上尿路尿路上皮癌组织中脂肪因子表达与临床病理特征及预后的相关性

doi:10.19723/j.issn.1671-167X.2022.04.005

摘要/Abstract

摘要：

目的: 基于生物信息数据分析及免疫组织化学染色，探究上尿路尿路上皮癌(upper tract urothelial carcinoma，UTUC)患者脂肪因子表达水平与临床病理特征及预后的相关性。方法: 纳入研究的脂肪因子包括脂联素(adiponectin，AdipoQ)、瘦素(leptin，LEP)、白细胞介素(interleukin, IL)-6、IL-10及各脂肪因子的受体(AdipoR1、AdipoR2、LEPR、IL-6R、IL-10RA、IL-10RB)。选取2014年1月至2021年4月在北京大学人民医院接受手术治疗的UTUC患者组织标本进行免疫组织化学染色，使用H-Score评估表达水平，同时回顾性收集患者临床数据并进行随访。从基因表达数据库(Gene Expression Omnibus database，GEO)GSE134292数据集中下载UTUC患者“转录组测序”数据进行对比。采用t检验比较非肌层浸润肿瘤与肌层浸润性肿瘤组间脂肪因子表达水平的差异，采用Cox回归分析和Kaplan-Meier生存曲线分析两队列中患者预后指标的独立预测因素，双侧P < 0.05为差异有统计学意义。结果: 共选取UTUC患者的组织切片63例，免疫组织化学染色结果表明AdipoQ(P=0.003 6)、AdipoR1(P=0.006 5)、LEP(P=0.007 7)、IL-10(P=0.006 9)、IL-10RA(P=0.008 9)在肌层浸润性肿瘤中呈高表达。同时纳入了GSE134292数据集中的57例UTUC患者，AdipoR1(P=0.000 4)、AdipoR2(P=0.000 4)、IL-6(P=0.005 0)、IL-10(P=0.001 7)、IL-10RA(P=0.008 1)在肌层浸润性肿瘤中呈高表达。生存曲线及多因素分析结果显示，IL-10RA高表达是无膀胱复发生存的独立保护因素(P=0.044，HR=0.996，95%CI：0.992~0.998)，GSE134292队列数据也同样验证了这一点(P=0.014，HR=0.515，95%CI：0.304~0.873)。结论: AdipoQ、AdipoR1、IL-10及IL-10RA在肌层浸润性肿瘤中呈高表达，表明AdipoQ和IL-10及其受体参与肿瘤进展过程。IL-10RA高表达是UTUC患者术后无膀胱复发生存的保护性因素，预示其在肿瘤复发中发挥重要作用。

关键词: 上尿路尿路上皮癌, 脂肪因子, 免疫组织化学

Abstract:

Objective: To investigate the correlation between expression levels of adipokine and clinicopathological features and prognosis of patients with upper tract urothelial carcinoma (UTUC) based on immunohistochemical staining and bioinformatics analysis. Methods: The 8 adipokines in this study included adiponectin (AdipoQ), leptin (LEP), interleukin (IL)-6, IL-10 and their receptors (AdipoR1, AdipoR2, LEPR, IL-6R, IL-10RA, IL-10RB). Tissue samples of patients with UTUC who underwent surgical treatment in Peking University People's Hospital from January 2014 to April 2021 were selected for immunohistochemical staining. Their quantitative gene expression data were calculated by H-Score, and relevant clinical and follow-up data were collected retrospectively. Transcription group sequencing data of UTUC patients in Gene Expression Omnibus database (GSE134292 dataset) were downloaded for comparison. Chi-square test or t-test was used to compare the expression level of adipokine between non-muscle invasive group and muscle invasive group. Univariate and multivariate Cox regression analysis and Kaplan-Meier survival curve were utilized to analyze independent predictors of overall survival (OS), disease-free survival (DFS), intravesical recurrence-free survival (IVRFS) in the both cohorts. The P < 0.05 was considered statistically significant. Results: In the study, 63 tissue samples of the patients with UTUC who underwent surgical treatment in Peking University People's Hospital and 57 UTUC patients in GSE134292 dataset were selected. In immunohistochemical cohort, the expressions of AdipoQ (P=0.003 6), AdipoR1 (P=0.006 5), LEP (P=0.007 7), IL-10 (P=0.006 9), and IL-10RA (P=0.008 9) were statistically higher in muscle invasive group. In GSE134292 cohort, the expressions of AdipoR1 (P=0.000 4), AdipoR2 (P=0.000 4), IL-6 (P=0.005 0), IL-10 (P=0.001 7), and IL-10RA (P=0.008 1) were statistically higher in muscle invasive group. Kaplan-Meier survival curve and multivariate Cox regression analysis showed that high IL-10RA expression was an independent predictive factor of IVRFS (P=0.044, HR=0.996, 95%CI: 0.992-0.998) in immunohistochemical cohort, which was confirmed in GSE134292 cohort (P=0.014, HR=0.515, 95%CI: 0.304-0.873). Conclusion: The expression levels of AdipoQ, AdipoR1, IL-10, and IL-10RA were correlated with tumor stage, suggesting that these adipokines played important roles in tumor progression. IL-10RA was an independent predictor of IVRFS, suggesting that IL-10 and its receptor played a critical role in tumor recurrence.

Key words: Upper tract urothelial carcinoma, Adipokine, Immunohistochemical

中图分类号:

R737.1

戴翔,王飞,杜依青,宋宇轩,徐涛. 上尿路尿路上皮癌组织中脂肪因子表达与临床病理特征及预后的相关性[J]. 北京大学学报（医学版）, 2022, 54(4): 605-614.

Xiang DAI,Fei WANG,Yi-qing DU,Yu-xuan SONG,Tao XU. Correlation between adipokine and clinicopathological features and prognosis in upper tract urothelial carcinoma[J]. Journal of Peking University (Health Sciences), 2022, 54(4): 605-614.

图/表 7

图1

表1

图2

图3

表2

免疫组织化学队列中单因素和多因素Cox分析"

Items	OS
	Univariate			Multivariate
	P	HR	95%CI	P	HR	95%CI
Age	0.239	2.264	0.581-8.821
Gender	0.847	1.133	0.320-4.018
T stage	0.046	6.669	1.020-54.223
Grade	0.427	2.324	0.291-18.579
Tumor diameter	0.813	0.871	0.278-2.734
Multifocality	0.614	0.670	0.141-3.176
AdipoQ	0.542	0.996	0.985-1.008
AdipoR1	0.342	1.008	0.992-1.024
AdipoR2	0.968	1.000	0.985-1.015
LEP	0.371	0.994	0.982-1.007
IL-6	0.960	0.999	0.977-1.023
IL-6R	0.900	1.001	0.988-1.014
IL-10	0.309	0.986	0.961-1.013
IL-10RA	0.585	1.003	0.993-1.012

Items	DFS
	Univariate			Multivariate
	P	HR	95%CI	P	HR	95%CI
Age	0.063	2.002	0.962-4.167	0.623	1.251	0.512-3.055
Gender	0.265	0.642	0.295-1.398
T stage	0.001	11.048	3.794-32.174	0.001	13.962	3.159-61.710
Grade	0.055	3.237	0.976-10.735	0.453	0.547	0.113-2.647
Tumor diameter	0.034	2.271	1.065-4.842	0.305	1.507	0.688-3.297
Multifocality	0.855	1.079	0.477-2.442
AdipoQ	0.363	1.003	0.997-1.009
AdipoR1	0.044	1.009	1.000-1.017	0.921	1.001	0.989-1.013
AdipoR2	0.477	1.004	0.994-1.014
LEP	0.223	1.004	0.998-1.010
IL-6	0.135	1.009	0.997-1.020
IL-6R	0.879	1.001	0.993-1.009
IL-10	0.194	1.008	0.996-1.020
IL-10RA	0.073	0.996	0.991-1.000	0.538	1.002	0.996-1.008

Items	IVRFS
	Univariate			Multivariate
	P	HR	95%CI	P	HR	95%CI
Age	0.084	1.038	0.995-1.082	0.586	1.277	0.529-3.083
Gender	0.258	0.622	0.273-1.415
T stage	0.001	45.300	6.093-336.812	0.001	14.418	3.292-63.149
Grade	0.043	4.451	1.048-18.898	0.453	0.545	0.112-2.655
Tumor diameter	0.009	3.054	1.319-7.069	0.307	1.504	0.688-3.288
Multifocality	0.554	1.287	0.558-2.964
AdipoQ	0.154	1.005	0.998-1.011
AdipoR1	0.056	1.009	1.000-1.018	0.975	1.000	0.989-1.010
AdipoR2	0.422	1.004	0.994-1.015
LEP	0.115	1.005	0.999-1.011
IL-6	0.283	1.007	0.995-1.019
IL-6R	0.945	1.000	0.991-1.008
IL-10	0.098	1.010	0.998-1.022	0.863	1.002	0.998-1.004
IL-10RA	0.017	0.994	0.989-0.999	0.044	0.996	0.992-0.998

表2

表3

图4

参考文献 24

1	Siegel RL , Miller KD , Jemal A . Cancer statistics, 2019[J]. CA Cancer J Clin, 2019, 69 (1): 7- 34. doi: 10.3322/caac.21551
2	黄健. 中国泌尿外科和男科疾病诊断治疗指南(2019版)[M]. 北京: 科学出版社, 2019.
3	Rouprêt M , Babjuk M , Burger M , et al. European Association of Urology Guidelines on upper urinary tract urothelial carcinoma: 2020 Update[J]. Eur Urol, 2021, 79 (1): 62- 79. doi: 10.1016/j.eururo.2020.05.042
4	Polito R , Nigro E , Fei L , et al. Adiponectin is inversely associa-ted with tumour grade in colorectal cancer patients[J]. Anticancer Res, 2020, 40 (7): 3751- 3757. doi: 10.21873/anticanres.14364
5	Di Zazzo E , Polito R , Bartollino S , et al. Adiponectin as link factor between adipose tissue and cancer[J]. Int J Mol Sci, 2019, 20 (4): 839. doi: 10.3390/ijms20040839
6	Hebbard L , Ranscht B . Multifaceted roles of adiponectin in cancer[J]. Best Pract Res Clin Endocrinol Metab, 2014, 28 (1): 59- 69. doi: 10.1016/j.beem.2013.11.005
7	Perrier S , Jardé T . Adiponectin, an anti-carcinogenic hormone? A systematic review on breast, colorectal, liver and prostate cancer[J]. Curr Med Chem, 2012, 19 (32): 5501- 5512. doi: 10.2174/092986712803833137
8	Kashiwagi E , Abe T , Kinoshita F , et al. The role of adipocytokines and their receptors in bladder cancer: Expression of adiponectin or leptin is an independent prognosticator[J]. Am J Transl Res, 2020, 12 (6): 3033- 3045.
9	Park EJ , Lee JH , Yu GY , et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression[J]. Cell, 2010, 140 (2): 197- 208. doi: 10.1016/j.cell.2009.12.052
10	Mannino MH , Zhu Z , Xiao H , et al. The paradoxical role of IL-10 in immunity and cancer[J]. Cancer Letters, 2015, 367 (2): 103- 107. doi: 10.1016/j.canlet.2015.07.009
11	Sato T , Terai M , Tamura Y , et al. Interleukin 10 in the tumor microenvironment: A target for anticancer immunotherapy[J]. Immunol Res, 2011, 51 (2/3): 170- 182.
12	Lippitz BE , Harris RA . Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis[J]. Oncoimmunology, 2016, 5 (5): e1093722. doi: 10.1080/2162402X.2015.1093722
13	Lee YC , Wu WJ , Lin HH , et al. Prognostic value of leptin receptor overexpression in upper tract urothelial carcinomas in Taiwan[J]. Clin Genitourin Cancer, 2017, 15 (4): e653- e659. doi: 10.1016/j.clgc.2017.01.002
14	Holland WL , Miller RA , Wang ZV , et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin[J]. Nat Med, 2011, 17 (1): 55- 63. doi: 10.1038/nm.2277
15	Hebbard LW , Garlatti M , Young LJ , et al. T-cadherin supports angiogenesis and adiponectin association with the vasculature in a mouse mammary tumor model[J]. Cancer Res, 2008, 68 (5): 1407- 1416. doi: 10.1158/0008-5472.CAN-07-2953
16	Sun LY , Li XJ , Sun YM , et al. LncRNA ANRIL regulates AML development through modulating the glucose metabolism pathway of AdipoR1/AMPK/SIRT1[J]. Mol Cancer, 2018, 17 (1): 127. doi: 10.1186/s12943-018-0879-9
17	Chou SH , Tseleni-Balafouta S , Moon HS , et al. Adiponectin receptor expression in human malignant tissues[J]. Horm Cancer, 2010, 1 (3): 136- 145. doi: 10.1007/s12672-010-0017-7
18	Hsu TI , Wang YC , Hung CY , et al. Positive feedback regulation between IL10 and EGFR promotes lung cancer formation[J]. Oncotarget, 2016, 7 (15): 20840- 20854. doi: 10.18632/oncotarget.7894
19	Qian Q , Wu C , Chen J , et al. Relationship between IL10 and PD-L1 in liver hepatocellular carcinoma tissue and cell lines[J]. Biomed Res Int, 2020, 2020, 8910183.
20	Satyam A , Singh P , Badjatia N , et al. A disproportion of TH1/TH2 cytokines with predominance of TH2, in urothelial carcinoma of bladder[J]. Urol Oncol, 2011, 29 (1): 58- 65. doi: 10.1016/j.urolonc.2009.06.002
21	Agrawal U , Kumari N , Mishra AK , et al. Immune signature of urothelial cancer associated with grade, recurrence, and invasion[J]. Urol Oncol, 2016, 34 (9): 418.
22	Cai T , Mazzoli S , Meacci F , et al. Interleukin-6/10 ratio as a prognostic marker of recurrence in patients with intermediate risk urothelial bladder carcinoma[J]. J Urol, 2007, 178 (5): 1906- 1912. doi: 10.1016/j.juro.2007.07.041
23	Rabinovich A , Medina L , Piura B , et al. Expression of IL-10 in human normal and cancerous ovarian tissues and cells[J]. Eur Cytokine Netw, 2010, 21 (2): 122- 128.
24	Ramos-Ramírez P , Malmhäll C , Tliba O , et al. Adiponectin/adipoR1 axis promotes IL-10 release by human regulatory T cells[J]. Front Immunol, 2021, 12, 677550. doi: 10.3389/fimmu.2021.677550

Metrics

Viewed

Full text

Abstract

Cited

Shared

Discussed

Items		IHC cohort	GSE134292 cohort	P value
Number		63	57
Age/years		68.25±9.26	68.58±10.45	0.858
Gender	Male	38 (60.3)	37 (64.9)	0.607
	Female	25 (39.7)	20 (35.1)
T stage	T_a-T₁	35 (55.6)	26 (45.6)	0.281
	T₂-T₄	28 (44.4)	31 (54.4)
Grade	Low-grade	15 (23.8)	12 (21.1)	0.721
	High-grade	48 (76.2)	45 (78.9)

Items	OS
	Univariate			Multivariate
	P	HR	95%CI	P	HR	95%CI
Age	0.723	1.008	0.966-1.052
Gender	0.830	1.108	0.434-2.829
T stage	0.004	6.108	1.766-21.119	0.043	4.330	1.047-17.905
Grade	0.222	27.340	0.134-5559.469
Tumor location	0.614	1.329	0.440-4.016
AdipoQ	0.450	1.905	0.358-10.137
AdipoR1	0.025	2.077	1.096-3.935	0.713	1.276	0.348-4.681
AdipoR2	0.011	1.950	1.169-3.253	0.915	1.066	0.330-3.449
LEP	0.522	1.338	0.548-3.267
IL-6	0.014	1.359	1.065-1.734	0.417	1.203	0.770-1.878
IL-6R	0.995	0.999	0.632-1.577
IL-10	0.545	1.390	0.479-4.032
IL-10RA	0.036	1.420	1.023-1.971	0.649	0.889	0.535-1.477

Items	DFS
	Univariate			Multivariate
	P	HR	95%CI	P	HR	95%CI
Age	0.435	0.990	0.964-1.016
Gender	0.408	1.299	0.700-2.411
T stage	0.059	1.814	0.979-3.360	0.189	1.555	0.805-3.005
Grade	0.169	1.720	0.795-3.721
Tumor location	0.124	1.873	0.841-4.168
AdipoQ	0.667	1.341	0.352-5.101
AdipoR1	0.077	1.499	0.957-2.350	0.345	1.264	0.777-2.056
AdipoR2	0.126	1.355	0.918-2.000
LEP	0.086	1.652	0.932-2.928	0.318	1.384	0.731-2.622
IL-6	0.659	1.044	0.864-1.261
IL-6R	0.619	1.070	0.820-1.396
IL-10	0.311	1.529	0.672-3.475
IL-10RA	0.315	1.157	0.871-1.539

Items	IVRFS
	Univariate			Multivariate
	P	HR	95%CI	P	HR	95%CI
Age	0.133	0.977	0.948-1.007
Gender	0.829	1.085	0.516-2.283
T stage	0.536	0.797	0.388-1.638
Grade	0.870	0.934	0.414-2.109
Tumor location	0.015	3.049	1.245-7.464	0.046	2.491	1.014-6.115
AdipoQ	0.239	0.026	0.001-11.313
AdipoR1	0.935	1.019	0.646-1.607
AdipoR2	0.490	0.847	0.529-1.357
LEP	0.317	0.499	0.128-1.947
IL-6	0.119	0.795	0.595-1.061
IL-6R	0.137	0.751	0.515-1.095
IL-10	0.067	0.279	0.071-1.093	0.720	1.397	0.225-8.694
IL-10RA	0.008	0.496	0.294-0.836	0.014	0.515	0.304-0.873

[1]	沈棋,刘亿骁,何群. 肾黏液样小管状和梭形细胞癌的临床病理特点及预后[J]. 北京大学学报（医学版）, 2023, 55(2): 276-282.
[2]	李东,邸吉廷,熊焰. 程序性细胞死亡1-配体1在不同免疫组织化学染色方法的一致性比较[J]. 北京大学学报（医学版）, 2023, 55(2): 339-342.
[3]	张崔建,何志嵩,周利群. 上尿路尿路上皮癌的淋巴清扫[J]. 北京大学学报（医学版）, 2022, 54(4): 592-594.
[4]	李志华,徐纯如,刘颖,贯华,张萌,车新艳,唐琦,黄燕波,李学松,周利群. 饮水习惯与上尿路尿路上皮癌病理特征的相关性分析[J]. 北京大学学报（医学版）, 2022, 54(4): 621-627.
[5]	于妍斐,何世明,吴宇财,熊盛炜,沈棋,李妍妍,杨风,何群,李学松. 延胡索酸水合酶缺陷型肾细胞癌的临床病理特征及预后[J]. 北京大学学报（医学版）, 2021, 53(4): 640-646.
[6]	邱敏,费月阳,邓绍晖,刘承,卢剑,何为,陆敏,田晓军,张树栋,马潞林. 后肾腺瘤的诊治经验及文献回顾[J]. 北京大学学报（医学版）, 2021, 53(2): 417-419.
[7]	池彦廷,张延平,张秋露,刘翠苓,李斌斌. 唾液腺干燥综合征继发黏膜相关淋巴组织淋巴瘤的临床病理分析[J]. 北京大学学报（医学版）, 2021, 53(1): 40-45.
[8]	马茹,李鑫宝,闫风彩,林育林,李雁. 肿瘤间质比评估阑尾来源腹膜假黏液瘤的临床价值[J]. 北京大学学报（医学版）, 2020, 52(2): 240-246.
[9]	张晓鹏,张维宇,霍飞,胡浩,王起,许克新. 原发性女性膀胱出口梗阻的手术疗效随访及其发病机制[J]. 北京大学学报（医学版）, 2019, 51(6): 1052-1055.
[10]	关豹,翁迈,凡航,彭鼎,方冬,熊耕砚,李学松,周利群. 术前贫血对上尿路尿路上皮癌预后的影响: 单中心686例患者回顾性研究[J]. 北京大学学报（医学版）, 2019, 51(6): 1056-1061.
[11]	马闰卓,夏海缀,陆敏,张智荧,张启鸣,卢剑,王国良,马潞林. 输尿管镜活体组织检查对上尿路尿路上皮癌根治性手术的影响[J]. 北京大学学报（医学版）, 2019, 51(4): 665-672.
[12]	张春凤,刘云,陆敏,杜晓娟. hUTP14a在非小细胞肺癌组织中的表达[J]. 北京大学学报（医学版）, 2019, 51(1): 145-150.
[13]	刘蕾,王丽华,任玉波,饶晓松,杨邵敏. 盆腹腔软组织侵袭性血管黏液瘤临床病理分析[J]. 北京大学学报（医学版）, 2018, 50(6): 1098-1101.
[14]	梅放，赵婷婷，高菲，郑杰. 肺罕见良性双相分化性肿瘤——肺腺纤维瘤1例并文献复习[J]. 北京大学学报(医学版), 2017, 49(6): 1076-1080.
[15]	刘畅, 崔立刚, 王宏磊. 肾尤文氏肉瘤/原始神经外胚层肿瘤: 1例报道并文献复习[J]. 北京大学学报(医学版), 2017, 49(5): 919-923.