总蛋白苏木化修饰与男性甲状腺乳头状癌的初步探究

doi:10.16139/j.1007-9610.2024.04.11

摘要/Abstract

摘要：

目的：探究蛋白质苏木化修饰水平(SUMOylation)与男性甲状腺乳头状癌（papillary thyroid carcinoma, PTC）预后的关系。方法：首先通过数据库与生物信息学分析，后续收集本地男性PTC病人手术切除的癌和癌旁组织配对样本，免疫组织化学(immunohistochemistry, IHC)、蛋白质印迹（Western blotting, WB）检测样本中蛋白质的苏木化水平，利用实时荧光定量聚合酶链反应(quantitative real-time polymerase chain reaction, qRT-PCR)检测样本中苏木化修饰相关因子的mRNA表达水平，比较癌组织与癌旁组织中蛋白质苏木化水平以及苏木化通路关键因子的mRNA表达水平，研究苏木化修饰与男性PTC的关系。结果：TCGA与GTEx数据库分析发现蛋白质苏木化水平在PTC的癌组织中呈现升高趋势（P<0.05），并与病人不良预后相关（P=0.021）。本院临床样本中验证了癌组织蛋白苏木化修饰水平高于对应的癌旁组织（P<0.05）；但是qRT-PCR显示苏木化通路中大部分因子的转录水平无明显变化。结论：PTC组织中蛋白质苏木化水平高于癌旁组织，癌组织中蛋白质苏木化水平越高，则病人生存时间越短。

关键词: 苏木化修饰, 男性, 甲状腺乳头状癌

Abstract:

Objective To investigate the relationship between protein SUMOylation level and the prognosis of papillary thyroid carcinoma(PTC) in males. Methods Protein SUMOylation levels in PTC was analyzed by bioinformatics based on GTEx and TCGA databases and validated by immunohistochemical staining and Western blotting in our clinical pairs specimens. The mRNA expression of the protein SUMOylation associated genes were measured by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR) in surgical pairs specimens. Results The expression level of SUMOylation in the tumor tissues of PTC showed an elevated trend（P<0.05）, and was associated with poor prognosis of the patients by TCGA and GTEx databases analysis(P=0.021）. In the clinical samples of our hospital, it was verified that the level of SUMOylation in tumor tissues was higher than that of the paired non-tumor tissues（P<0.05）. However, qRT-PCR showed no significant changes in the transcriptional level of the protein SUMOylation associated genes in most cases. Conclusions Protein SUMOylation in thyroid tumor tissues were higher than that in paired non-tumor tissues, and the higher SUMOylation levels levels in tumor tissues were, the shorter overall survival time of the patients was.

Key words: SUMOylation, Males, Papillary thyroid carcinoma (PTC)

中图分类号:

R736.1

吴巧, 刘威, 郑佼皎, 王聪, 艾志龙. 总蛋白苏木化修饰与男性甲状腺乳头状癌的初步探究[J]. 外科理论与实践, 2024, 29(04): 336-344.

WU Qiao, LIU Wei, ZHENG Jiaojiao, WANG Cong, AI Zhilong. Correlationship between total proteins SUMOylation and papillary thyroid carcinoma in males[J]. Journal of Surgery Concepts & Practice, 2024, 29(04): 336-344.

图/表 7

表1

图1

表2

图2

图3

表3

图4

参考文献 19

[1]	田文. 甲状腺癌诊治之中国经验与未来走向[J]. 临床外科杂志, 2020, 28(3):201-204.
	TIAN W. Chinese experience and future trends in the diagnosis and treatment of thyroid cancer[J]. J Clin Surg, 2020, 28(3):201-204.
[2]	田文, 郗洪庆. 分化型甲状腺癌外科诊疗进展及展望[J]. 中国实用外科杂志, 2020, 40(1):78-82.
	TIAN W, XI H Q. Progress and prospects of surgical diagnosis and treatment of differentiated thyroid cancer[J]. Chin J Pract Surg, 2020, 40(1):78-82.
[3]	LI M, DAL MASO L, VACCARELLA S. Global trends in thyroid cancer incidence and the impact of overdiagnosis[J]. Lancet Diabetes Endocrinol, 2020, 8(6):468-470.
[4]	MAMMEN J S R, CAPPOLA A R. Autoimmune thyroid disease in women[J]. JAMA, 2021, 325(23):2392-2393. doi: 10.1001/jama.2020.22196 pmid: 33938930
[5]	LUNDGREN C I, HALL P, DICKMAN P W, et al. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study[J]. Cancer, 2006, 106(3):524-531. doi: 10.1002/cncr.21653 pmid: 16369995
[6]	HAN Z J, FENG Y H, GU B H, et al. The post-translational modification, SUMOylation, and cancer (Review)[J]. Int J Oncol, 2018, 52(4):1081-1094.
[7]	BECARES N, GAGE M C, PINEDA-TORRA I. Posttranslational modifications of lipid-activated nuclear receptors: focus on metabolism[J]. Endocrinology, 2017, 158(2):213-225. doi: 10.1210/en.2016-1577 pmid: 27925773
[8]	SEELER J S, DEJEAN A. SUMO and the robustness of cancer[J]. Nat Rev Cancer, 2017, 17(3):184-197.
[9]	CUI W, SUN M, ZHANG S, et al. A SUMO-acetyl switch in PXR biology[J]. Biochim Biophys Acta, 2016, 1859(9):1170-1182. doi: S1874-9399(16)30030-X pmid: 26883953
[10]	DE CRISTOFARO T, MASCIA A, PAPPALARDO A, et al. Pax8 protein stability is controlled by sumoylation[J]. J Mol Endocrinol, 2009, 42(1):35-46. doi: 10.1677/JME-08-0100 pmid: 18974227
[11]	FLOTHO A, MELCHIOR F. Sumoylation: a regulatory protein modification in health and disease[J]. Annu Rev Biochem, 2013,82:357-385.
[12]	DAVIES L, WELCH H G. Current thyroid cancer trends in the United States[J]. JAMA Otolaryngol Head Neck Surg, 2014, 140(4):317-322.
[13]	Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma[J]. Cell, 2014, 159(3):676-690. doi: 10.1016/j.cell.2014.09.050 pmid: 25417114
[14]	MONGELLI M N, GIRI S, PEIPERT B J, et al. Financial burden and quality of life among thyroid cancer survivors[J]. Surgery, 2020, 167(3):631-637.
[15]	AL-QURAYSHI Z, FARAG M, SHAMA M A, et al. Total thyroidectomy versus lobectomy in small nodules suspicious for papillary thyroid cancer: cost-effectiveness analysis[J]. Laryngoscope, 2020, 130(12):2922-2926.
[16]	DE ANDRADE J P, LORENZEN A W, WU V T, et al. Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer[J]. Oncotarget, 2017, 8(70):114801-114815.
[17]	KESSLER J D, KAHLE K T, SUN T, et al. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis[J]. Science, 2012, 335(6066):348-353. doi: 10.1126/science.1212728 pmid: 22157079
[18]	BIEDERSTÄDT A, HASSAN Z, SCHNEEWEIS C, et al. SUMO pathway inhibition targets an aggressive pancreatic cancer subtype[J]. Gut, 2020, 69(8):1472-1482. doi: 10.1136/gutjnl-2018-317856 pmid: 32001555
[19]	GÂTEL P, PIECHACZYK M, BOSSIS G. Ubiquitin, SUMO, and Nedd8 as therapeutic targets in cancer[J]. Adv Exp Med Biol, 2020,1233:29-54.

Item	1	2	3	4	5	6
Age	27	36	56	42	30	41
The maximum focal diameter (cm)	0.7	1.1	1.2	0.8	2.0	1.5
Lymph node metastasis	Yes	Yes	Yes	No	Yes	Yes
Neoplasm staging	T1N1M0	T3N1M0	T1N1M0	T1N0M0	T1N1M0	T1N1M0

SUMO1 expresstion level	Female (n=76)	Male (n=24)	Total (n=100)
High	39 （51.32）	19 （79.17）	58 （58.00）
Medium	10 （13.16）	3 （12.50）	13 （13.00）
Low	27 （35.52）	2 （8.33）	29 （29.00）

Item	Female	Male	Subtotal	Total	Rank sum test
No.	H (39)	H(19)	H(58)	100
	M(10)	M(3)	M(13)	F(76)
	L(27)	L(2)	L(29)	M(24)
The maximum focal diameter(cm)	H(1.79±1.50)	H(1.35±0.83)	H(1.76±1.47)	1.46±0.96	H vs. M&L, P<0.01
	M(1.25±0.72)	M(1.07±0.48)	M(1.21±0.68)	F(1.51±1.16)
	L(1.19±0.64)	L(0.95±0.46)	L(1.19±0.75)	M(1.28±0.76)
The mean lesion No.	H(1.79±0.51)	H(1.74±0.50)	H(1.77±0.56)	1.75±0.96	ns
	M(2.00±1.00)	M(1.33±0.72)	M(1.84±0.83)	F(1.79±0.86)
	L(1.70±0.70)	L(1.00±0)	L(1.65±0.65)	M(1.63±0.46)
Membrane immersion	H(61.53%/24)	H(68.42%/13)	H(63.79%/37)	53.00%/53	H vs. M&L，P=0.012
	M(50.00%/5)	M(33.33%/1)	M(46.15%/6)	F(51.32%/39)
	L(37.03%/10)	L(0)	L(34.48%/10)	M(58.33%/14)
Peripheral tissue invasion	H(28.20%/11)	H(15.79%/3)	H(24.14%/14)	19.00%/19	ns
	M(20.00%/2)	M(0)	M(15.38%/2)	F(21.05%/16)
	L(11.11%/3)	L(0)	L(10.34%/3)	M(12.50%/3)
Cevical lymph node metastasis	H(64.10%/25)	H(42.11%/8)	H(56.90%/33)	50.00%/50	ns
	M(30.00%/3)	M(33.33%/1)	M(30.77%/4)	F(53.95%/41)
	L(48.15%/13)	L(0)	L(44.83%/13)	M(37.50%/9)