Yuan Jia-Qi, Zhang Ke-Jing, Wang Shou-Man, Guo Lei
Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.
Gland Surg. 2021 Sep;10(9):2799-2814. doi: 10.21037/gs-21-612.
To evaluate the association of potential YAP1/MMP7/CXCL16 axis and tumor infiltrating lymphocytes (TILs) related chemo-response in triple-negative breast cancer (TNBC) patients.
We estimated the messenger RNA (mRNA) expression levels of Yes-associated protein 1 (YAP1), MMP7, and CXCL16 in paired TNBC tumor/para-tumor tissues by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and performed statistical analysis according to neoadjuvant chemotherapy (NAC) response. Based on The Cancer Genome Atlas (TCGA) data, we noticed outstanding expression of MMP7/CXCL16 in TNBC cases, as well as associations between MMP7/CXCL16 and HIPPO-YAP1-relevant kinases. We also performed gene set enrichment analysis (GSEA) between MMP7/CXCL16 and YAP1-associated pathways. Western blotting assay was employed to evaluate YAP1/MMP7/CXCL16 expression and their modulation sequence. Logistic model stepwise regression analysis was used to assess YAP1, MMP7, CXCL16, and TILs as therapeutic predictors. Residual cancer burden (RCB) score was calculated and statistically analyzed according to intensity of these variables, and receiver operating characteristic (ROC) curve also showed their predictive value in NAC response. Recruitment efficacy for CD4+/CD8+ TIL cells (TCGA data) as well as quantified TIL cells density were both explored according to YAP1, MMP7, and CXCL16 expression level.
Up-regulation of YAP1/MMP7 and down-regulation of CXCL16 were both significant in TNBC cases with poor NAC response. Inhibition of YAP1 induced down-regulation of MMP7 and up-regulation of CXCL16, whereas inhibition of MMP7 also induced up-regulation of CXCL16. It was also shown that MMP7/CXCL16 was enriched in the YAP1-related pathway. Activation of the YAP1/MMP7/CXCL16 axis obviously affected RCB of TNBC cases. The ROC curve also supported the predictive value of YAP1/MMP7/CXCL16 axis and TILs density in NAC response prospect. The density of TILs, meanwhile, demonstrated a strong link with the YAP1/MMP7/CXCL16 axis. Over expression of YAP1/MMP7 significantly suppressed recruitment of CD4+/CD8+ TILs, while CXCL16 over expression had a beneficial impact on anti-tumor immune.
Over expression of causes up-regulation of MMP7 and down-regulation of CXCL16, which suppressed CD4+/CD8+ TILs recruitment and indirectly affected NAC response of TNBC patients.
评估三阴性乳腺癌（TNBC）患者中潜在的YAP1/MMP7/CXCL16轴与肿瘤浸润淋巴细胞（TILs）相关化疗反应之间的关联。
我们通过定量实时逆转录聚合酶链反应（qRT-PCR）估计配对的TNBC肿瘤/癌旁组织中Yes相关蛋白1（YAP1）、MMP7和CXCL16的信使核糖核酸（mRNA）表达水平，并根据新辅助化疗（NAC）反应进行统计分析。基于癌症基因组图谱（TCGA）数据，我们注意到TNBC病例中MMP7/CXCL16的显著表达，以及MMP7/CXCL16与HIPPO-YAP1相关激酶之间的关联。我们还对MMP7/CXCL16与YAP1相关通路进行了基因集富集分析（GSEA）。采用蛋白质免疫印迹法评估YAP1/MMP7/CXCL16表达及其调控序列。采用逻辑模型逐步回归分析评估YAP1、MMP7、CXCL16和TILs作为治疗预测指标。根据这些变量的强度计算并统计分析残余癌负担（RCB）评分，受试者工作特征（ROC）曲线也显示了它们在NAC反应中的预测价值。根据YAP1、MMP7和CXCL16表达水平，探索CD4+/CD8+TIL细胞的募集效率（TCGA数据）以及定量的TIL细胞密度。
在NAC反应较差的TNBC病例中，YAP1/MMP7上调和CXCL16下调均显著。抑制YAP1导致MMP7下调和CXCL16上调，而抑制MMP7也导致CXCL16上调。还显示MMP7/CXCL16在YAP1相关通路中富集。YAP1/MMP7/CXCL16轴的激活明显影响TNBC病例的RCB。ROC曲线也支持YAP1/MMP7/CXCL16轴和TILs密度在NAC反应前景中的预测价值。同时，TILs密度与YAP1/MMP7/CXCL16轴显示出密切联系。YAP1/MMP7的过表达显著抑制CD4+/CD8+TILs的募集，而CXCL16的过表达对抗肿瘤免疫有有益影响。
YAP1的过表达导致MMP7上调和CXCL16下调，抑制CD4+/CD8+TILs募集并间接影响TNBC患者的NAC反应。
