Tumor exosome promotes Th17 cell differentiation by transmitting the lncRNA CRNDE-h in colorectal cancer

Junfeng Sun,Tianyu Zhu,Haowei Jia,Xingqi Bao,Yue Wu,Ruixin Li,Hongchao Zhao

doi:10.1038/s41419-020-03376-y

Junfeng Sun, Tianyu Zhu + Show 5 more

Open Access

https://doi.org/10.1038/s41419-020-03376-y

Copy DOI

Abstract

The T helper 17 (Th17) cells in tumor microenvironment play an important role in colorectal cancer (CRC) progression. This study investigated the mechanism of Th17 cell differentiation in CRC with a focus on the role of tumor exosome-transmitted long noncoding RNA (lncRNA). Exosomes were isolated from the CRC cells and serum of CRC patients. The role and mechanism of the lncRNA CRNDE-h transmitted by CRC exosomes in Th17 cell differentiation were assessed by using various molecular biological methods. The serum exosomal CRNDE-h level was positively correlated with the proportion of Th17 cells in the tumor-infiltrating T cells in CRC patients. CRC exosomes contained abundant CRNDE-h and transmitted them to CD4+ T cells to increase the Th17 cell proportion, RORγt expression, and IL-17 promoter activity. The underlying mechanism is that, CRNDE-h bound to the PPXY motif of RORγt and impeded the ubiquitination and degradation of RORγt by inhibiting its binding with the E3 ubiquitin ligase Itch. The in vivo experiments confirmed that the targeted silence of CRNDE-h in CD4+ T cells attenuated the CRC tumor growth in mice. The present findings demonstrated that the tumor exosome transmitted CRNDE-h promoted Th17 cell differentiation by inhibiting the Itch-mediated ubiquitination and degradation of RORγt in CRC, expanding our understanding of Th17 cell differentiation in CRC.

Highlights

Colorectal cancer (CRC) is the most common cancer in the digestive system and is the second leading cause of cancer-related death; with a mortality rate of 8%-9%1,2
We innovatively demonstrated that colorectal cancer (CRC) exosomes transmit Colorectal neoplasia differentially expressed (CRNDE)-h to CD4+ T cells to promote T helper 17 (Th17) cell differentiation
We found that the CRC exosomes promoted the differentiation of CD4+ T cells into Th17 cells

Summary

Introduction

Colorectal cancer (CRC) is the most common cancer in the digestive system and is the second leading cause of cancer-related death; with a mortality rate of 8%-9%1,2. CRC development and progression are correlated with diverse factors, and many studies have shown that tumor immune microenvironment is closely correlated with the development and progression of CRC3,4. The increased proportion of T helper 17 (Th17), a subset of T cells derived from CD4+ T cells, in a tumor immune microenvironment have been reported to be associated with the occurrence and development of malignant tumors[5,6,7]. Studies have shown that a large number of differentiated and mature Th17 cells are accumulated in colorectal tissues of patients with CRC, which can. It has been found that tumor-derived exosomes can alter a tumor microenvironment via their involvement in angiogenesis and in the regulation of matrix cells, and remodeling of extracellular matrix[15].

Methods

Results

Conclusion