THAP7-AS1 orchestrates IGF2BP3-m6A-dependent CCN2 mRNA stabilization to promote lymphatic metastasis in bladder
Qiuyan Li1,2, Junjie Bai1,2, Shiwen Zheng3
1Shengli Clinical College of Fujian Medical University Fuzhou 350001, Fujian, P. R. China.
Abstract:
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 m6A reader IGF2BP3 and facilitates IGF2BP3 association with CCN2 mRNA, thereby promoting m6A-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-m6A-CCN2 axis that couples post-transcriptional mRNA stabilization to lymphatic metastasis and nominate THAP7-AS1 as a potential biomarker and therapeutic target in BCa.
Insights
THAP7-AS1, a long noncoding RNA, promotes bladder cancer spread to lymph nodes by stabilizing CCN2 mRNA. This pathway highlights THAP7-AS1 as a potential therapeutic target for muscle-invasive bladder cancer (MIBC).
Area of Science:
- Molecular Biology
- Oncology
- RNA Biology
Background:
- Lymphatic metastasis is a key factor in muscle-invasive bladder cancer (MIBC) treatment failure.
- The specific RNA mechanisms driving lymphatic spread in bladder cancer are not fully understood.
Purpose of the Study:
- To identify novel RNA regulators involved in bladder cancer lymphatic metastasis.
- To elucidate the molecular mechanisms by which THAP7-AS1 influences bladder cancer progression.
Main Methods:
- Identification and characterization of THAP7-AS1 in bladder cancer tissues.
- In vitro assays for cell invasion and transendothelial migration.
- In vivo studies of lymph node metastasis.
- RNA immunoprecipitation and Western blot analyses to investigate molecular interactions.
Main Results:
- THAP7-AS1 is upregulated in lymph node metastatic bladder cancer and linked to poor outcomes.
- THAP7-AS1 enhances bladder cancer cell invasion, migration, and lymph node metastasis.
- THAP7-AS1 interacts with IGF2BP3 to stabilize CCN2 mRNA, increasing CCN2 protein levels.
Conclusions:
- A novel THAP7-AS1-IGF2BP3-m6A-CCN2 pathway promotes lymphatic metastasis in bladder cancer.
- THAP7-AS1 is a potential biomarker and therapeutic target for bladder cancer (BCa).
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