A systematic screen for micro-RNAs regulating the canonical Wnt pathway.

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• MicroRNAs (miRs) and the Wnt pathway are frequently dysregulated in human cancers.
• These molecules play critical roles in cancer initiation and progression.

Purpose of the Study:

• To identify miRs that modulate the canonical Wnt pathway activity.
• To investigate the potential of Wnt-modulating miRs as cancer biomarkers and therapeutics.

Main Methods:

• A cell-based overexpression screen of 470 miRs in HEK293 cells.
• Literature survey and epistasis-based functional validation of candidate miRs.
• Assessment of miR effects on cell proliferation, viability, and Wnt pathway reporter gene expression in cancer cells and organoids.

Main Results:

• 38 candidate miRs were identified that either activate or repress the Wnt pathway.
• Wnt-repressing miRs were found to be anti-oncomiRs downregulated in cancers, while Wnt-activating miRs were oncomiRs upregulated during tumorigenesis.
• miR-1, miR-25, and miR-613 were validated as Wnt pathway repressors, with miR-25 acting at the β-catenin level and miR-1/miR-613 acting upstream.
• miR-1 and miR-25 inhibited proliferation and viability in colon cancer cells.
• miR-1 expression reduced Wnt pathway activity in mouse mammary organoids.

Conclusions:

• Wnt-modulating miRs, such as miR-1 and miR-25, can inhibit cancer cell proliferation and viability.
• These miRs represent potential diagnostic and therapeutic tools for Wnt-dependent diseases, including cancer.