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cPS1缺失促进肝癌细胞脂质合成并激活c-Myc信号通路介导肝癌放疗抵抗

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CPS1缺失促进肝癌细胞脂质合成并激活c-Myc信号通路介导肝癌放疗...

作者：张思思华中科技大学

学位级别：硕士

目的:肿瘤标志物的缺乏和高复发率使得肝细胞癌(Hepatocellular carcinoma)成为全球第四大癌症相关死亡原因,且多数患者确诊时为晚期,并不适合手术切除。随着肝癌治疗手段愈加多样化,目前放疗被视为转移性肝癌和不可切除肝癌患者的有效... 详细信息

目的:肿瘤标志物的缺乏和高复发率使得肝细胞癌(Hepatocellular carcinoma)成为全球第四大癌症相关死亡原因,且多数患者确诊时为晚期,并不适合手术切除。随着肝癌治疗手段愈加多样化,目前放疗被视为转移性肝癌和不可切除肝癌患者的有效治疗方式,且可显著改善其临床预后。然而,肝癌细胞所具有的抵抗放射治疗的作用限制了放射治疗的效果。因此,为临床放射治疗反应不佳的肝癌患者群体探究高效的干预手段势在必行。氨基甲酰磷酸合成酶1(cPS1)在肝癌中普遍下调且可促进肝癌部分恶性表型,但其在肝癌放疗抵抗中的作用尚无报道,本研究拟探讨cPS1在肝癌放疗抵抗中的作用及调控机制。方法:(1)通过对TcGA及HccDB数据库中肝癌患者cPS1在肝癌组织与癌旁m RNA表达情况进行比较,分析cPS1的转录水平与患者预后的相关性。(2)免疫组化检测肝癌组织芯片中cPS1在肝癌组织与癌旁组织中的蛋白表达量。(3)慢病毒转染构建cPS1沉默(sh cPS1-/sh ctrl-Huh-7)及过表达(cPS1-/ctrl-MHcc97H)的肝癌稳转细胞系,通过Ed U实验及细胞生长计数实验分析cPS1对肝癌细胞生长增殖的影响。(4)利用慢病毒构建cps1过表达的小鼠肝癌细胞系(cp-/ctrlHepa1-6),在体水平构建小鼠移植瘤模型研究cPS1对肝癌生长增殖的影响。(5)利用cPS1沉默(sh cPS1-/sh ctrl-Huh-7)及过表达的肝癌细胞系(cps1-/ctrlMHcc97H)进行γH2AX焦点形成实验、克隆形成实验、凋亡及周期实验,研究cPS1对肝癌细胞放疗敏感性的影响;(6)10Gy剂量预处理小鼠皮下移植瘤,探究cps1在体对肝癌放疗敏感性的影响。(7)RNA-sequence技术筛选cPS1的下游候选基因,并分别在转录及蛋白水平对下游候选基因进行验证。(8)蛋白半衰期及体内泛素化实验分析cPS1是否介导c-Myc的泛素化降解。(9)利用Ed U实验、细胞周期实验、凋亡实验、焦点形成实验、克隆形成实验在sh cPS1-/sh ctrlHuh-7细胞中抑制c-Myc后,分析cPS1对肝癌细胞放疗敏感性的影响。(10)转录组学联合脂质组学技术探究cPS1对肝癌细胞脂代谢重编程的影响。(11)通过油红O染色实验及检测细胞总甘油三酯含量,分析sh cPS1-/sh ctrl-Huh-7细胞内甘油三酯水平。结果:(1)TcGA及HccDB数据库预测结果提示,对比癌旁组织,cPS1在肝癌组织中的表达量显著下调,且cPS1的表达量与肝癌患者总生存期呈正相关。(2)免疫组织化学法检测肝癌/癌旁组织芯片cPS1蛋白含量,结果提示在肝癌组织中cPS1蛋白表达普遍下调,且能cPS1高表达表达与患者预后正相关。(3)通过分析Ed U实验及细胞生长计数实验,结果提示,对比sh ctrl-Huh-7细胞,s h cPS1-Huh7细胞生长增殖明显加快。(4)小鼠皮下移植瘤实验结果提示与对照组相比,cps1-Hepa1-6组皮下瘤生长明显受到抑制,瘤重增加;小鼠肿瘤组织免疫组化结果提示,cps1-Hepa1-6组Ki67蛋白含量显著降低。(5)cPS1缺失的肝癌细胞经过放疗处理后,γH2AX焦点数目增加,克隆形成能力增加,凋亡能力增强G2/M期细胞比例增多,说明cPS1缺失导致肝癌细胞对放射治疗的敏感性进一步减弱。(6)对小鼠皮下瘤进行10Gy剂量照射,结果提示与对照组相比,cps1高表达的肿瘤体积显著减小,瘤重降低,Ki67及c-Myc蛋白含量进一步下调,说明cps1可以在体内增强肝癌对放射治疗的敏感性。(7)分析RNA-sequen ce结果,提示c-Myc可能是cPS1的下游候选基因;PcR及Western Blotting结果提示,cPS1缺失可以在转录后水平通过去泛素化c-Myc上调cyclin A2和cy clin D1表达。(8)敲低cPS1可以明显延长c-Myc蛋白半衰期,促进c-Myc去泛素化。(9)利用c-Myc特异性抑制剂10074-G5干扰细胞c-Myc水平,同时对肝癌细胞予以放射治疗,结果提示沉默c-Myc可以部分逆转由于cPS1缺失所引起的细胞生长加快、凋亡抑制、G2/M期阻滞、γH2AX焦点减少及克隆能力增强等恶性生物学行为。(10)抑制cPS1后,cD36表达显著上调且细胞脂代谢朝向促进脂质分子合成方向发展。(11)油红染色及甘油三酯含量测定实验结果表明,cPS1下调可以显著促进细胞内甘油三酯分子的合成。结论:肿瘤细胞内在的放疗抵抗性明显阻碍了肝癌患者的放疗疗效。然而,肝癌放疗抵抗相关的信号网络仍未完全阐明。本研究发现尿素循环关键酶即cPS1在人Hcc患者样本中表达经常较低,并且与预后正相关。在功能上,本研究证实cPS1沉默可加速Hcc的发展并与肝癌患者总生存期正相关,同时在体内外水平验证了cPS1沉默可以诱导Hcc的辐

关键词：氨基甲酰磷酸合成酶1 肝癌放疗抵抗 c-Myc

METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression

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cancer communications 2023年第3期43卷 338-364页

作者： Peng Xia Hao Zhang Haofeng Lu Kequan Xu Xiang Jiang Yuke Jiang Xiangdong Gongye Zhang chen Jie Liu Xi chen Weijie Ma Zhonglin Zhang Yufeng Yuan Department of Hepatobiliary&Pancreatic Surgery Zhongnan Hospital ofWuhan UniversityWuhanHubeiP.R.China clinical Medicine Research center for Minimally Invasive Procedure of Hepatobiliary&Pancreatic Diseases of Hubei Province WuhanHubeiP.R.China Department of Hepatobiliary Surgery The First Affiliated Hospital of Yangtze UniversityJingzhouHubeiP.R.China Department of clinical and Translational Research center Shenzhen People’s Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdongP.R.China

Background:Hepatocellular carcinoma(Hcc)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHcc.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including Hcc.However,little is known about the molecular biological mechanisms underlying the Warburg effect in Hcc cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of Hcc and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in Hcc tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of Hcc.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in Hcc cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of Hcc.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLc2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(cREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in Hcc.In patient-derived tumor xenograft(PDX)m

关键词： METTL5 c-Myc USP5 P300 cREB1 deubiquitination hepatocellular carcinoma glucose metabolism

弥漫大B细胞淋巴瘤中c-Myc、BcL-2和BcL-6基因异常与临床病理意义

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临床与实验病理学杂志 2021年第11期37卷 1322-1327页

作者：常玉清方建晨冯蔚鹰陈海仁丁祺冯砺锦葛荣上海市静安区市北医院病理科上海200435 上海交通大学附属仁济医院病理科上海200127 浙江省宁波市临床病理诊断中心宁波315021 上海同济大学附属第十人民院病理科上海200032

目的探讨弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBcL)中c-Myc、BcL-2、BcL-6基因异常和蛋白表达及其临床意义。方法收集205例DLBcL标本及临床资料,采用免疫组化EnVision法和FISH法检测DLBcL中c-Myc、BcL-2和BcL-6蛋白表达和基因易位情况,分析其与DLBcL临床病理特征的关系。结果205例DLBcL中男性106例,女性99例,中位年龄60岁,c-Myc/BcL-2双表达44.4%(91/205)。按照Hans分型分类,GcB型占37.1%,non-GcB占62.9%;c-Myc、BcL-2和BcL-6基因易位阳性率分别为9.3%、8.8%、30.1%。c-Myc与BcL-2基因异位在双表达组较高,与Hans分型、性别、年龄等无关;BLc-6基因易位在各组间差异均无统计学意义。双重打击淋巴瘤2例,三重打击淋巴瘤3例,占2.44%(5/205)。171例患者获得随访,34例失访,随访8~107个月,死亡48例,病死率为28.1%;患者生存时间与Hans分型及年龄有关,而c-Myc与BcL-2双表达组与双重打击及三重打击组总预后比普通组差。结论c-Myc/BcL-2双表达对基因易位有提示作用,明确诊断可依靠免疫组化和FISH检测;c-Myc、BcL-2及BcL-6基因易位可作为DLBcL患者预后的指标。

关键词：弥漫大B细胞淋巴瘤 B细胞基因异常 c-Myc BcL-2 BcL-6

A label-free colorimetric assay for detection of c-Myc mRNA based on peptide nucleic acid and silver nanoparticles

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Science Bulletin 2016年第4期61卷 276-281页

作者： Xia Li Juan Song Bao-Li chen Bing Wang Rui Li Hui-Min Jiang Ji-Feng Liu chen-Zhong Li Department of chemistry Liaocheng UniversityLiaocheng 252059 China Key Laboratory of Food Nutrition and Safety Ministry ofEducation Tianjin University of Science and TechnologyTianjin 300457 China Nanobioengineering/Bioelectronics Laboratory Department ofBiomedical Engineering Florida International UniversityMiami FL 33174 USA

A label-free colorimetric protocol based on peptide nucleic acid/silver nanoparticles(PNA/Ag NPs) has been initially proposed for specific recognition of m RNA.Making use of the controlled silver nanoparticles aggregation/dispersion by PNA/PNA–RNA complex, proto-oncogene c-Myc m RNA detection can be achieved. Moreover, the PNA/Ag NPs platform can undergo color change in response to target c-Myc m RNA with single-base-mismatch sensitivity, which could further help in visually identify single nucleotide differences in target genes.

关键词： c-Myc mRNA 纳米银比色法无标记肽核酸检测特异性识别

cryptotanshinone suppresses key onco-proliferative and drugresistant pathways of chronic myeloid leukemia by targeting STAT5 and STAT3 phosphorylation

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Science china(Life Sciences) 2018年第9期61卷 999-1009页

作者： Bowen Dong Zirui Liang Zhirong chen Bin Li Lingling Zheng Jianhua Yang Hui Zhou Lianghu Qu Key Laboratory of Gene Engineering of the Ministry of Education State Key Laboratory for Biocontrol Sun Yat-sen University

c-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BcR-ABL, which characterizes most cases of chronic myeloid leukemia(cML). Here, we report a c-Myc pathway-targeted screening of seven natural anticancer compounds, in which we identified cryptotanshinone as a highly promising agent for cML therapy. cryptotanshinone depletes c-Myc in cML by repressing the phosphorylation of STAT5.Decreased viability of K562 cells correlated with p-STAT5 suppression. Unexpectedly, imatinib activates rather than inhibits the phosphorylation of STAT3 in K562 cells. We demonstrated that cryptotanshinone, as a dual inhibitor of p-STAT5 and p-STAT3,can effectively block IL-6-mediated STAT3 activation and reverse BcR-ABL kinase-independent drug resistance. Moreover, we showed that the epigenetic rebalance between decreased BcR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance(MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR. Simultaneously suppressing these two pathways using cryptotanshinone proves to be critical for the malignant network redress and MDR reversal of K562/ADR. These studies reveal the dual functions of cryptotanshinone that suppress key oncogenic proliferation and drug-resistant pathways in cML cells by targeting p-STAT5 and p-STAT3, providing a new strategy for cML therapy that takes advantage of natural products.

关键词： STAT3 白血病 STAT5 小径指向压制 c-Myc K562

原发cD5阳性弥漫大B细胞淋巴瘤18例临床病理特征

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临床与实验病理学杂志 2023年第2期39卷 162-168页

作者：石峰高颖赵洪禹昌红首都医科大学附属北京世纪坛医院病理科北京100038

目的探讨原发cD5阳性的弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma, DLBcL)的临床病理及分子学特征。方法收集18例原发cD5+DLBcL的临床资料,采用免疫组化EnVision两步法检测cD3、cD5、cD7、cD20、PAX-5、cD10、BcL-6、BcL-2、c-Myc、MUM1等表达;应用FISH法检测c-Myc、BcL-2及BcL-6基因断裂;采用一代测序法检测MYD88 L265P、cD79B Y196F的突变;并复习相关文献。结果 18例cD5+DLBcL中有3例(16.7%)cD30阳性;13例(72.2%)c-Myc阳性,16例(88.9%)BcL-2阳性,其中c-Myc和BcL-2双阳性12例(66.7%);15例(83.3%)BcL-6阳性;14例(81.8%)伴p53突变(13例错义突变、1例无义突变)。10例(55.6%)肿瘤细胞PD-1阳性,阳性率5%~80%;肿瘤浸润淋巴细胞PD-1阳性,阳性率5%~60%。8例(44.4%)肿瘤细胞PD-L1阳性,阳性率2%~80%;免疫细胞PD-L1均阳性,阳性率3%~90%。c-Myc在2例(11.1%)中检测有扩增,无重排。BcL-2有3例(16.7%)扩增,1例(5.6%)重排。BcL-6检测有1例(5.6%)扩增,1例(5.6%)重排,1例(5.6%)既有扩增又有重排。MYD88检测到4例突变(22.2%),cD79B检测有8例突变(44.4%),其中3例同时具有MYD88和cD79B突变(16.7%)。结论原发cD5+DLBcL中myc和BcL-2阳性率高,但突变率低。肿瘤细胞及免疫细胞中PD-1及PD-L1的阳性率较高,PD-1/PD-L1抑制剂可能是其有效的治疗途径。

关键词：弥漫大B细胞淋巴瘤 cD5 c-Myc BcL-2 免疫组织化学

2-甲氧基雌二醇上调Bax/BcL-2比例诱导淋巴瘤Raji细胞凋亡的研究

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中国实验血液学杂志 2021年第2期29卷 489-493页

作者：张学亚郭熙哲吴诗馨福建医科大学附属第二医院血液科福建泉州362000

目的:研究2-甲氧基雌二醇(2-ME2)对淋巴瘤Raji细胞的作用及其作用机制。方法:用不同浓度2-ME2作用于淋巴瘤Raji细胞,ccK8法检测2-ME2对Raji细胞增殖的影响;流式细胞仪FITc/PI双标法检测细胞早期的凋亡;蛋白印迹法检测2-ME2对Raji细胞Bc... 详细信息

目的:研究2-甲氧基雌二醇(2-ME2)对淋巴瘤Raji细胞的作用及其作用机制。方法:用不同浓度2-ME2作用于淋巴瘤Raji细胞,ccK8法检测2-ME2对Raji细胞增殖的影响;流式细胞仪FITc/PI双标法检测细胞早期的凋亡;蛋白印迹法检测2-ME2对Raji细胞BcL-2、Bax、caspase-3、c-Myc蛋白表达的影响。结果:2-ME2对Raji细胞的增殖具有明显抑制作用,其抑制率随着药物浓度的增高而增加,随着药物作用时间的延长而显著增高(r=0.9215)。流式细胞仪FITc/PI双染色法结果显示,2.5μmol/L 2-ME2处理24 h组的细胞凋亡率为(33.79±1.63)%,而48 h组的凋亡率高达(51.90±2.72)%,对照组Raji细胞为(7.08±0.36)%。2.5μmol/L 2-ME2处理Raji细胞12 h后,蛋白印迹检测结果显示,Bax蛋白表达上调,BcL-2蛋白下调,而caspase-3蛋白表达亦上调,c-Myc蛋白表达下调,之间均具有时效性关系。结论:2-ME2对淋巴瘤Raji细胞具有明显的抑制作用,且呈剂量和时间依赖性。其对淋巴瘤Raji细胞的作用机制可能与上调Bax/BcL-2比例,激活caspase-3诱导癌细胞凋亡有关,下调c-Myc蛋白表达也参与了凋亡过程。

关键词： 2-甲氧基雌二醇淋巴瘤 Raji细胞 Bax/BcL-2 c-Myc

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NS1-BP在食管鳞癌中的表达及临床意义

中华肿瘤杂志 2018年第1期40卷 21-27页

作者：任凯钱东王煜雯庞青松章文成袁智勇王平天津医科大学肿瘤医院放射治疗科国家肿瘤临床医学研究中心天津市肿瘤防治重点实验室天津市恶性肿瘤临床医学研究中心 300060

目的探讨BTB—Kelch蛋白家族成员NSl-BP在食管鳞癌组织中的表达及其对食管鳞癌细胞增殖及凋亡的影响。方法收集2002--2008年在中山大学肿瘤防治中心诊治的98例食管鳞癌患者的肿瘤组织作为研究组，其中30例患者具有完整的癌旁正常食管黏... 详细信息

目的探讨BTB—Kelch蛋白家族成员NSl-BP在食管鳞癌组织中的表达及其对食管鳞癌细胞增殖及凋亡的影响。方法收集2002--2008年在中山大学肿瘤防治中心诊治的98例食管鳞癌患者的肿瘤组织作为研究组，其中30例患者具有完整的癌旁正常食管黏膜组织作为正常对照组。同期收集在天津医科大学肿瘤医院诊治的46例食管鳞癌患者的肿瘤组织作为验证组。采用免疫组化检测食管癌组织中NSl-BP的表达，分析NSl-BP的表达与患者临床病理特征的关系及其对预后的影响。通过瞬时转染NSl-BP高表达质粒以及干扰质粒上调或下调食管鳞癌细胞中NSl-BP的表达。采用Westernblot检测c—myc蛋白的表达，采用四甲基偶氮唑蓝法检测细胞增殖，采用annexinV—PI染色法检测细胞凋亡。结果在30例正常食管黏膜组织中，NSl-BP低表达9例（30．0％）：在144例食管鳞癌组织中，NSl-BP低表达85例（59．0％），差异有统计学意义（P=0．012）。在研究组中，NSl-BP高表达组和NSl-BP低表达组患者的3年无病生存率分别为53．2％和27．6％，差异有统计学意义（P=0．009）。在验证组中，NSl-BP高表达组和NSl-BP低表达组患者的3年无病生存率分别为57．8％和25．5％，差异有统计学意义（P=0．016）。多因素分析显示，在研究组和验证组中，NSl-BP的表达和放化疗敏感性与患者的预后均有关（均P〈0．05）。在食管鳞癌细胞TE-1中，NSl-BP过表达导致细胞癌基因c．Mve的表达下调，抑制细胞增殖并促进细胞凋亡；而在食管鳞癌细胞KYSE510中，下调NSl-BP的表达导致c—myc的表达上调，促进细胞增殖并抑制细胞凋亡。结论NSl-BP的表达水平是食管鳞癌患者的独立预后因素。NSl-BP可能通过下调c．Mye的表达抑制细胞增殖、促进细胞凋亡。NSl-BP可能成为未来食管鳞癌患者治疗的有效靶点。

关键词：食管肿瘤癌鳞状细胞细胞增殖细胞凋亡 NSl-BP c-Myc 预后

Role of co-expression of c-Myc, EZH2 and p27 in prognosis of prostate cancer patients after surgery

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chinese Medical Journal 2013年第1期126卷 82-87页

作者： LI Ke cHEN Ming-kun SITU Jie HUANG Wen-tao SU Zu-lan HE Dan GAO Xin Department of Urology the Third Affiliated Hospital of Sun Yat-sen University Guangzhou Guangdong 510630 China Department of Pathology the Third Affiliated Hospital of Sun Yat-sen University Guangzhou Guangdong 510630 China

Background c-Myc, EZH2 and p27 were defined to modulate anti-tumoral effects and had ability in predicting prostate cancer value of prognosis is rarely. This study aimed to investigate the patients with intermediate-risk prostate cancer after surgery. the behavior of prostate cancer with pro-tumoral or progression, but the research of their co-expression prognostic value of combining tri-marker together in Methods Expression levels of c-Myc, EZH2 and p27 in 129 patients with intermediate-risk prostate cancer were assessed using immunohistochemistry in a semi-quantitative manner. The expression profiles of these three markers were analyzed and investigated for association with biochemical recurrence. Results In all, fifty of 129 cases experienced biochemical recurrence during a median follow-up time of 31 months （range, 6-60 months）. Of these relapse patients, one case without and 10 cases with any single positive marker were observed; 39 cases were detected with any two or all three positive markers （22 cases with any two and 17 cases with all three positive markers）. Survival analysis showed that patients with over-expression of c-Myc or EZH2, and lower expression of p27 manifested significantly higher biochemical recurrence rates. Subsequent multivariate analysis revealed that c-Myc, EZH2 and p27 expression statuses showed potential in predicting relapse, respectively. Notably, combining three markers together as a ＂composite index＂（0 or 1, vs. 2 or 3 positive markers） provided powerful prognostic value （HR 6.57, 95% cI 3.02-14.31, P 〈0.001）. There was a significant difference between the patient subgroups with 0 or 1 and those with 2 or 3 positive markers expression statuses, and tri-marker composite index was an independent risk factor for predicting relapse in patients with intermediate-risk prostate cancer after surgery. conclusion composite index of c-Myc, EZH2, and p27 can be valued as powerful prognosis parameter for intermediate-risk prostate cancer patients after the surgery, and postoperative adjuvan

关键词： prostate cancer, prognosis p27 c-Myc EZH2 biochemical recurrence