Correlation between adipokine and clinicopathological features and prognosis in upper tract urothelial carcinoma
Received date: 2022-03-14
Online published: 2022-08-11
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。
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 . DOI: 10.19723/j.issn.1671-167X.2022.04.005
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
| 1 | Siegel RL , Miller KD , Jemal A . Cancer statistics, 2019[J]. CA Cancer J Clin, 2019, 69 (1): 7- 34. |
| 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. |
| 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. |
| 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. |
| 6 | Hebbard L , Ranscht B . Multifaceted roles of adiponectin in cancer[J]. Best Pract Res Clin Endocrinol Metab, 2014, 28 (1): 59- 69. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 , Malmh?ll C , Tliba O , et al. Adiponectin/adipoR1 axis promotes IL-10 release by human regulatory T cells[J]. Front Immunol, 2021, 12, 677550. |
/
| 〈 |
|
〉 |