THAP7-AS1 orchestrates IGF2BP3-m6A-dependent CCN2 mRNA stabilization to promote lymphatic metastasis in bladder cancer
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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