The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis

Area of Science:

• Molecular Oncology
• RNA Biology
• Cancer Genomics

Background:

• Noncoding RNAs can produce microproteins with oncogenic potential.
• The role of microproteins in alternative splicing-driven tumor progression is largely unexplored.

Purpose of the Study:

• To investigate the function and mechanism of the microprotein TPM3P9 in clear cell renal cell carcinoma (ccRCC).
• To explore TPM3P9's role in alternative splicing and its clinical significance in ccRCC.

Main Methods:

• Identified TPM3P9 as a microprotein encoded by the lncRNA tropomyosin 3 pseudogene 9.
• Investigated TPM3P9's interaction with splicing factor RBM4 and its effect on TCF7L2 splicing.
• Analyzed TPM3P9 expression in ccRCC tissues and correlated it with clinical outcomes.

Main Results:

• TPM3P9 overexpression promotes ccRCC cell proliferation and tumor growth.
• TPM3P9 inhibits RBM4-mediated exon skipping in TCF7L2, increasing the oncogenic TCF7L2-L variant.
• TPM3P9 upregulates the NF-κB signaling pathway component RELB.
• TPM3P9 expression correlates with TCF7L2-L and RELB levels and predicts poor patient survival.

Conclusions:

• The noncoding RNA-derived microprotein TPM3P9 is oncogenic in ccRCC by modulating RNA splicing.
• TPM3P9, RBM4, TCF7L2-L, and RELB represent potential prognostic and therapeutic targets for renal cancer.