Wang Qi, Li Dandan, Ma Haixiu, Li Zengyan, Wu Juan, Qiao Jinwan, Liu Jun, Zhao Jing, Ma Ronghua, Tian Lin, Zhang Lei, Yang Jianye, Wang Jianing, Qin Shanshan, Su Zhanhai
Research Center for High-Altitude Medicine, Key Laboratory of High-Altitude Medicine, Ministry of Education, Laboratory for High Altitude Medicine of Qinghai Province, Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High-Altitude Medicine), Qinghai University, Xining, China.
Department of Pathology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Cell Death Dis. 2025 Feb 27;16(1):143. doi: 10.1038/s41419-025-07464-9.
The role of epithelial membrane protein 1 (EMP1) in tumor microenvironment (TME) remodeling has not yet been elucidated. In addition, the biological function of EMP1 in triple-negative breast cancer (TNBC) is largely unclear. In this study, we examined the infiltration landscape of cell types in the TME of breast cancer, and found that EMP1 expression was positively correlated with stromal and microenvironmental scores. Infiltration analysis and immunohistochemical (IHC) staining of serial sections confirmed the critical role of EMP1 in cancer-associated fibroblast (CAF) infiltration. Cell co-culture assays, xenograft tumor experiments, loss-of-function, gain-of-function, RNA sequencing studies, and rescue assays were performed to confirm the role of EMP1 in CAF infiltration in vitro and in vivo. These findings revealed that EMP1 depletion in TNBC cells resulted in considerable inhibition of CAF infiltration in vivo and in vitro. Mechanistically, EMP1 knockdown induced a substantial decrease in IL6 secretion from TNBC through the NF-κB signaling pathway, hindering CAF proliferation and subsequently inhibiting TNBC progression and metastasis. These cumulative results indicate that EMP1 functions as an oncogene in TNBC by mediating the cell communication of TNBC and CAFs. Targeted inhibition of EMP1 by suppressing CAF infiltration is a promising strategy for TNBC treatment.
上皮膜蛋白1（EMP1）在肿瘤微环境（TME）重塑中的作用尚未阐明。此外，EMP1在三阴性乳腺癌（TNBC）中的生物学功能在很大程度上尚不清楚。在本研究中，我们研究了乳腺癌TME中细胞类型的浸润情况，发现EMP1表达与基质和微环境评分呈正相关。连续切片的浸润分析和免疫组织化学（IHC）染色证实了EMP1在癌症相关成纤维细胞（CAF）浸润中的关键作用。进行了细胞共培养试验、异种移植肿瘤实验、功能丧失、功能获得、RNA测序研究和挽救试验，以证实EMP1在体外和体内CAF浸润中的作用。这些发现表明，TNBC细胞中EMP1的缺失导致体内和体外CAF浸润受到显著抑制。从机制上讲，EMP1基因敲低通过NF-κB信号通路导致TNBC分泌的IL6大幅减少，阻碍CAF增殖，进而抑制TNBC的进展和转移。这些累积结果表明，EMP1通过介导TNBC与CAF之间的细胞通讯在TNBC中发挥癌基因作用。通过抑制CAF浸润来靶向抑制EMP1是一种有前景的TNBC治疗策略。
