WAVE2与替代型结直肠癌肝转移生长模式的相关性研究

Correlation ofWAVE2 expression with replacement histopathological growth pattern of colorectal liver metastases

背景与目的:结直肠癌肝转移(CLM)存在不同的病理生长模式(HGP),其中替代型HGP(RHGP)与血管选定形成密切相关,直接影响抗血管生成疗法效果,导致不良临床预后。因此,本研究初步探讨HGP的分子病理特征,以期为CLM分子机制研究提供基础。方法:收集2010—2020年中南大学湘雅医院普通外科行手术切除的103例CLM患者临床资料及石蜡标本,其中,58例为促纤维组织增生型HGP(DHGP)、45例为RHGP。根据HGP国际专家共识指南,评估RHGP与CLM患者临床病理因素的相关性。通过免疫组化方法检测WAVE2和CD31的蛋白表达,分析RHGP与血管选定和WAVE2的关系。TIMER2.0数据库分析WAVE2与免疫浸润相关性。KEGG数据库分析WAVE2相互作用分子。结果:HGP与肝转移瘤发生时间和淋巴结转移明显有关(均P<0.05)。DHGP组和RHGP组CD31阳性率分别为27.5%和37.0%,WAVE2蛋白高表达率分别为58.6%和82.2%,差异有统计学意义(P=0.023,P=0.011)。WAVE2表达与B细胞(r=0.258,P=1.41e-07)、CD4+T细胞(r=0.467,P=3.67e-23)、CD8+T细胞(r=0.318,P=5.47e-11)、中性粒细胞(r=0.407,P=2.02e-17)、巨噬细胞(r=0.301,P=6.63e-10)和树突状细胞(r=0.438,P=3.01e-20)免疫浸润明显相关。WAVE2表达与CTTN(r=0.454,P=1.26e-24)、HDAC4(r=0.54,P=5.43e-36)、CYFIP1(r=0.39,P=4.24e-18)、CDC42(r=0.443,P=2.12e-23)、PDGFB(r=0.316,P=4.25e-12)、PRKACA(r=0.363,P=1.05e-15)等下游分子均呈明显正相关。结论:WAVE2表达可能通过促进结直肠癌细胞迁移运动,调节血管选定和肿瘤免疫微环境,参与RHGP的形成。

Background and Aims:Colorectal cancer liver metastases(CLM)have different histopathological growth patterns(HGP),among which replacement HGP(RHGP)is closely associated with vessel cooption,which directly affects the effect of anti-angiogenic therapy and leads to poor prognosis.Therefore,this study was conducted to investigate the molecular pathological features of HGP,so as to provide a basis for the study of the molecular mechanism of CLM.Methods:The clinical data and paraffin-embedded specimens of 103 patients with CLM undergoing surgical resection between 2010 to 2020 in the Department of General Surgery of Xiangya Hospital,Central South University were collected,in which 58 cases were desmoplastic HGP(DHGP)and 45 cases were RHGP.The correlation between RHGP and clinicopathologic factors of CLM patients was assessed based on the international HGP consensus guidelines.The associations of RHGP with vessel cooption and WAVE2 were analyzed through immunohistochemical staining for the protein expressions of WAVE2 and CD31.The correlation between WAVE2 and immune infiltration was analyzed using TIMER2.0 database.WAVE2 interaction signaling molecules were analyzed by KEGG database.Results:HGP was significantly associated with the time to liver metastasis occurrence and lymph metastasis(both P<0.05).The CD31 positive rate was 27.5%and 37.0%in DHGP group and RHGP group,and high WAVE2 expression rate was 58.6%in DHGP group and 82.2%in RHGP group respectively,and the differences had statistical significance(P=0.023,P=0.011).WAVE2 expression was significantly correlated with B cells(r=0.258,P=1.41e-07),CD4+T cells(r=0.467,P=3.67e-23),CD8+T cells(r=0.318,P=5.47e-11),and neutrophils(r=0.407,P=2.02e-17),macrophages(r=0.301,P=6.63e-10)and dendritic cells(r=0.438,P=3.01e-20)immune infiltration.WAVE2 expression was significantly positively associated with CTTN(r=0.454,P=1.26e-24),HDAC4(r=0.54,P=5.43e-36),CYFIP1(r=0.39,P=4.24e-18),CDC42(r=0.443,P=2.12e-23),PDGFB(r=0.316,P=4.25e-12),PRKACA(r=0.363,P=1.05e-15),and other downstream molecules.Conclusion:WAVE2 expression may be involved in the formation of RHGP by promoting the migration of colorectal cancer cells and regulating vessel co-option and tumor immune microenvironment.