Exosomal circEIF3K from cancer-associated fibroblast promotes colorectal cancer (CRC) progression via miR-214/PD-L1 axis

Kaihua Yang,Chuanqing Bao,Jie Zhang

doi:10.1186/s12885-021-08669-9

Kaihua Yang, Chuanqing Bao + Show 1 more

Open Access

https://doi.org/10.1186/s12885-021-08669-9

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Abstract

BackgroundTumor microenvironment (e.g., cancer-associated fibroblast) plays a key role in cancer tumorigenesis and metastasis. However, the detailed mechanism of whether hypoxia promotes CRC progression via tumor microenvironment remains unclear.MethodsIn this study, circEIF3K exosome was examined by NanoSight Tracking Analysis and RT-qPCR. We used cell colony formation assay, transwell assay and tube formation assay to determine proliferation, invasion and metastasis of HCT116 or SW620 cells. Xenograft tumor assay was employed to show in vivo tumor growth of HCT116 cells.ResultsWe found that hypoxia could induce secretion of circEIF3K exosome. Conditioned medium (CM) and exosome from circEIF3K knockdown CAF significantly attenuated proliferation, invasion and tube formation of HCT116 or SW620 cells, which could be reverted by miR-214 under hypoxia treatment. Besides, we observed that circEIF3K knockdown evidently impaired tumor growth in mice. TCGA dataset analysis showed that low expression of circEIF3K was observed in normal tissues and associated with prolonged survival time. Finally, PD-L1 was confirmed as important target for miR-214 in CRC.ConclusionIn conclusion, our study reveals that a novel axis circEIF3K/miR-214/PD-L1 mediates hypoxia-induced CRC progression via CAF, providing the rationale for developing new targeted therapeutics to treat CRC.

Highlights

Tumor microenvironment plays a key role in cancer tumorigenesis and metastasis
We hypothesized that hypoxia might contribute to cancer progression via tumor microenvironment
We found that Cancer-associated fibroblast (CAF) could secrete exosomes under hypoxia treatment (Fig. 1A)

Summary

Introduction

Tumor microenvironment (e.g., cancer-associated fibroblast) plays a key role in cancer tumorigenesis and metastasis. The detailed mechanism of whether hypoxia promotes CRC progression via tumor microenvironment remains unclear. Colorectal cancer is the third common tumor type and caused cancer-related mortality [1]. Most of CRC tumor will progress to liver metastasis state [3]. Tumor microenvironment plays a critical role in cancer progression. Hypoxia is a common feature of solid tumors, which circRNA are originally regarded as non-functional junk RNA. Some recent evidences showed that circRNAs are involved in a variety of pathological processes, such as tumors [7, 8]. In CRC, some circRNAs are found to regulate tumor phenotypes. CircCCDC66 regulated miR-3140/autophagy to promote CRC tumorigenesis [5]. CircEIF3K was shown to modulate apoptosis and autophagy in bacterial cells [9]

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