CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling

Qian Zhong,Qiuhua Lai,Aimin Li,Yuxin Fang,Qun Yan,Side Liu,Chengcheng He,Shanci Wang

doi:10.1186/s13046-020-01637-4

Abstract

BackgroundCrosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC.MethodsThe expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice.ResultsDecreased CPEB3 expression in CRC was associated with fewer CD86+ TAMs and more CD163+ TAMs. CPEB3 knockdown in CRC cells increased the number of CD163+ TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163+ TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo.ConclusionsCPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

Highlights

Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC)
Decreased Cytoplasmic polyadenylation element binding protein 3 (CPEB3) in human CRC correlates with low CD86+ TAM content and high CD163+ TAM content
To evaluate how CPEB3 in CRC cells may inhibit M2like TAM polarization, we first assessed the expression of CPEB3, CD86 and CD163 in 82 pairs of CRC tissues and adjacent non-cancer tissues using qRT-PCR

Summary

Introduction

Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). CRC cells recruit vasculature and stroma (including immune cells, fibroblasts, cytokines, and the extracellular matrix that surrounds them) to the tumor microenvironment (TME); an activated TME, in turn, modifies the malignant behaviors of cancer cells [4]. M2 macrophages with a high expression of CD163 or CD206 play a key role in the antiinflammatory response, wound healing, and protumorigenic properties [11, 12]. It has been proven to play an important role in the immune regulation, the inflammatory response, and the epithelial-mesenchymal transition (EMT) of tumor cells [17, 18]. The crosstalk between tumor cells and TAMs is a key step during tumor progression

Methods

Results

Conclusion