Hypoxia-induced ZEB1 promotes cervical cancer progression via CCL8-dependent tumour-associated macrophage recruitment

Abstract

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.

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…The effect of chronic hypoxia on CCL3/MIP-1α and CCL4/MIP-1β expression in a tumor cell depends on the type of tumor. In the cultured cervical squamous carcinoma cells [46], hepatocellular carcinoma [143,193] and lung adenocarcinoma [13], CCL3/MIP-1α expression is not elevated. However, in the breast tumor cells lines MDA-435S and MCF-7, chronic hypoxia increases the expression CCL3/MIP-1α [203].…”

“…Chronic hypoxia has been reported to decrease the expression of this chemokine in glioma cells [154,155], HUVEC [156], monocytes and macrophages [144,157,158], and in uveal melanoma [159]. In contrast, it has also been reported to increase in breast cancer cells [142], cervical squamous carcinoma cells [46], hepatoma cells [160], in another study on HUVEC [161], dermal fibroblasts [162], Lewis lung carcinoma cells [163,164], multiple myeloma [165], primary mouse astrocytes [166], and vascular endothelial cells [167,168]. These discrepancies are associated with the complex regulation of expression of this chemokine in hypoxia.…”

“…HIF-1 is directly responsible for increasing ZEB1 expression due to the presence of the HRE sequence in the ZEB1 gene promoter [186,187]. This increase in CCL8/MCP-2 expression in cervical squamous carcinoma cells increases the recruitment of TAM to the hypoxic tumor niche [46].…”

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…A tumor is not a homogenous environment and consists of areas with different properties. The most significant is the area affected by chronic hypoxia [ 9 ], characterized by the accumulation of tumor-associated macrophages (TAM) [ 10 , 11 , 12 , 13 ], regulatory T cells (T reg ) [ 14 , 15 , 16 ], and myeloid-derived suppressor cells (MDSC) [ 17 , 18 ]. The functions of these recruited pro-cancer cells in this microenvironment are enhanced by chronic hypoxia [ 11 , 19 , 20 , 21 ] and cancer acidification [ 22 ], which increases the resistance of cancer cells to anticancer therapy and the action of the immune system [ 20 , 22 , 23 , 24 ].…”

Combined Snail and E-cadherin Predicts Overall Survival of Cervical Carcinoma Patients: Comparison Among Various Epithelial-Mesenchymal Transition Proteins

“…Intra-tumoural hypoxia is commonly found in carcinoma, and hypoxia-induced proteome changes promote cervical carcinoma cell invasion and migration by participating in tumor necrosis factor (TGF)-β1-induced EMT (Wilson and Hay, 2011). Hypoxia can enhance ZEB1 expression and promote cervical carcinoma progression through increased CCL8 secretion and tumorassociated macrophage recruitment (Chen et al, 2019). Other EMT inducers include the inflammatory-based cytokines [i.e., interleukin (IL)-6, TNF-α, TGF-β].…”