THAP7-AS1 orchestrates IGF2BP3-m(6)A-dependent CCN2 mRNA stabilization to promote lymphatic metastasis in bladder cancer.

Lymphatic dissemination is a major cause of treatment failure in muscle-invasive bladder cancer (MIBC), yet the RNA circuits linking post-transcriptional regulation to lymphatic metastasis remain incompletely defined. Here, we identify THAP7-AS1 as a predominantly cytoplasmic long noncoding RNA that is markedly upregulated in lymph node (LN) metastatic bladder cancer (BCa) and is associated with poor clinical outcome. Functionally, THAP7-AS1 promotes invasion and transendothelial migration in vitro and enhances LN metastasis in vivo. Mechanistically, THAP7-AS1 interacts with the m(6)A reader IGF2BP3 and facilitates IGF2BP3 association with CCN2 mRNA, thereby promoting m(6)A-dependent stabilization of CCN2 transcripts and increasing CCN2 protein abundance. Genetic depletion of IGF2BP3 or CCN2 abrogates THAP7-AS1-driven invasive and metastatic phenotypes, whereas CCN2 re-expression partially rescues the effects of THAP7-AS1 silencing. Collectively, these findings define a THAP7-AS1-IGF2BP3-m(6)A-CCN2 axis that couples post-transcriptional mRNA stabilization to lymphatic metastasis and nominate THAP7-AS1 as a potential biomarker and therapeutic target in BCa.