Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 510120, Guangzhou, China.
Cell Death Dis. 2019 Jul 1;10(7):508. doi: 10.1038/s41419-019-1748-1.
The accumulation of tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is associated with malignant progression in cancer. However, the mechanisms by which the hypoxic TME facilitates TAM infiltration are not fully understood. This study showed that high ZEB1 expression in hypoxic cervical cancer cell islets was positively correlated with CD163 TAM accumulation. ZEB1 in hypoxic cancer cells promoted the migration of TAMs in vitro and altered the expression of multiple chemokines, especially CCL8. Mechanistically, hypoxia-induced ZEB1 activated the transcription of CCL8, which attracted macrophages via the CCR2-NF-κB pathway. Furthermore, ZEB1 and CCL8 were independent prognostic factors in cervical cancer patients based on The Cancer Genome Atlas (TCGA) data analysis. In conclusion, hypoxia-induced ZEB1 exerts unexpected functions in cancer progression by fostering a prometastatic environment through increased CCL8 secretion and TAM recruitment; thus, ZEB1 may serve as a candidate biomarker of tumour progression and provide a potential target for disrupting hypoxia-mediated TME remodelling.
肿瘤相关巨噬细胞（TAMs）在缺氧肿瘤微环境（TME）中的积累与癌症的恶性进展有关。然而，缺氧 TME 促进 TAM 浸润的机制尚不完全清楚。本研究表明，缺氧宫颈癌细胞岛中高表达的 ZEB1 与 CD163 TAM 积累呈正相关。缺氧癌细胞中的 ZEB1 促进了 TAMs 的体外迁移，并改变了多种趋化因子的表达，特别是 CCL8。在机制上，缺氧诱导的 ZEB1 激活了 CCL8 的转录，通过 CCR2-NF-κB 通路吸引巨噬细胞。此外，基于癌症基因组图谱（TCGA）数据分析，ZEB1 和 CCL8 是宫颈癌患者的独立预后因素。总之，缺氧诱导的 ZEB1 通过增加 CCL8 分泌和 TAM 募集来促进促转移环境，从而在癌症进展中发挥意想不到的作用；因此，ZEB1 可能成为肿瘤进展的候选生物标志物，并为破坏缺氧介导的 TME 重塑提供潜在的靶点。
