Hypoxia-induced ZEB1 promotes cervical cancer progression via CCL8-dependent tumour-associated macrophage recruitment
Hypoxia-induced ZEB1 promotes cervical cancer progression via CCL8-dependent tumour-associated macrophage recruitment
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缺氧诱导的ZEB1通过CCL8依赖性肿瘤相关巨噬细胞募集促进宫颈癌进展
DOI：
10.1038/s41419-019-1748-1
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发表时间：
2019-07-01
影响因子：
9
通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Chen, Xiao-Jing;Deng, Yuan-Run;Wang, Wei
肿瘤相关巨噬细胞（tam）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，低氧TME促进TAM浸润的机制尚不完全清楚。本研究表明，低氧宫颈癌细胞胰岛ZEB1高表达与CD163+TAM积累呈正相关。ZEB1在缺氧癌细胞中促进了TAMs的体外迁移，并改变了多种趋化因子的表达，尤其是CCL8。机制上，缺氧诱导的ZEB1激活了CCL8的转录，CCL8通过CCR2-NF -κB途径吸引巨噬细胞。此外，基于The cancer Genome Atlas （TCGA）数据分析，ZEB1和CCL8是宫颈癌患者的独立预后因素。综上所述，缺氧诱导的ZEB1通过增加CCL8分泌和TAM募集来促进前转移环境，从而在癌症进展中发挥意想不到的功能；因此，ZEB1可能作为肿瘤进展的候选生物标志物，并提供破坏缺氧介导的TME重塑的潜在靶点。
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.