2. Academic Validation
  3. Targeting high circDNA2v levels in colorectal cancer induces cellular senescence and elicits an anti-tumor secretome

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

  • Cell Rep. 2024 Apr 23;43(4):114111. doi: 10.1016/j.celrep.2024.114111.
Shuang Wu 1,  Xiangyu Dai 1,  Yang Xia 1,  Qingsong Zhao 1,  Heng Zhao 1,  Zhimin Shi 1,  Xin Yin 1,  Xue Liu 1,  Aijie Zhang 1,  Zhihui Yao 2,  Hao Zhang 3,  Qun Li 1,  Rick Francis Thorne 2,  Shangxin Zhang 3,  Weiwei Sheng 4,  Wanglai Hu 5,  Hao Gu 6
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
  • 2 Translational Research Institute, People's Hospital of Zhengzhou University, Academy of Medical Science, Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450003, China.
  • 3 Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
  • 4 Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: 2024700012@ahmu.edu.cn.
  • 5 Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Translational Research Institute, People's Hospital of Zhengzhou University, Academy of Medical Science, Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450003, China. Electronic address: wanglaihu@ahmu.edu.cn.
  • 6 Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China. Electronic address: guhao@ahmu.edu.cn.
PMID: 38615319 DOI: 10.1016/j.celrep.2024.114111
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.

Keywords

CP: Cancer.

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