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目的:研究通路阻断剂Wortmannin和LiCl对急性髓细胞白血病细胞系Hedgehog/gli通路的调节作用。方法:选取HL-60和K562细胞系,采用Western blot方法检测gli1和gli2蛋白表达,定量PCR检测gli1和gli2 mRNA的变化,WST-1检测不同通路阻断剂联合对细胞增殖的抑制作用。结果:Wortmannin和LiCl均可以上调两细胞系中gli蛋白和mRNA的表达,并可减弱gli阻断剂GANT61对AML细胞系的毒性作用。结论:Wortmannin和LiCl可以上调AML细胞系中Hedgehog通路的表达。 相似文献
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Sonic Hedgehog(SHH)信号通路在胚胎发育过程中参与调控多个器官以及组织的生长发育,并维持其正常的结构和功能,但在成年人组织中处于抑制状态.异常激活的SHH信号通路在多种恶性肿瘤的发生、发展以及耐药过程中起着重要作用.SHH信号通路在白血病中表现出和实体肿瘤相似的作用机制.随着对SHH信号通路研究的深入,出现了许多该信号通路的靶向抗肿瘤药物,针对该通路研制新的靶向抑制剂将成为治疗白血病的一种新方法.文章就SHH信号通路的靶向抑制剂在白血病中的研究进展作一综述. 相似文献
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目的:探讨骨髓基质细胞(bone marrow-derived mesenchymal stromal cells,BM-MSCs)对急性髓系白血病(acute myeloid leukemia,AML)细胞影响的作用机制。方法:构建MLL-AF9过表达诱导的AML小鼠模型,通过PCR比较AML小鼠和野生型小鼠(WT)BM-MSCs内TSP-1的表达差异。通过慢病毒载体使AML小鼠来源的BM-MSCs高表达TSP-1后,与AML细胞行transwell共培养,检测AML细胞表面TSP-1受体CD36及CD47的表达及AML细胞的生长情况。在共培养体系中加入CD36抑制剂N-油酰基硫代琥珀酰亚胺,检测AML细胞增殖、凋亡的变化。结果:AML小鼠BM-MSCs中TSP-1的表达低于对照组。过表达TSP-1的BM-MSCs与AML细胞行transwell共培养后AML细胞的生长受到抑制,且AML细胞表面的CD36受体表达升高,但CD47表达无明显差异。在共培养体系中加入CD36抑制剂N-油酰基硫代琥珀酰亚胺后,AML细胞增殖加快,凋亡减少。结论:TSP-1/CD36信号通路有望成为治疗AML... 相似文献
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目的:探究miR-181在急性B淋巴细胞白血病Nalm-6细胞中表达及其过表达对细胞增殖及凋亡的影响。方法:利用实时荧光定量PCR检测miR-181在急性B淋巴细胞白血病患者骨髓单个核细胞中的表达水平,利用慢病毒转染技术使miR-181过表达,利用CCK-8实验检测过表达miR-181对人急性 B 淋巴细胞白血病细胞Nalm-6增殖的影响,利用流式细胞仪检测过表达miR-181对Nalm-6细胞凋亡的影响,利用蛋白印迹实验检测Wnt/β-catenin信号通路中关键蛋白的表达水平。结果:实时荧光定量PCR结果显示,与正常人相比,急性B淋巴细胞白血病患者骨髓单个核细胞中miR-181的表达水平显著下调;CCK-8检测细胞增殖结果显示,过表达miR-181显著抑制了人急性 B 淋巴细胞白血病细胞Nalm-6的增殖;流式细胞仪检测细胞凋亡结果显示,过表达miR-181显著促进了Nalm-6细胞的凋亡;Western blotting 结果显示,miR-181过表达,Wnt1、β-catenin、cyclin D1 和c-myc蛋白的表达均显著下调。结论:急性B淋巴细胞白血病患者骨髓单个核细胞中miR-181的表达水平下调,过表达miR-181抑制Nalm-6细胞增殖、促进Nalm-6细胞凋亡,其机制可能与Wnt/β-catenin信号转导通路的受抑有关。 相似文献
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目的探讨miR-214通过PTEN调控下游AKT信号通路激活对鼻咽癌细胞凋亡的影响。方法miR-214抑制剂转染鼻咽癌5-8F和6-10B细胞。MTT法评估细胞增殖情况。Annexin-V/PI染色法检测两种鼻咽癌细胞凋亡情况。Western blot和real-time PCR检测miR-214抑制剂对PTEN基因转录和蛋白表达以及对AKT信号通路和凋亡相关蛋白表达水平的影响。检测shRNA沉默PTEN基因转录和蛋白表达后,miR-214抑制剂对鼻咽癌细胞凋亡影响。结果miR-214抑制剂可抑制鼻咽癌细胞生长,诱导5-8F和6-10B细胞凋亡。miR-214通过靶向3'-UTR区域调控PTEN基因转录和蛋白表达。抑制miR-214可促进PTEN的表达,抑制AKT信号通路激活,进而调控下游细胞周期和凋亡相关蛋白表达。沉默PTEN基因转录和蛋白表达可逆转miR-214抑制剂对鼻咽癌细胞AKT信号通路活性和凋亡的影响。结论miR-214可通过直接靶向PTEN基因转录促进AKT信号通路激活抑制鼻咽癌细胞凋亡。 相似文献
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Hedgehog(Hh)信号通路在胚胎发育、细胞增殖和分化中起着重要的调节作用,此通路异常激活可能会导致全身恶性肿瘤(肺癌、胃癌)的发生,尤其是口腔鳞癌的发生,因此Hh信号通路与口腔鳞癌密切相关。Hh信号通路主要有分泌型糖蛋白配体 Hedgehog(SHH)配体,跨膜蛋白受体Ptched(PTCH)受体,跨膜蛋白Smoothened(SMO),核转录因子GLI蛋白、Fu抑制子(SuFu)及下游目的基因组成。其中GLI1作为Hh信号通路的正向调控基因,起着激活Hh信号通路的作用。而SuFu作为Hh信号通路负向调控基因,起着抑制Hh信号通路的作用。本文就Hh信号通路在口腔鳞癌中信号传导机制及其相关基因GLI1、SuFu的研究进展进行综述,为未来口腔鳞癌的治疗、诊断和预防提供依据。 相似文献
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徐安 《中国肿瘤生物治疗杂志》2010,17(2):204-204
染色体易位是大多数慢性粒细胞白血病(CML)的主要发病机制,染色体易位导致断裂点簇集区(breakpoint cluster region。BCR)和酪氨酸激酶ABL1形成融合蛋白。酪氨酸激酶抑制剂伊马替尼(imatinib)可控制CML患者的病程,但是BCR—ABL1 T3151点突变的CML患者对伊马替尼等酪氨酸激酶抑制剂表现出耐药性。 相似文献
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目的:探讨芒柄花黄素对白血病HL-60细胞增殖、凋亡的影响及其机制。方法:以不同浓度(0、12.5、25、50、100和200 μg/ml)芒柄花黄素处理HL-60细胞24、48和72 h后,采用MTT法检测细胞存活率,并计算出IC50以筛选出合适的作用浓度。采用流式细胞仪检测芒柄花黄素对HL-60细胞周期和凋亡的影响,实时荧光定量PCR检测芒柄花黄素对HL-60细胞中miR-21表达的影响,免疫印迹法检测芒柄花黄素对HL-60细胞中PTEN、AKT和p-AKT蛋白表达的影响。结果:与0 μg/ml处理组相比,25、50、100和200 μg/ml芒柄花黄素处理24 h后HL-60细胞的存活率明显降低(P<0.05);同时,12.5、25、50、100和200 μg/ml芒柄花黄素分别处理48 h和72 h后HL-60细胞的存活率明显低于0 μg/ml处理组(P<0.05);芒柄花黄素作用HL-60细胞24、48和72 h后的IC50值分别为146.50 μg/ml、120.10 μg/ml和89.00 μg/ml。50、100和150 μg/ml芒柄花黄素处理后HL-60细胞在G0/G1期的百分比、细胞凋亡率和PTEN蛋白的表达水平均逐渐升高,而细胞在S期和G2/M期的百分比、miR-21的表达水平以及p-AKT蛋白的表达水平均逐渐降低,且与0 μg/ml相比,差异均有统计学意义(P<0.05),但HL-60细胞中AKT蛋白的表达水平与0 μg/ml组比较差异无统计学意义(P>0.05)。结论:芒柄花黄素可抑制白血病HL-60细胞增殖并诱导细胞凋亡,其作用机制可能与调控miR-21/PTEN/AKT信号通路有关。 相似文献
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Yang Yang Saradhi Mallampati Baohua Sun Jing Zhang Sang-Bae Kim Ju-Seog Lee Yun Gong Zhen Cai Xiaoping Sun 《Cancer letters》2013
Leukemia cells are protected by various components of their microenvironment, including marrow stromal cells (MSCs). To understand the molecular mechanisms underlying this protection, we cultured acute lymphoblastic leukemia (ALL) cells with MSCs and studied the effect of the latter on the molecular profiling of ALL cells at the mRNA and protein levels. Our results indicated that activated Wnt signaling in ALL cells is involved in MSC-mediated drug resistance. Blocking the Wnt pathway sensitized the leukemia cells to chemotherapy and improved overall survival in a mouse model. Targeting the Wnt pathway may be an innovative approach to the treatment of ALL. 相似文献
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Baicalin induces apoptosis in leukemia HL-60/ADR cells via possible down-regulation of the PI3K/Akt signaling pathway
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Zheng J Hu JD Chen YY Chen BY Huang Y Zheng ZH Liu TB 《Asian Pacific journal of cancer prevention》2012,13(4):1119-1124
Background: The effect and possible mechanism of traditional Chinese medicine, baicalin, on the PI3K/Akt signaling pathway in drug-resistant human myeloid leukemia HL-60/ADR cells have been investigated inthis current study. Methods: HL-60/ADR cells were treated by 20, 40, 80 μmol/L baicalin followed by cell cycleanalysis at 24h. The mRNA expression level of the apoptosis related gene, Bcl-2 and bad, were measured byRT-PCR on cells treated with 80 μmol/L baicalin at 12, 24 and 48hr. Western blot was performed to detect thechanges in the expression of the proteins related to HL-60/ADR cell apoptosis and the signaling pathway beforeand after baicalin treatment, including Bcl-2, PARP, Bad, Caspase 3, Akt, p-Akt, NF-κB, p-NF-κB, mTOR andp-mTOR. Results: Sub-G1 peak of HL-60/ADR cells appeared 24 h after 20 μmol/L baicalin treatment, andthe ratio increased as baicalin concentration increased. Cell cycle analysis showed 44.9% G0/G1 phase cells24 h after baicalin treatment compared to 39.6% in the control group. Cells treated with 80 μmol/L baicalindisplayed a trend in decreasing of Bcl-2 mRNA expression over time. Expression level of the Bcl-2 and PARPproteins decreased significantly while that of the PARP, Caspase-3, and Bad proteins gradually increased. Nosignificant difference in Akt expression was observed between treated and the control groups. However, theexpression levels of p-Akt, NF-κB, p-NF-κB, mTOR and p-mTOR decreased significantly in a time-dependentmanner. Conclusions: We conclude that baicalin may induce HL-60/ADR cell apoptosis through the PI3K/AKTsignaling pathway. 相似文献
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目的:观察RNA干扰Hedgehog信号通路关键因子Glil对胃癌细胞的生物学行为的影响并分析相关机制.方法:人工合成靶向Hedgehog信号通路活化关键因子Glil的siRNA(Glil siRNA)和对照无关siRNA(Con siRNA),应用脂质体将其转入人胃癌细胞SGC-7901,48 h后收集细胞,分别应用MTT法和流式细胞仪检测对细胞增殖、周期和凋亡的影响,同时应用TaqMan探针实时定量PCR检测靶基因Glil、Hedgehog活化标志基因PTCH1、细胞周期负调控蛋白基因CDKN1A(p21)和抗凋亡基因Bel-2的表达变化.结果:以单纯转染剂对照组为参照,siRNA转染后48 h,Glil siRNA和Con siRNA的抑制率分别为(53.33±6.06)%和(13.33±6.11)%,两组差异有统计学意义,t=5.701,P=0.005,n=3;G0/G1期分别为(80.67±4.51)%和(66.00±3.10)%,两组差异有统计学意义,t=5.500,P=0.005,n=3;凋亡率分别为(15.97±1.76)%和(7.77±1.11)%,两组差异有统计学意义,t=4.671,P=0.01,n=3;GlilsiRNA转染细胞内Glil、PTCH1、Bcl-2和CDKN1A(p21)基因的相对(参照单纯转染剂)表达分别为对照的0.24±0.11、0.43±0.09、0.52±0.13和2.10±0.30.分别与Con siRNA相比4条基因表达均差异有统计学意义,t=9.759,P=0.001,n=3;t=8.645,P=0.001,n=3;t=4.940,P=0.008,n=3;t=5.962,P=0.004,n=3.结论:应用RNA干扰技术可以阻断Hedgehog信号通路关键因子Glil的表达,抑制Hedgehog信号通路活化,从而有效地抑制胃癌细胞的增长,诱导凋亡,可能成为治疗胃癌新的生物靶向治疗途径. 相似文献
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Sung-Hyun Kim Gang-Sik Choo Eun-Seon Yoo Joong-Seok Woo Jae-Han Lee So-Hee Han Soo-Hyun Jung Hyeong-Jin Kim Ji-Youn Jung 《Oncology Letters》2021,21(6)
Silymarin is a purified mixture of four isomeric flavonoids extracted from the seeds and fruit of the milk thistle plant, Silybum marianus (L.). Silymarin exhibits a wide variety of biological effects and is commonly used in traditional medicine. Therefore, the anticancer effects of silymarin on human breast cancer cells were investigated to determine its pharmacological mechanisms in vitro and in vivo. The viability and proliferation of MDA-MB- 231 and MCF-7 breast cancer cells were investigated using MTT and wound healing assays. Silymarin decreased the viability and proliferation of MDA-MB-231 and MCF-7 cells in a concentration-dependent manner. The number of apoptotic bodies, as shown by DAPI staining, was increased in a concentration-dependent manner, indicating that silymarin induces apoptosis. Additionally, changes in the expression levels of apoptosis-related proteins were demonstrated in human breast cancer cells using western blotting. Silymarin increased the levels of Bax, cleaved poly-ADP ribose polymerase, cleaved caspase-9 and phosphorylated (p-)JNK, and decreased the levels of Bcl-2, p-P38 and p-ERK1/2. Furthermore, the inhibitory effects of silymarin on MCF-7 tumor growth were investigated. In mice treated with silymarin for 3 weeks (25 and 50 mg/kg), MCF-7 tumor growth was inhibited without organ toxicity. In MCF-7 tumors, silymarin induced apoptosis and decreased p-ERK1/2 levels, as assessed using a TUNEL assay and immunohistochemistry. These results indicated that silymarin inhibited breast cancer cell proliferation both in vitro and in vivo by modulating the MAPK signaling pathway. Therefore, silymarin may potentially be used as a chemo-preventive or therapeutic agent. 相似文献
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Sadegh Babashah Majid Sadeghizadeh Abbas Hajifathali Mostafa Rezaei Tavirani Mina Soufi Zomorod Mojtaba Ghadiani Masoud Soleimani 《International journal of cancer. Journal international du cancer》2013,133(3):579-589
Aberrant expression and function of microRNAs (miRNAs) in leukemia have added a new layer of complexity to the understanding of development and progression of the disease state. However, their targeting of specific signaling pathways responsible for the maintenance and survival properties of leukemic stem cell (LSC) still remains to be further clarified. Hedgehog (Hh) signaling, a highly conserved developmental pathway, has been proven as a functional pathway for LSCs, and loss of this pathway impairs the development of BCR‐ABL‐induced chronic myeloid leukemia (CML) and depletes CML stem cells. Here, we revealed that upregulation of the Hh smoothened (Smo) signal transducer was associated with reduced expression of miR‐326 in the CD34+ cells from a group of patients with CML at diagnosis. Additionally, overexpression of miR‐326 led to downregulation of Smo, resulted in decreased cell proliferation and elevated rate of apoptosis in CML CD34+ cells. Interestingly, restoration of Smo expression levels reversed the effect of miR‐326 and rescued K562 cells from the antiproliferative effects of this miRNA. Thus, Smo appears to be an essential target of miR‐326 during the pathogenesis of CML. These findings lead us to suggest that downregulation of miR‐326 may be a possible mechanism for unrestricted activation of Smo signal transducer of the oncogenic Hh pathway in CML; therefore, the restoration of miR‐326 expression could be of benefit in eradicating CD34+ CML stem/progenitor cells that represent a potential source of relapse in patients suffering CML. 相似文献
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背景与目的:有研究表明Sonic Hedgehog(SHH)信号通路参与多种肿瘤的发生和发展,本研究通过检测SHH信号通路中蛋白Shh、Gli2在肝细胞癌(hepatocellular carcinoma,HCC)中的表达情况,探讨其与HCC各临床病理特征的关系和意义。方法:采用免疫组织化学法检测30例肝癌组织及10例正常肝组织中蛋白Shh、Gli2的表达;RT-PCR法检测10例HCC组织及相应癌旁组织中和肝癌细胞系HepG2、Huh7中Shh和Gli2mRNA的表达。结果:免疫组织化学法检测结果显示Shh、Gli2在HCC组织中阳性率分别为63.3%(19/30)和66.7%(20/30);Gli2的表达与HCC病理分级和肝门静脉侵犯相关(P=0.017,P=0.024)。Shh、Gli2在正常肝组织中无表达。RT-PCR检测结果显示HCC组织和HepG2、Huh7细胞系中都存在Shh、Gli2 mRNA的表达。HCC组织中Shh、Gli2基因表达高于癌旁组织(P〈0.05);Shh、Gli2 mRNA在Huh7中的表达强度高于HepG2,但两者间差异无统计学意义(P〉0.05)。结论:Shh和Gli2在HCC细胞系和组织中的高表达,可能参与了肝癌的发生和发展,为肝癌的防治研究提供了新的实验依据。 相似文献
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The human promyelocytic leukemia cell line known as HL-60 can be triggered to mature to functional granulocytes and/or macrophages after exposure to a variety of compounds. The findings have generated enthusiasm for possible therapy of leukemia using compounds that induce leukemic cell differentiation. We investigated whether five compounds known to trigger HL-60 differentiation to granulocytes could trigger the maturation of blast cells from 12 patients with myelogenous leukemia. Maturation was judged by morphology, superoxide production, phagocytosis, expression of Fc receptors, and development of alpha-napthyl acetate esterase activity. The blast cells from most patients showed little morphological, histological or functional maturation after exposure to the various compounds as compared to the blast cells cultured without the compounds. Actinomycin was able to induce significant maturation of leukemic cells of some patients when maturation was analyzed by several statistical methods. Our study suggests that many compounds which trigger differentiation of promyelocytic leukemia cells may not trigger differentiation of less mature myeloid leukemic cells. 相似文献