Zhu Qin, Zhang Kejing, Cao Yukun, Hu Yu
Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Cancer Cell Int. 2024 Nov 20;24(1):385. doi: 10.1186/s12935-024-03557-1.
Triple-negative breast cancer (TNBC) is characterized by high invasiveness and metastasis potential. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is strongly associated with breast cancer progression, although the underlying mechanisms are largely unknown.
The gene expression profiles of TNBC samples were downloaded from the TCGA database, and ubiquitination enzymes related to immune regulation were screened. UCHL1 expression in the TNBC tissues and in adipose-derived mesenchymal stem cells (ADSCs) stimulated in vitro with pro-inflammatory cytokines were analyzed. Exosomes were isolated from these stimulated ADSCs and transfected with scrambled (si-NC) or UCHL1-specific (si-UCHL1) siRNA constructs. TNBC cells were treated with the ADSCs-derived exosomes (ADSCs-Exos) and then co-cultured with macrophages or T cells. Finally, the tumorigenic potential of the ADSCs-Exos was evaluated by injecting the exosomes into mice bearing TNBC xenografts.
UCHL1 was highly expressed in TNBC tissues and the stimulated ADSCs. The exosomes derived from stimulated ADSCs increased the viability and migration capacity of TNBC cells in vitro, and significantly increased Ki-67 expression through UCHL1. Furthermore, ADSCs-Exos induced M2 polarization of THP-1 monocytes by upregulating CD206 and Arg-1, and downregulating TNF-α and iNOS, and also decreased the proportion of CD3CD8 T cells. Mechanistically, UCHL1 regulated the STAT3 and PD-L1 signaling pathways through HDAC6. Exosomes derived from the control and cytokine-stimulated ADSCs also promoted tumor growth in vivo, and increased the expression of UCHL1, CD206, HDAC6, STAT3, and PD-L1. However, UCHL1 knockdown reversed the pro-tumorigenic effects of the ADSCs-derived exosomes in vivo and in vitro.
Pro-inflammatory factors (IFN-γ + TNF-α) stimulating ADSCs-Exos enhance immune evasion in triple-negative breast cancer by regulating the HDAC6/STAT3/PD-L1 pathway via UCHL1 transporter. Thus, UCHL1 inhibition may enhance the response of TNBC to immunotherapy.
三阴性乳腺癌（TNBC）具有高侵袭性和转移潜能。泛素羧基末端水解酶L1（UCHL1）与乳腺癌进展密切相关，但其潜在机制大多未知。
从TCGA数据库下载TNBC样本的基因表达谱，并筛选与免疫调节相关的泛素化酶。分析TNBC组织以及体外经促炎细胞因子刺激的脂肪来源间充质干细胞（ADSCs）中UCHL1的表达。从这些受刺激的ADSCs中分离外泌体，并用乱序（si-NC）或UCHL1特异性（si-UCHL1）siRNA构建体进行转染。用ADSCs来源的外泌体（ADSCs-Exos）处理TNBC细胞，然后与巨噬细胞或T细胞共培养。最后，通过将外泌体注射到携带TNBC异种移植瘤的小鼠体内，评估ADSCs-Exos的致瘤潜能。
UCHL1在TNBC组织和受刺激的ADSCs中高表达。受刺激的ADSCs来源的外泌体在体外增加了TNBC细胞的活力和迁移能力，并通过UCHL1显著增加了Ki-67的表达。此外，ADSCs-Exos通过上调CD206和精氨酸酶-1，下调肿瘤坏死因子-α（TNF-α）和诱导型一氧化氮合酶（iNOS），诱导THP-1单核细胞向M2极化，同时也降低了CD3+CD8+T细胞的比例。机制上，UCHL1通过组蛋白去乙酰化酶6（HDAC6）调节信号转导和转录激活因子3（STAT3）和程序性死亡受体配体1（PD-L1）信号通路。对照和细胞因子刺激的ADSCs来源的外泌体在体内也促进肿瘤生长，并增加UCHL1、CD206、HDAC6、STAT3和PD-L1的表达。然而，UCHL1基因敲低逆转了ADSCs来源的外泌体在体内和体外的促肿瘤作用。
促炎因子（γ干扰素 + TNF-α）刺激的ADSCs-Exos通过UCHL1转运体调节HDAC6/STAT3/PD-L1通路，增强三阴性乳腺癌的免疫逃逸。因此，抑制UCHL1可能增强TNBC对免疫治疗的反应。
