An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2

Area of Science:

• Molecular Biology
• Genetics
• Oncology

Background:

• MicroRNAs (miRNAs) are known to regulate gene expression, primarily through targeting messenger RNAs (mRNAs).
• The role of animal miRNAs targeting coding sequences (CDSs) in disease pathophysiology is largely unexplored.
• Adult-type granulosa cell tumors (AGCTs) are a type of ovarian cancer often associated with specific genetic mutations.

Purpose of the Study:

• To investigate the pathophysiological significance of microRNA targeting of coding sequences.
• To elucidate the molecular mechanism by which a FOXL2 mutation contributes to AGCT development.
• To identify the specific microRNA and protein complex involved in regulating the mutated FOXL2.

Main Methods:

• Analysis of a specific somatic heterozygous missense mutation (c.402C>G; p.C134W) in the FOXL2 gene.
• Investigation of the interaction between the mutated FOXL2 mRNA and miR-1236.
• Identification of the RNA-induced silencing complex (miRISC) components, including Argonaute3 (AGO3) and DHX9.
• Correlation analysis of variant FOXL2 and miR-1236 levels with AGCT malignancy in patients and a mouse model.

Main Results:

• The FOXL2 mutation creates a target site for miR-1236, leading to selective degradation of the variant FOXL2 mRNA and tumor suppressor haploinsufficiency.
• A distinct miRISC complex, involving AGO3 and DHX9, mediates this selective mRNA degradation.
• Inverse correlation between variant FOXL2 and miR-1236 levels with AGCT malignant features was observed in both patients and a mouse model.

Conclusions:

• The study reveals a novel mechanism of microRNA targeting disease-associated mutations within the coding sequence.
• This miR-1236-mediated degradation of FOXL2 contributes to the etiology of adult-type granulosa cell tumors.
• The findings provide a molecular basis for understanding FOXL2 mutation-driven AGCT pathogenesis.