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

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 IGF2BP3 half-life, which in turn sustains the mRNA level 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 IL-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 reduction in CD8+ T-cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence and tumor infiltrating lymphocytes thus provides a rationale approach for improving immunotherapy in CRC.

ORGANISM(S): Homo Sapiens

SUBMITTER: Hao Gu  

PROVIDER: PXD051359 | iProX | Thu Apr 11 00:00:00 BST 2024

REPOSITORIES: iProX