Targeting high circDNA2v levels in colorectal cancer induces cellular senescence and elicits an anti-tumor secretome

• Published in: Cell reports (Cambridge) 2024-04, Vol.43 (4), p.114111, Article 114111
• Main Authors: Wu, Shuang, Dai, Xiangyu, Xia, Yang, Zhao, Qingsong, Zhao, Heng, Shi, Zhimin, Yin, Xin, Liu, Xue, Zhang, Aijie, Yao, Zhihui, Zhang, Hao, Li, Qun, Thorne, Rick Francis, Zhang, Shangxin, Sheng, Weiwei, Hu, Wanglai, Gu, Hao
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cellular Senescence; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Gene Expression Regulation, Neoplastic; Humans; Mice; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA, Circular - genetics; RNA, Circular - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction; STAT1 Transcription Factor - metabolism; Tumor Microenvironment - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114111

The efficacy of immunotherapy against colorectal cancer (CRC) is impaired by insufficient immune cell recruitment into the tumor microenvironment. Our study shows that targeting circDNA2v, a circular RNA commonly overexpressed in CRC, can be exploited to elicit cytotoxic T cell recruitment. circDNA2v functions through binding to IGF2BP3, preventing its ubiquitination, and prolonging the IGF2BP3 half-life, which in turn sustains mRNA levels of the protooncogene c-Myc. Targeting circDNA2v by gene silencing downregulates c-Myc to concordantly induce tumor cell senescence and the release of proinflammatory mediators. Production of CXCL10 and interleukin-9 by CRC cells is elicited through JAK-STAT1 signaling, in turn promoting the chemotactic and cytolytic activities of CD8+ T cells. Clinical evidence associates increased circDNA2v expression in CRC tissues with reductions in CD8+ T cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence, and tumor-infiltrating lymphocytes thus provides a rational approach for improving immunotherapy in CRC. [Display omitted] •circDNA2v prevents IGF2BP3 turnover in CRC cells to stabilize c-Myc mRNA levels•Knockdown of circDNA2v induces high levels of senescence and proinflammatory SASP release•Enhanced CXCL10/IL-9 production by senescent CRC cells results from JAK-STAT signaling•CXCL10 and IL-9 release by senescent CRC cells recruits and activates CD8+ T cells Wu et al. disclose the oncogenic function of circDNA2v in colorectal cancer linked with maintaining c-Myc expression. circDNA2v silencing induces senescence in CRC cells, with the associated proinflammatory cytokine release promoting intratumoral T cell infiltration, proposing that targeting circDNAv2 can reprogram the tumor immune balance and potentially augment immunotherapy approaches.