiting elevated NF-κB activity in prostate cancer. Finally intratumoral administration of IGFBP-3 resulted in significant tumor suppression as well as sensitization of antitumor effect of doxorubicin. Our findings indicate that IGFBP-3 exerts antitumor effects via IGF-independent mechanisms which involve activation of caspase-dependent apoptosis and cross-talk with NF-κB signaling. The use of IGFBP-3 as a cancer therapeutic with this distinctive suppression mechanism may offer alternate means to treat chemotherapy resistant tumors.     

Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells

Background

Nuclear factor-κB (NF-κB) is constitutively activated in many cancers and plays a key role in promoting cell proliferation, survival, and invasion. Our understanding of NF-κB signaling in thyroid cancer, however, is limited. In this study, we have investigated the role of NF-κB signaling in thyroid cancer cell proliferation, invasion, and apoptosis using selective genetic inhibition of NF-κB in advanced thyroid cancer cell lines.

Results

Three pharmacologic inhibitors of NF-κB differentially inhibited growth in a panel of advanced thyroid cancer cell lines, suggesting that these NF-κB inhibitors may have off-target effects. We therefore used a selective genetic approach to inhibit NF-κB signaling by overexpression of a dominant-negative IκBα (mIκBα). These studies revealed decreased cell growth in only one of five thyroid cancer cell lines (8505C), which occurred through a block in the S-G2/M transition. Resistance to TNFα-induced apoptosis was observed in all cell lines, likely through an NF-κB-dependent mechanism. Inhibition of NF-κB by mIκBα sensitized a subset of cell lines to TNFα-induced apoptosis. Sensitive cell lines displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway, defining a potential mechanism of response. Finally, NF-κB inhibition by mIκBα expression differentially reduced thyroid cancer cell invasion in these thyroid cancer cell lines. Sensitive cell lines demonstrated approximately a two-fold decrease in invasion, which was associated with differential expression of MMP-13. MMP-9 was reduced by mIκBα expression in all cell lines tested.

Conclusions

These data indicate that selective inhibition of NF-κB represents an attractive therapeutic target for the treatment of advanced thyroid. However, it is apparent that global regulation of thyroid cancer cell growth and invasion is not achieved by NF-κB signaling alone. Instead, our findings suggest that other important molecular processes play a critical role in defining the extent of NF-κB function within cancer cells.     

c-FLIP和NF-κB p65在乳腺癌组织中的表达及临床意义

目的:探讨凋亡相关蛋白c-FLIP和NF-κB p65在人乳腺癌的表达及相关性,分析其与乳腺癌转移复发的关系。方法:应用免疫组织化学法检测80例乳腺癌组织和相应的癌旁组织中c-FLIP和NF-κBp65的表达情况。结果:80例乳腺癌组织中c-FLIP及NF-κB p65表达的阳性率显著高于相应的癌旁组织(P<0.05),c-FLIP的表达与TNM分期、组织学分级、腋窝淋巴结转移、术后复发及C-erbB-2表达密切相关(P<0.05);NF-κB p65的表达组织学分级、肿瘤大小及腋窝淋巴结转移密切相关(P<0.05)。c-FLIP和NF-κB p65的表达有显著正相关性(γ=0.271,P=0.015)。结论:c-FLIP和NF-κB p65的高表达可能在乳腺癌的发生及进展中起着重要作用。     

Low T-cell subsets prior to development of virus-associated cancer in HIV-seronegative men who have sex with men

Immunological parameters that influence susceptibility to virus-associated cancers in HIV-seronegative individuals are unclear. We conducted a case–control cohort study of immunological parameters associated with development of incident virus-associated cancers among 532 HIV-seronegative men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study (MACS) with median (IQR) 21 (8–26) years of follow-up. Thirty-two incident virus-associated cancers (anal cancer, non-Hodgkin lymphoma, liver cancer, other cancers with etiologies linked to human papillomavirus, Epstein–Barr virus, hepatitis B virus, or human herpesvirus-8) were identified among 3,408 HIV-seronegative men in the MACS during 1984–2010. Cases were matched for demographics, smoking, and follow-up to 500 controls without cancer. Mixed-effects and Cox regression models were used to examine associations between nadir or recent CD4, CD8, and white blood cell (WBC) counts or CD4:CD8 ratios and subsequent diagnosis of virus-associated cancers. Men with incident virus-associated cancers had lower CD4 and WBC counts over a 6-year window prior to diagnosis compared to men without cancer (p?=?0.001 and 0.03, respectively). Low CD4 cell count and nadir, CD4 count-nadir differential, and CD4:CD8 ratio nadir were associated with increased 2-year risk of incident virus-associated cancers in models adjusted for demographics and smoking (hazard ratios 1.2–1.3 per 100 or 0.1 unit decrease, respectively; p?<?0.01). Other associated factors included heavy smoking and past or current hepatitis B virus infection. These findings show that low CD4 cell counts, CD4 nadir, and CD4:CD8 cell ratios are independent predictors for subsequent risk of virus-associated cancers in HIV-seronegative MSM.     

Knockdown of metallopanstimulin-1 inhibits NF-κB signaling at different levels: the role of apoptosis induction of gastric cancer cells

The ribosomal protein S27 (metallopanstimulin-1, MPS-1) has been reported to be a multifunctional protein, with increased expression in a number of cancers. We reported previously that MPS-1 was highly expressed in human gastric cancer. Knockdown of MPS-1 led to spontaneous apoptosis and repressed proliferation of human gastric cancer cells in vitro and in vivo. However, how does MPS-1 regulate these processes is unclear. Here we performed microarray and pathway analyses to investigate possible pathways involved in MPS-1 knockdown-induced apoptosis in gastric cancer cells. Our results showed that knockdown of MPS-1 inhibited NF-κB activity by reducing phosphorylation of p65 at Ser536 and IκBα at Ser32, inhibiting NF-κB nuclear translocation, and down-regulating its DNA binding activity. Furthermore, data-mining the Gene-Regulatory-Network revealed that growth arrest DNA damage inducible gene 45β (Gadd45β), a direct NF-κB target gene, played a critical role in MPS-1 knockdown-induced apoptosis. Over-expression of Gadd45β inhibited MPS-1 knockdown-induced apoptosis via inhibition of JNK phosphorylation. Taken together, these data revealed a novel pathway, the MPS-1/NF-κB/Gadd45β signal pathway, played an important role in MPS-1 knockdown-induced apoptosis of gastric cancer cells. This study sheds new light on the role of MPS-1/NF-κB in apoptosis and the possible use of MPS-1 targeting strategy in the treatment of gastric cancer.     

NF-κB activity is downregulated by KRAS knockdown in SW620 cells via the RAS-ERK-IκBα pathway

The relationship between KRAS and NF-κB in colorectal cancer is not clear. Western blotting was used to determine whether KRAS knockdown in SW620 cells altered the levels of NF-κB-p65 and other molecules. Furthermore, we investigated the association between the KRAS status and NF-κB expression in 167 colorectal cancers tumor tissues and their correlation with overall survival (OS) of patients with KRAS mutations and activated NF-κB. RAS, p-ERK, p-IκBα and p65 expression was decreased in SW620 cells with KRAS knockdown. The MEK inhibitor U0126 downregulated p-ERK, p-IκBα and p65 levels in SW620 cells. p65 activation in tumors with KRAS mutations was higher (50.8%) than in tumors with the wild-type KRAS gene (30.6%) (P=0.012). Compared to patients with other types of tumors, OS was lower (median 28.4 months) in patients with KRAS mutations and NF-κB activation, vs. a median of 46.3 months in patients with other types of tumors (P=0.005). NF-κB activation was reduced in SW620 cells with KRAS knockdown, possibly via the RAS-ERK-IκBα pathway. The presence of both KRAS mutations and the active form of NF-κB in CRC tumors indicates poor patient prognosis.