摘要
目的:研究巨噬细胞相关信号因子C-X-C趋化因子受体4型(CXCR4)、Krüppel样因子4(KLF4)以及分化簇38(CD38)在肝细胞癌(HCC)中的表达及对预后的预测价值。方法:选取2015年5月至2020年10月收治的HCC患者90例,术中采集肿瘤组织及癌旁正常组织。采用免疫蛋白印记法检测CXCR4、KLF4、CD38在HCC组织及癌旁正常组织中的表达水平,分析CXCR4、KLF4、CD38表达水平与HCC临床病理特征的关系。随访3年,计算HCC患者总生存期,比较死亡组与存活组CXCR4、KLF4、CD38表达水平,采用受试者工作特征(ROC)曲线分析CXCR4、KLF4、CD38对HCC预后的预测价值,采用Cox回归模型进行HCC预后单因素和多因素分析。通过免疫组织化学染色分析CD38、CD8^(+)、CD56^(+)、CD4^(+)表达,分析HCC样本中CD38表达与免疫细胞浸润的关系。结果:与癌旁正常组织比较,HCC组织CXCR4蛋白表达量明显升高,KLF4、CD38蛋白表达量显著降低(P<0.01)。TNM分期Ⅲ期、发生淋巴结转移、肿瘤低分化者CXCR4蛋白表达量显著高于TNM分期Ⅰ^(+)Ⅱ期、未发生淋巴结转移、肿瘤中高分化者(P<0.05),TNM分期Ⅲ期、发生淋巴结转移、肿瘤低分化者KLF4、CD38蛋白表达量显著低于TNM分期Ⅰ^(+)Ⅱ期、未发生淋巴结转移、肿瘤中高分化者(P<0.05)。90例HCC患者随访3年期间失访8例,最终获得随访者82例。死亡组患者CXCR4蛋白表达量显著高于存活组(P<0.05),KLF4、CD38蛋白表达量显著低于存活组(P<0.05)。绘制ROC曲线发现,CXCR4、KLF4、CD38单独或联合预测HCC预后的曲线下面积(AUC)95%CI分别为0.718(0.545~0.890)、0.757(0.630~0.885)、0.723(0.545~0.901)、0.802(0.689~0.915),联合预测的效能显著优于单项检测(P<0.05)。淋巴结转移、TNM分期、肿瘤分化水平低、CXCR4表达升高、KLF4、CD38表达降低与HCC有较强的相关性(P<0.05)。CD38的表达可能与HCC肿瘤微环境(TME)的免疫浸润有关,表现为CD38的高表达增加调节性T细胞(Tregs)的比例,减少CD8^(+)T细胞和自然杀伤细胞的浸润。结论:HCC患者肿瘤组织中CXCR4高表达,KLF4、CD38低表达,其表达水平与淋巴结转移、肿瘤分化程度、TNM分期及3年总生存率相关,三者联合检测有助于预测HCC预后。CD38是HCC中TME预测的潜在生物标志物。
Objective:An investigation was conducted to determine whether macrophage-related factors C-X-C chemokine receptor type 4(CXCR4),Krüppel-like factor 4(KLF4)and cluster of differentiation 38(CD38)were associated with a better prognosis in hepatocellular carcinoma(HCC).Methods:A total of 90 patients with hepatocellular carcinoma(HCC)treated at our hospital from May 2015 to October 2020 were selected.Tumor tissues and adjacent normal tissues were collected during surgery.The expression levels of CXCR4,KLF4,and CD38 in HCC tissues and adjacent normal tissues were detected by Western blotting.The relationship between the expression levels of CXCR4,KLF4,and CD38 and the clinical pathological characteristics of HCC was analyzed.The patients were followed up for 3 years to calculate overall survival,and the expression levels of CXCR4,KLF4,and CD38 were compared between the deceased and surviving groups.The prognostic value of CXCR4,KLF4,and CD38 for HCC was evaluated using receiver operating characteristic(ROC)curve analysis.Univariate and multivariate Cox regression analyses were conducted to assess HCC prognosis.Immunohistochemical staining was used to analyze the expression of CD38,CD8^(+),CD56^(+),and CD4^(+)and to investigate the relationship between CD38 expression and immune cell infiltration in HCC samples.Results:In comparison to para-cancer normal tissues,the expression levels of CXCR4 and CD38 were found to be significantly elevated in HCC tissues(P<0.01),while the expression levels of KLF4 and CD38 were significantly reduced(P<0.01).Furthermore,the study found that CXCR4 protein levels were significantly higher in patients with TNM stagesⅢ,lymph node metastases,and low tumor differentiation when compared to those with TNM stagesⅠ^(+)Ⅱ,no lymph node metastases,and high tumor differentiation(P<0.05).Additionally,lower expression levels of KLF4 and CD38 proteins were observed in patients with TNM stageⅢ,lymph node metastasis,and low tumor differentiation compared to patients with TNM stageⅠ^(+)Ⅱ,no lymph node metastasis,and moderate to high tumor differentiation(P<0.05).A total of eight cases of HCC out of 90 originally included in the study were lost to follow-up,resulting in 82 patients for the 3-year follow-up.Significant differences in the expression levels of CXCR4,KLF4,and CD38 proteins were observed between the groups of patients who survived and those who did not(P<0.05).AUC values for CXCR4,KLF4,and CD38 alone or in conjunction with HCC were 0.718(0.545-0.890),0.757(0.630-0.885),0.723(0.545-0.901),0.802(0.689-0.915),respectively.The combined prediction model showed significantly higher efficiency compared to individual protein detection(P<0.05).The results of Cox regression analysis indicated that lymph node metastasis,TNM stageⅢ,low tumor differentiation,elevated CXCR4 expression,and decreased KLF4 and CD38 expression were statistically significant prognostic risk factors for HCC at a significance level of P<0.05.Furthermore,the expression of CD38 may be associated with immune invasion within the HCC tumor microenvironment(TME),as evidenced by the correlation between high CD38 expression and increased regulatory T cell(Treg)abundance,as well as decreased invasion of CD8^(+)T cells and natural killer cells.Conclusion:It has been demonstrated that CXCR4,KLF4,and CD38 expression levels in tumor tissues of individuals diagnosed with HCC exhibit significant correlations with lymph node metastases,tumor differentiation,and TNM stage.The integration of these markers in prognostic evaluation may enhance the ability to predict outcomes in HCC patients.Additionally,CD38 shows promise as a potential biomarker for predicting the TME in HCC.
作者
杨新顺
任伟强
侯凤霞
董志强
何从容
王军委
张蓓
YANG Xin-shun;REN Wei-qiang;HOU Feng-xia(The Second Department of Vascular Intervention,Handan Central Hospital(Handan Hebei,056000),China)
出处
《中西医结合肝病杂志》
2025年第12期1528-1533,共6页
Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases
基金
河北省医学科学研究重点课题计划项目(No.20181679)。
关键词
肝细胞癌
趋化因子4受体
Krüppel样因子4
肿瘤微环境
分化簇38
预后
hepatocellular carcinoma
C-X-C chemokine receptor type 4
krüppel-like factor 4
tumor microenvironment
cluster of differentiation 38
prognosis
