您的位置：山东大学 -> 科技期刊社 -> 《山东大学学报（医学版）》

山东大学学报 (医学版) ›› 2021, Vol. 59 ›› Issue (3): 67-73.doi: 10.6040/j.issn.1671-7554.0.2020.1734

• 临床医学 • 上一篇    下一篇

抑癌基因SOCS1、SOCS3的甲基化与急性髓系白血病患者治疗转归及预后的关联分析

张晓慧1,罗建民2,索晓慧1,孙国锋1,李静3   

  1. 1. 邯郸市中心医院血液内科, 河北 邯郸 056001;2. 河北省医科大学第二医院血液内科, 河北 石家庄 050000;3. 邯郸市中心医院肿瘤内科, 河北 邯郸 056001
  • 发布日期:2021-04-06
  • 通讯作者: 张晓慧. E-mail:zhangxiaohuiqq@163.com索晓慧. E-mail:linsuo@163.com
  • 基金资助:
    河北省卫生健康委员会科研基金(20190195)

Relationship between methylation of tumor suppressor genes SOCS1 and SOCS3 and remission and prognosis of 80 acute myeloid leukemia patients

ZHANG Xiaohui1, LUO Jianmin2, SUO Xiaohui1, SUN Guofeng1, LI Jing3   

  1. 1. Department of Hematology, Handan Central Hospital, Handan 056001, Hebei, China;
    2. Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, China;
    3. Department of Oncology, Handan Central Hospital, Handan 056001, Hebei, China
  • Published:2021-04-06

PDF (PC)

231

摘要： 目的 探讨抑癌基因细胞因子信号转导抑制因子1和3(SOCS1、SOCS3)的甲基化与急性髓系白血病(AML)患者临床治疗效果及预后的关系。 方法 采用RT-qPCR、甲基化特异性PCR和蛋白质印迹法检测80例初治AML患者及20例正常对照者SOCS1、SOCS3基因的甲基化状态及表达水平,利用R+G显带法检测染色体核型。将AML组分别根据SOCS1、SOCS3基因是否存在甲基化分为SOCS1甲基化组(n=39)和SOCS1非甲基化组(n=41);SOCS3甲基化组(n=44)和SOCS3非甲基化组(n=36)。比较两组年龄、性别、AML分型的差异。同时比较双基因甲基化组(n=29)、单一基因甲基化组(n=25)和双非甲基化组(n=26)中融合基因、染色体核型、治疗缓解率和AML预后分层的差别。 结果 AML组SOCS1、SOCS3基因甲基化率高于正常对照组(48.75% vs 0, 55% vs 0),而基因的mRNA表达AML组［SOCS1:0.080(0.003,1.090);SOCS3:0.140(0.002,1.044)］较正常对照组［SOCS1: 1.677(0.422,1.972);SOCS3:2.395±1.540］明显下降(P<0.001)。初治AML患者中, SOCS1、SOCS3甲基化组基因的 mRNA及蛋白表达水平均低于非甲基化组和正常对照组(P<0.001), AML预后不良因素WT1/ABL基因突变高于非甲基化组(χ2=9.674,P=0.008),治疗缓解率低于非甲基化组(χ2=10.583,P=0.005)。基因甲基化与预后分层的分析结果显示,SOCS1、SOCS3的甲基化状态与分子遗传学(χ2=6.137,P=0.046)预后不良相关,双非甲基化状态与细胞遗传学(χ2=6.675,P=0.036)、分子遗传学(χ2=9.693,P=0.008)预后良好相关。 结论 SOCS1、SOCS3的甲基化可导致基因表达沉默,与AML的不良治疗转归及预后均有相关性。

关键词: SOCS1基因, SOCS3基因, 急性髓系白血病, 甲基化, WT1/ABL基因, FLT3-ITD基因

Abstract: Objective To explore the relationship between SOCS1 and SOCS3 methylation, remission and prognosis of acute myeloid leukemia(AML). Methods The methylation and expressions of SOCS1 and SOCS3 in 80 AML patients and 20 healthy controls were detected with RT-qPCR, MS-PCR and Western blotting. The chromosome karyotypes were determined with R+G banding method. The AML group was subdivided into SOCS1 methylation group(n=39)and SOCS1 non-methylation group(n=41), SOCS3 methylation group(n=44)and SOCS3 non-methylation group(n=36). The age, sex and AML typing were compared. The gene mutation, karyotypes, complete remission rate and AML prognosis stages were compared among the two-gene methylation group(n=29), single-gene methylation group(n=25)and double-unmethylation group(n=26). Results The AML group had higher methylation rates of SOCS1 and SOCS3 genes than the control group(48.75% vs 0, 55% vs 0), and the mRNA expressions were lower ［SOCS1: 0.080(0.003, 1.090)vs 1.677(0.422, 1.972); SOCS3: 0.140(0.002, 1.044)vs 2.395±1.540］(P<0.001). In AML patients, the mRNA and protein expressions of SOCS1 and SOCS3 methylation groups were lower than those in non-methylation groups and control group(P<0.001). The positive rate of WT1/ABL in SOCS1 and SOCS3 methylation groups was higher than that in non-methylation groups(χ2=9.674, P=0.008). The SOCS1 and SOCS3 methylation groups had a lower therapy remission rate than the non-methylation groups(χ2=10.583, P=0.005). Analysis of gene methylation and prognosis revealed that methylation of SOCS1 and SOCS3 was correlated with poor molecular abnormalities(χ2=6.137, P=0.046). Double unmethylation of SOCS1 and SOCS3 was correlated with good cytogenetics(χ2=6.675, P=0.036)and molecular abnormalities(χ2=9.693, P=0.008)of AML. Conclusion Methylation of SOCS1 and SOCS3 genes can cause gene silencing, which is associated with poor remission and prognosis of AML.

Key words: SOCS1 gene, SOCS3 gene, Acute myeloid leukemia, Methylation, WT1/ABL gene, FLT3-ITD gene

中图分类号: 

  • R552
[1] Ghazawi FM, Le M, Cyr J, et al. Analysis of acute myeloid leukemia incidence and geographic distribution in Canada from 1992 to 2010 reveals disease clusters in Sarnia and other industrial US border cities in Ontario [J]. Cancer, 2019, 125(11): 1886-1897.
[2] Takami A. Hematopoietic stem cell transplantation for acute myeloid leukemia [J]. Int J Hematol, 2018, 107(5): 513-518.
[3] Orla CO, Gargan S, Michelle KM, et al. The hepatitis C virus(HCV)protein, p7, suppresses inflammatory responses to tumor necrosis factor(TNF)-α via signal transducer and activator of transcription(STAT)3 and extracellular signal-regulated kinase(ERK)-mediated induction of suppressor of cytokine signaling(SOCS)3 [J]. FASEB J, 2019, 33(8): 8732-8744.
[4] Liu KK, Wu ZY, Chu JH, et al. Promoter methylation and expression of SOCS3 affect the clinical outcome of pediatric acute lymphoblastic leukemia by JAK/STAT pathway [J]. Biomed Pharmacother, 2019, 115(7): 108913. doi: 10.1016/j.biopha.2019.108913.
[5] Shao N, Ma G, Zhang JY, et al. miR-221-5p enhances cell proliferation and metastasis through post-transcriptional regulation of SOCS1 in human prostate cancer [J]. BMC Urology, 2018, 18(1): 14. doi: 10.1186/s12894-018-0325-8.
[6] Khan MGM, Ghosh A, Variya B, et al. Hepatocyte growth control by SOCS1 and SOCS3 [J]. Cytokine, 2019, 9(121): 154733. doi: 10.1016/j.cyto.2019.154733.
[7] Liau NPD, Laktyushin A, Lucet IS, et al. The molecular basis of JAK/STAT inhibition by SOCS1 [J]. Nat Commun, 2018, 9(1): 1558. doi: 10.1038/s41467-018-04013-1.
[8] Feng RY, Wang XF, Li JN, et al. Interaction of Abl tyrosine kinases with SOCS3 impairs its suppressor function in tumorigenesis [J]. Neoplasia, 2018, 20(11): 1095-1105.
[9] Wang YM, Lu C, Huang HX, et al. A lipid-soluble extract of pinellia pedatisecta schott orchestrates intratumoral dendritic cell-driven immune activation through SOCS1 signaling in cervical cancer [J]. J Ethnopharmacology, 2021, 267(3): 112837. doi: 10.1016/j.jep.2020.112837.
[10] Karki P, Ke YB, Zhang CO, et al. SOCS3-microtubule interaction via CLIP-170 and CLASP is critical for modulation of endothelial inflammation and lung injury [J]. J Biol Chem, 2020, 120(12): 14232. doi: 10.1074/jbc.RA120.014232.
[11] Ying J, Qiu XY, Lu Y, et al. SOCS1 and its potential clinical role in tumor [J]. Pathol Oncol Res, 2019, 25(4): 1295-1301.
[12] Khan MGM, Ghosh A, Variya B, et al. Prognostic significance of SOCS1 and SOCS3 tumor suppressors and oncogenic signaling pathway genes in hepatocellular carcinoma [J]. BMC Cancer, 2020, 20(1): 774. doi: 10.1186/s12885-020-07285-3.
[13] Gong Y, Wan JH, Zou W, et al. MiR-29a inhibits invasion and metastasis of cervical cancer via modulating methylation of tumor suppressor SOCS1 [J]. Future Oncol, 2019, 15(15): 1729-1744.
[14] Pasha HF, Mohamed RH, Radwan MI. RASSF1A and SOCS1 genes methylation status as a noninvasive marker for hepatocellular carcinoma [J]. Cancer Biomark, 2019, 24(2): 241-247.
[15] 冼海兵, 冯卫能, 张华, 等. miR-155与SOCS1在非小细胞肺癌中表达及临床意义[J]. 肿瘤学杂志, 2020, 26(7):586-590. XI Haibing, FENG Weineng, ZHANG Hua, et al. Expression of miR-155 and SOCS-1 in non-small cell lung cancer and its clinical significance [J]. Journal of Oncology, 2020, 26(7): 586-590.
[16] Villalobos-Hernandez A, Bobbala D, Kandhi R, et al. SOCS1 inhibits migration and invasion of prostate cancer cells, attenuates tumor growth and modulates the tumor stroma [J]. Prostate Cancer Prostatic Dis, 2017, 20(1): 36-47.
[17] Zhao R, Chen K, Zhou J, et al. The prognostic role of BORIS and SOCS3 in human hepatocellular carcinoma [J]. Medicine(Baltimore), 2017, 96(12): e6420. doi: 10.1097/MD.0000000000006420.
[18] Jiang MM, Zhang WW, Zhang R, et al. Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer [J]. Oncogene, 2020, 39(24): 4681-4694.
[19] Li MZ, Lai DH, Zhao HB, et al. SOCS3 overexpression enhances ADM resistance in bladder cancer T24 cells [J]. Eur Rev Med Pharmacol Sci, 2017, 21(13): 3005-3011.
[20] Yoneda T, Kunimura N, Kitagawa K, et al. Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo [J]. Cancer Gene Therapy, 2019, 26(11): 388-399.
[21] Zhang XH, Yang L, Liu XJ, et al. Association between methylation of tumor suppressor gene SOCS1 and acute myeloid leukemia [J]. Oncol Rep, 2018, 40(2): 1008-1016.
[22] 张晓慧, 罗建民, 索晓慧, 等. SOCS1的表观遗传学修饰与急性髓系白血病的关系[J]. 中国癌症杂志, 2020, 30(8): 577-585. ZHANG Xiaohui, LUO Jianmin, SUO Xiaohui, et al. Relationship between epigenetic modification of SOCS1 and acute myeloid leukemia [J]. China Oncology, 2020, 30(8): 577-585.
[23] Chu QJ, Shen D, He L, et al. Prognostic significance of SOCS3 and its biological function in colorectal cancer [J]. Gene, 2017, 627(9): 114-122.
[1] 王景,谢艳,李培龙,杜鲁涛,王传新. GZMB基因cg16212145位点的异常甲基化芯片测定对胃癌早筛的价值[J]. 山东大学学报 (医学版), 2022, 60(6): 26-34.
[2] 刘岩,张曼,姜朝阳,卞姝,杜艾家,陈鹤. LncRNA-HOTAIR调控H3K27me3影响巨噬细胞迁移的机制[J]. 山东大学学报 (医学版), 2022, 60(6): 1-9.
[3] 郑昊天,王光辉,赵小刚,王亚东,曾榆凯,杜贾军. 基于数据库LKB1突变肺腺癌DNA异常甲基化位点构建的预后风险模型[J]. 山东大学学报 (医学版), 2022, 60(3): 51-58.
[4] 褚晏,刘端瑞,朱文帅,樊荣,马晓丽,汪运山,郏雁飞. DNA甲基化转移酶在胃癌中的表达及其临床意义[J]. 山东大学学报 (医学版), 2021, 59(7): 1-9.
[5] 毕亚珍,冯洒然,李红,刘倩,于靖宜,王焱,朱传升. 以高钙血症为首发表现的成人急性髓系白血病1例报告[J]. 山东大学学报 (医学版), 2021, 59(5): 116-118.
[6] 罗兵. EB病毒对胃癌表观遗传学的影响[J]. 山东大学学报 (医学版), 2021, 59(5): 30-39.
[7] 梁婷婷,杨勇霞,侯丛哲,黄太胜,王华丽,朱琳. PAX1基因甲基化与宫颈高级别上皮内病变及高危型HPV分型的关联性[J]. 山东大学学报 (医学版), 2021, 59(11): 48-52.
[8] 王艳,张宇卉,胡耐博,滕广帅,周圆,白洁. 基于单细胞测序分析急性髓系白血病患者骨髓免疫微环境的特点[J]. 山东大学学报 (医学版), 2021, 59(10): 30-38.
[9] 王建祥,顾闰夏. 急性髓系白血病的靶向治疗进展[J]. 山东大学学报 (医学版), 2019, 57(7): 6-12.
[10] 黄金献,李栋,李聪,时庆,鞠秀丽. 三维和二维培养的脐带间充质干细胞DNA甲基化水平比较[J]. 山东大学学报 (医学版), 2019, 57(11): 1-8.
[11] 陈琦,李佳琪,郭智彬,贾惊宇,何林生. 环氧化酶-2基因启动子区甲基化水平在子宫内膜异位症中的作用[J]. 山东大学学报（医学版）, 2017, 55(1): 44-48.
[12] 周雪,王燕蓉,田龙,马良宏,颜贝,田稼,张帆,周岳,王红燕. 冷冻复苏过程对人精子印记基因SNRPN和GRB10DNA甲基化及表达的影响[J]. 山东大学学报（医学版）, 2017, 55(1): 54-59.
[13] 杨娟, 邱宗建, 宋强. 辛伐他汀对急性髓系白血病NB4细胞株DNA甲基转移酶的影响[J]. 山东大学学报（医学版）, 2015, 53(6): 28-32.
[14] 任洪波, 刘海南, 刘承, 颜克强, 夏传友, 范医东. 肾癌尿沉渣中人端粒酶逆转录酶基因启动子区甲基化检测的临床意义[J]. 山东大学学报（医学版）, 2015, 53(1): 73-76.
[15] 李洪丽，王焱，徐文伟，董琳，郭燕，朱传升，毕可红. K562细胞TMS1基因去甲基化后NF-κB表达的变化[J]. 山东大学学报（医学版）, 2014, 52(4): 62-66.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] 史爽,李娟,米琦,王允山,杜鲁涛,王传新. 胃癌miRNAs预后风险评分模型的构建与应用[J]. 山东大学学报 (医学版), 2020, 1(7): 47 -52 .
[2] 黄飞,王怀经,邢毅,高薇,李永刚,邢子英,李振中. NGF和GM1联合应用对坐骨神经损伤大鼠初级传入神经元的保护作用[J]. 山东大学学报(医学版), 2006, 44(4): 332 -335 .
[3] 姜保东,马祥兴,王青,王茜,冯晓源,李克,于富华 . 脑CT静脉造影扫描时相及重建层厚的选择[J]. 山东大学学报(医学版), 2008, 46(11): 1084 -1086 .
[4] 李洧,李道卫,叶茜,高顺翠,姜淑娟. 经支气管镜针吸活检在纵隔疾病诊断中的价值[J]. 山东大学学报(医学版), 2008, 46(11): 1063 -1065 .
[5] 王旭平,赵玲,冯玉新,商林珊,刘金成,曹伟朋,朱晓音,辛华. 绞股蓝总苷对谷氨酸诱导的胎鼠大脑皮层神经元氧化性损伤保护机制的研究[J]. 山东大学学报(医学版), 2006, 44(6): 564 -567 .
[6] 王学萍,杨洪玲. 洛汀新治疗高血压50例报告[J]. 山东大学学报(医学版), 2007, (2): 213 .
[7] 吕龙飞,李林,李树海,亓磊,鲁铭,程传乐,田辉. 腔镜下细针导管空肠造瘘在微创McKeown食管癌切除术中的应用[J]. 山东大学学报 (医学版), 2020, 1(7): 77 -81 .
[8] 邵海港, 王璇, 王青. 山东地区人下颌第一前磨牙根管系统解剖研究[J]. 山东大学学报（医学版）, 2014, 52(9): 85 -89 .
[9] 黄圣运,张东升,张世周,刘桂军,赵跃然,王来成,刘义庆 . 重组表达载体pIRES-CD、pIRES-TK的构建及其在ACC-2细胞中的表达[J]. 山东大学学报(医学版), 2007, 45(2): 117 -123 .
[10] 唐芳1,2 ，张颖倩3 ，王志强4 ,康殿民4 ,王洁贞1 ,薛付忠1 . 自然疫源性疾病疫源地空间结构的二维
最小生成树模型及其应用
[J]. 山东大学学报(医学版), 2009, 47(01): 106 -110 .
版权所有 © 2018 《山东大学学报(医学版)》编辑部　
地址:山东大学科技期刊社（济南市历城区山大南路27号山东大学中心校区明德楼B座721室） 电话: 0531-88366918 E-mail: xbyxb@sdu.edu.cn
本系统由北京玛格泰克科技发展有限公司设计开发