Targeting high circDNA2v levels in colorectal cancer induces cellular senescence and elicits an anti-tumor secretome
Shuang Wu, Xiangyu Dai, Yang Xia, Qingsong Zhao, Zhao Heng, Zhimin Shi, Xin Yin, Xue Liu, Aijie Zhang, Zhihui Yao, Hao Zhang, Qun Li, Rick F. Thorne, Shangxin Zhang, Weiwei Sheng, Wanglai Hu, Hao Gu
Abstract
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.