脑和肌肉ARNT样蛋白1、周期昼夜节律调节因子2、Notch1、糖原合成酶激酶-3β在结直肠腺癌组织中的表达及意义.pdf

癌症进展2023 年 4 月第 21 卷第 8 期ONCOLOGY PROGRESS,Apr 2023 V ol.21,No.8*论著*脑和肌肉脑和肌肉ARNTARNT样蛋白样蛋白1 1、周期昼夜节律调节因子周期昼夜节律调节因子2 2、NotchNotch1 1、糖原合成酶激酶糖原合成酶激酶-3 3 在结直肠腺癌组织中的表达及意义在结直肠腺癌组织中的表达及意义蒋海涛1，杜胜奇2，李福青1，王红1#1遵义医科大学附属医院消化病医院/遵义医科大学附属医院消化内科，贵州 遵义 5630002荆州市第一人民医院消化内科，湖北 荆州 4340000摘要摘要：目的目的探讨脑和肌肉ARNT样蛋白1（BMAL1）、周期昼夜节律调节因子2（PER2）、Notch1、糖原合成酶激酶-3（GSK-3）在结直肠腺癌组织中的表达及意义。方法方法实时荧光定量逆转录聚合酶链反应（RT-PCR）检测11例结直肠癌患者手术切除的新鲜结直肠癌组织及相应癌旁组织中BMAL1、PER2、Notch1、GSK-3 mRNA的相对表达量；免疫组化法检测50例手术切除的结直肠腺癌及癌旁组织、30例经内镜切除的结直肠腺瘤组织中BMAL1、PER2、Notch1、GSK-3蛋白的表达情况。结果结果结直肠癌组织中，BMAL1、PER2 mRNA的相对表达量均低于癌旁组织，差异均有统计学意义（P0.05）；结直肠癌组织和癌旁组织中Notch1、GSK-3 mRNA的相对表达量比较，差异均无统计学意义（P0.05）。免疫组化结果显示，结直肠腺癌组织、结直肠腺瘤组织及结直肠腺癌癌旁组织中，BMAL1、PER2的表达呈递增趋势，而Notch1、GSK-3的表达呈递减趋势。淋巴结转移、TNM分期为期结直肠腺癌患者结直肠腺癌组织中BMAL1、Notch1蛋白表达均高于无淋巴结转移、TNM分期为期患者（P0.05）；病理类型为黏液腺癌的结直肠腺癌组织中PER2蛋白的表达高于管状腺癌（P0.05），GSK-3的表达低于管状腺癌（P0.05）。Spearman相关分析结果显示，结直肠癌组织中BMAL1的表达与PER2的表达呈正相关（r=0.332，P=0.018），PER2的表达与GSK-3的表达呈负相关（r=-0.291，P=0.040），Notch1的表达与GSK-3的表达呈正相关（r=0.285，P=0.045），其余指标间的表达无相关性。结论结论BMAL1、Notch信号通路、GSK-3均可能参与调控结直肠癌的发生、发展过程，且GSK-3可能与BMAL1和Notch信号通路之间存在相互调控作用。关键词关键词：结直肠腺癌；脑和肌肉ARNT样蛋白1；周期昼夜节律调节因子2；Notch1；糖原合成酶激酶-3中图分类号中图分类号：R R735735.3 3文献标志码文献标志码：AdoiAdoi：10.11877/j.issn.1672-1535.2023.21.08.07Expression of brain and muscle ARNT-like proteinExpression of brain and muscle ARNT-like protein 1 1,period circadian regulator,period circadian regulator2 2,Notch,Notch1 1,and glycogen synthase kinase-,and glycogen synthase kinase-3 3 in colorectal adenocarcinoma andin colorectal adenocarcinoma andtheir clinical significancetheir clinical significanceJIANG Haitao1,DU Shengqi2,LI Fuqing1,WANG Hong1#1Department of Gastroenterology,Digestive Disease Hospital,Affiliated Hospital of Zunyi Medical University,Zunyi 563000,Guizhou,China2Department of Gastroenterology,the First People s Hospital of Jingzhou,Jingzhou 434000,Hubei,ChinaAbstract:ObjectiveAbstract:ObjectiveTo investigate the expression of brain and muscle ARNT-like protein 1(BMAL1),period circa-dian regulator 2(PER2),Notch1,glycogen synthase kinase-3(GSK-3)in colorectal adenocarcinoma and their clinicalsignificance.MethodMethodThe relative expression of BMAL1,PER2,Notch1,and GSK-3 mRNA in fresh colorectal cancertissues and corresponding paracancerous tissues of 11 patients were detected by real-time fluorescent quantitative reversetranscription-polymerase chain reaction(RT-PCR).The expression of BMAL1,PER2,Notch1,and GSK-3 proteins in50 surgically resected colorectal adenocarcinoma and adjacent tissues,and 30 endoscopically resected colorectal adeno-mas were detected by immunohistochemical method.ResultResultThe relative expression levels of BMAL1,PER2 mRNA incolorectal cancer tissues were lower than those in paracancerous tissues,and the differences were statistically significant(P0.05).The results of immunohistochemistry showed that in colorectal adeno-carcinoma tissue,colorectal adenoma tissue,and colorectal adenocarcinoma adjacent tissue,the expression of BMAL1and PER2 increased,while the expression of Notch1 and GSK-3 decreased.The expression of BMAL1 and Notch1 pro-teins in colorectal adenocarcinoma cancer tissues of patients with lymph node metastasis and TNM stage III-IV were high-er than those in patients without lymph node metastasis and TNM stage I-II(P0.05).The expression of PER2 protein incolorectal adenocarcinoma cancer tissues of mucinous adenocarcinoma patients was higher than that in tubular adenocar-cinoma(P0.05),and the expression of GSK-3 was lower than that in tubular adenocarcinoma(P0.05).Spearman cor-基金项目：遵义医科大学附属医院硕士科研启动基金项目（院字【2017】51 号）#通信作者（corresponding author），邮箱：837癌症进展2023年4月第21卷第8期relation analysis results showed that the expression of BMAL1 in colorectal cancer tissues was positively correlated withthe expression of PER2(r=0.332,P=0.018),and the expression of PER2 was negatively correlated with the expression ofGSK-3(r=-0.291,P=0.040),the expression of Notch1 was positively correlated with the expression of GSK-3(r=0.285,P=0.045),and there was no correlation between the expression of other indicators.ConclusionConclusionBMAL1,theNotch signaling pathway,and GSK-3 may all be involved in the regulation of the occurrence and development ofcolorectal cancer.And GSK-3 may interact with BMAL1 and the Notch signaling pathway.Key words:Key words:colorectal adenocarcinoma;brain and muscle ARNT-like protein 1;period circadian regulator 2;Notch1;glycogen synthase kinase-3Oncol Prog,2023,21(8)结直肠癌是消化系统常见的恶性肿瘤，发病率居全球男性恶性肿瘤第三位，女性恶性肿瘤第二位1。结直肠癌的发生发展机制复杂，涉及多个基因及信号通路，具体机制不明，探索与之相关的基因和信号通路将有助于结直肠癌的早期诊断及治疗。昼夜节律是哺乳动物维持机体正常代谢的重要前提，节律基因异常表达与多种恶性肿瘤的发生发展密切相关，节律基因脑和肌肉ARNT样蛋白1（brain and muscle ARNT-like protein 1，BMAL1）和周期昼夜节律调节因子 2（period circadian regula-tor 2，PER2）表达缺失可促进结直肠癌的发生2-3。Notch 通路是进化上高度保守的细胞信号转导通路，主要由跨膜Notch受体（Notch14）、Notch配体（DLL1、DLL3、DLL4、JAG1 及 JAG2）及 DNA 结合蛋白CSL组成，在结直肠癌、肝癌、胰腺癌、前列腺癌、卵巢癌等多种肿瘤中发挥重要作用，Notch信号通路异常所发挥的抑癌/促癌作用取决于细胞和组织内环境；但在结直肠癌中，Notch1普遍被认为是促癌基因4-5。糖原合成酶激酶-3（glycogen synthasekinase-3，GSK-3）是糖原合成的一种丝氨酸/苏氨酸蛋白激酶，有GSK-3和GSK-