甲状腺乳头状癌中VCAN、THBS2蛋白的表达与肿瘤相关成纤维细胞的关系  

Expression of VCAN and THBS2 proteins and their relationship with cancer-associated fibroblasts in papillary thyroid carcinoma

作　　者：武胤彤 方艳 彭薇 汪树静 黄山[1,2] 王弦[1,2] 虞红珍[1,2] 吴强[1,2] Wu Yintong;Fang Yan;Peng Wei;Wang Shujing;Huang Shan;Wang Xian;Yu Hongzhen;Wu Qiang(Department of Pathology,the Second Affiliated Hospital of Anhui Medical University,Hefei 230601,China;Department of Pathology,Anhui Medical University,Hefei 230032,China)

机构地区：[1]安徽医科大学第二附属医院病理科,合肥230601 [2]安徽医科大学基础医学院病理学教研室,合肥230032

出　　处：《临床与实验病理学杂志》2025年第1期60-69,共10页Chinese Journal of Clinical and Experimental Pathology

基　　金：安徽医科大学校科研基金(2021xkj174);安徽医科大学第二附属医院临床研究培育计划(2020LCYB14);安徽省卫生健康科研项目(AHWJ2023A20145)。

摘　　要：目的 探讨甲状腺乳头状癌(papillary thyroid carcinoma, PTC)中多功能蛋白聚糖(versican, VCAN)、血小板反应蛋白2(thrombospondin 2, THBS2)的表达及与肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)的关系和临床病理意义。方法 采用生物信息学技术分析,从基因表达综合数据库(gene expression omnibus, GEO)及癌症基因组图谱(the cancer genome atlas, TCGA)数据库提取PTC单细胞测序数据,利用加权基因共表达网络分析识别CAFs相关基因,并对与CAFs相关的枢纽基因进行富集分析;采用免疫组化EnVision法检测130例PTC组织中VCAN、THBS2和α-SMA的表达,采用Masson染色法评估肿瘤间质纤维化程度。分析它们之间的关系,探讨其临床病理意义。结果 生物信息学分析显示VCAN、THBS2位于GEO数据库和TCGA数据库与CAFs相关性最强模块的交集核心基因中,与CAFs显著相关,富集分析显示VCAN、THBS2主要参与细胞外基质相关通路。PTC中CAFs的增生率为83.1%(108/130),VCAN、THBS2阳性率分别为96.9%(126/130)、75.4%(98/130)。PTC的间质纤维化指数中位数为32.4,四分位距为22.7~50.0。CAFs的高度增生与淋巴结转移(P<0.001)、高TNM分期(P<0.05)呈正相关,并且与PTC的组织学亚型相关。VCAN表达、THBS2表达及PTC间质纤维化程度与淋巴结转移均呈正相关(P<0.001,P<0.05,P<0.001),并且THBS2表达及PTC间质纤维化程度与PTC的组织学亚型相关。肿瘤间质α-SMA阳性细胞百分比与VCAN及THBS2的免疫反应评分(IRS)均呈正相关(r_(s)=0.713,P<0.001;r_(s)=0.646,P<0.001)。PTC中Masson染色面积百分比与肿瘤间质α-SMA阳性细胞百分比、VCAN及THBS2的IRS均呈正相关(r_(s)=0.892,P<0.001;r_(s)=0.729,P<0.001;r_(s)=0.616,P<0.001)。结论 VCAN与THBS2可作为评估PTC侵袭性与淋巴结转移的潜在标志物;VCAN、THBS2与CAFs的密切关系为进一步探究PTC的恶性生物学行为提供了依据。Purpose To investigate the expression of Versican(VCAN)and thrombospondin 2(THBS2)and their relationship with cancer-associated fibroblast(CAFs)and clinicopathological significance in papillary thyroid carcinoma(PTC).Methods Bioinformatics analyses were performed using PTC single-cell sequencing data from the GEO and TCGA database.Weighted correlation network analysis identified CAFs-related genes,and enrichment analysis highlighted pivotal genes associated with CAFs;the expression of VCAN,THBS2,andα-SMA in 130 PTC tissue samples were detected by immunohistochemistry EnVision method.Masson staining evaluated tumor stromal fibrosis.Relationships between these markers,clinicopathological parameters,and CAF proliferation were analyzed.Results Bioinformatics analysis identified VCAN and THBS2 as core genes significantly associated with CAFs,and extracellular matrix-related pathways.The proliferation rate of CAFs in PTC was 83.1%(108/130),with positivity rate of 96.9%(126/130)for VCAN and 75.4%(98/130)for THBS2.The median mesenchymal fibrosis index was 32.4(interquartile range:22.7-50.0).High CAF proliferation correlated positively with lymph node metastasis(P<0.001),higher TNM stage(P<0.05),and specific histologic subtypes of PTC.Similarly,VCAN expression,THBS2 expression,and the degree of PTC stromal fibrosis were positively correlated with lymph node metastasis(P<0.001,P<0.05,and P<0.001,respectively).Both THBS2 expression and the degree of PTC stromal fibrosis correlated with the histologic subtype of PTC.The percentage of tumor mesenchymalα-SMA-positive cells strongly correlated with the immune response score(IRS)of VCAN and THBS2(r s=0.713,P<0.001;r s=0.646,P<0.001).Additionally,the percentage of Masson-stained area was positively correlated with the percentage of tumor mesenchymalα-SMA-positive cells,and the IRS of VCAN and THBS2(r s=0.892,P<0.001;r s=0.729,P<0.001;r s=0.616,P<0.001).Conclusion VCAN and THBS2 serve as potential marke r s for assessing invasiveness and lymph node metastasis of PTC.Their stron

关 键 词：甲状腺肿瘤 甲状腺乳头状癌 肿瘤相关成纤维细胞 VCAN THBS2 

分 类 号：R736.1[医药卫生—肿瘤]