LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5

Area of Science:

• Oncology
• Molecular Biology
• Gene Regulation

Background:

• Lemur tyrosine kinase-3 (LMTK3) is implicated in the progression of various cancers, including breast, lung, gastric, and colorectal cancers.
• MicroRNAs (miRNAs) are key regulators of gene expression and play critical roles in tumorigenesis by typically inhibiting target genes post-transcriptionally.

Purpose of the Study:

• To investigate the role of LMTK3 in regulating miRNA expression.
• To elucidate the mechanism by which LMTK3 influences miRNA biogenesis and its impact on cancer cells.

Main Methods:

• miRNA expression profiling to identify miRNAs modulated by LMTK3.
• Co-immunoprecipitation assays to study the interaction between LMTK3 and DEAD-box RNA helicase p68 (DDX5).
• Analysis of miRNA binding to LMTK3 mRNA 3'UTR and its effect on gene expression in breast cancer cell lines.

Main Results:

• LMTK3 was found to induce the levels of miR-34a, miR-196-a2, and miR-182 by interacting with DDX5 and binding to pri-miRNAs, sequestering them from processing.
• Ectopic expression of miR-34a and miR-182 significantly inhibited proliferation, invasion, and migration in LMTK3-overexpressing breast cancer cells.
• miR-34a and miR-182 were shown to directly bind to the 3'UTR of LMTK3 mRNA, reducing its stability and translation, thus acting as tumor suppressors.

Conclusions:

• LMTK3 modulates miRNA biogenesis by interacting with the Microprocessor complex, leading to the induction of specific miRNAs.
• These induced miRNAs, including miR-34a and miR-182, exert tumor suppressor functions by targeting LMTK3 itself, establishing a negative feedback loop.