miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein...

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Biology

Background:

• The miR-200 family maintains the epithelial state by inhibiting genes driving epithelial-mesenchymal transition (EMT).
• EMT contributes to cancer metastasis and progression.
• Alternative splicing significantly impacts cellular functions and disease states.

Purpose of the Study:

• To investigate the role of miR-200c and miR-375 in regulating alternative splicing during EMT.
• To identify the downstream targets and mechanisms through which these miRNAs influence cancer cell plasticity.
• To elucidate the interplay between microRNAs, RNA-binding proteins, and alternative splicing in cancer.

Main Methods:

• Analysis of microRNA and RNA-binding protein expression in cancer cells.
• RNA sequencing and splicing analysis to identify alternative splicing targets.
• Functional assays to assess the impact of QKI modulation on cell migration, invasion, and tumor growth.
• Bioinformatic analysis to identify conserved splicing signatures across cancer types.

Main Results:

• miR-200c and miR-375 suppress the RNA-binding protein Quaking (QKI).
• QKI-5 directly regulates hundreds of alternative splicing targets during EMT, influencing cell migration and invasion without affecting mRNA levels.
• QKI-5 is essential and sufficient for EMT-associated alternative splicing changes, conserved across epithelial cancers.
• Coordinated regulation of actin cytoskeleton-associated genes by QKI and miR-200c highlights combined control of splicing and mRNA abundance.

Conclusions:

• A novel miR-200/miR-375/QKI axis controls cancer cell plasticity.
• Widespread regulation of alternative splicing by this axis impacts EMT and cancer progression.
• Targeting this axis offers potential therapeutic strategies for epithelial-derived cancers.