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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

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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.
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