Exosomal lncRNA SNHG10 derived from colorectal cancer cells suppresses natural killer cell cytotoxicity by upregulating INHBC

Cancer Cell International

Yiwen Huang¹  Yanbo Luo²  Yuqi Luo²  Dong Dong³  Wentao Ou³  Xiaowen Peng⁴  Yuanyuan Wang⁵ 

[1] Department of Emergency, Nansha Hospital, Guangzhou First People’s Hospital, School of Medicine, Southern China University of Technology, Guangzhou, Guangdong, China;Department of Gastrointestinal and Hepatobiliary Surgery, Shenzhen Longhua District Central Hospital, No. 187, Guanlan Road, Longhua District, 518110, Shenzhen, Guangdong Province, China;Department of General Surgery, Nansha Hospital, Guangzhou First People’s Hospital, School of Medicine, Southern China University of Technology, Guangzhou, Guangdong, China;Department of Laboratory Medicine, Guangzhou First People’s Hospital, School of Medicine, Nansha Hospital, Southern China University of Technology, Guangzhou, Guangdong, China;Department of Neurology, Nansha Hospital, Guangzhou First People’s Hospital, School of Medicine, Southern China University of Technology, Guangzhou, Guangdong, China;

关键词: Colorectal cancer;    Exosomal lncRNA;    Epithelial–mesenchymal transition;    Immune escape;    Natural killer cells;   

DOI  :  10.1186/s12935-021-02221-2

来源: Springer

【 摘 要 】

BackgroundExosome-mediated crosstalk between cancer cells and immune cells contributes to tumor growth. In this study, we investigated the mechanism underlying the exosome-mediated immune escape of colorectal cancer (CRC) cells from natural killer (NK) cells via the transfer of long noncoding RNAs (lncRNAs).MethodsAn epithelial–mesenchymal transition (EMT) model of SW480 cells was established by transforming growth factor beta (TGF-β), followed by the assessment of the effect of EMT-derived exosomes (EMT-exo) on the functions of NK cells. RNA sequencing was performed to identify exosomal lncRNAs and target genes. The function of exosomal lncRNAs in tumor growth was further verified in vivo.ResultsEMT-exo suppressed the proliferation, cytotoxicity, IFN-γ production, and perforin-1 and granzyme B secretion of NK cells. RNA sequencing revealed that SNHG10 expression was upregulated in EMT-exo compared with that in non-EMT-exo. Moreover, SNHG10 expression was upregulated in tumor tissues in CRC, which was associated with poor prognosis. Overexpression of SNHG10 in exosomes (oe-lnc-SNHG10 exo) significantly suppressed the viability and cytotoxicity of NK cells. Transcriptome sequencing of NK cells revealed that the expression levels of 114 genes were upregulated in the oe-lnc-SNHG10 exo group, including inhibin subunit beta C (INHBC), which was involved in the TGF-β signaling pathway. Si-INHBC treatment abrogated the effect of oe-lnc-SNHG10 exo on NK cells. oe-lnc-SNHG10 exo induced tumor growth and upregulated INHBC expression in mice and downregulated the expression of perforin, granzyme B, and NK1.1 in tumor tissues.ConclusionsThe CRC cell-derived exosomal lncRNA SNHG10 suppresses the function of NK cells by upregulating INHBC expression. This study provides evidence that exosomal lncRNAs contribute to immune escape by inducing NK cell inhibition and proposes a potential treatment strategy for CRC.

【 授权许可】

CC BY