Biological Performance and Molecular Mechanisms of Mesyl MicroRNA-Targeted Oligonucleotides in Colorectal Cancer...

Area of Science:

• Molecular oncology
• Oligonucleotide therapeutics
• Cancer genomics

Background:

• Colorectal cancer (CRC) is a leading cause of cancer mortality, often resistant to therapy.
• Specific microRNAs (miRNAs) like miR-21, miR-17, and miR-155 are key drivers of CRC progression.
• Antisense oligonucleotides (ASOs) offer a targeted approach to modulate miRNA activity.

Purpose of the Study:

• To investigate the molecular mechanisms of methanesulfonyl phosphoramidate-modified antisense oligonucleotides (µ-ASOs) targeting oncogenic miRNAs in CRC.
• To assess the anti-proliferative and anti-migratory effects of individual and combination µ-ASO treatments.
• To identify novel miRNA targets and understand their role in CRC pathogenesis.

Main Methods:

• Utilized human colorectal adenocarcinoma Caco-2 cells.
• Transfected cells with individual or triple combination µ-ASOs targeting miR-21, miR-17, and miR-155.
• Performed miRNA quantification, antiproliferative/anti-migratory assays, and comprehensive proteomic profiling.
• Analyzed protein-protein interaction networks and correlated protein expression with clinical data.

Main Results:

• Each µ-ASO demonstrated distinct effects on cellular processes: µ-21 on apoptosis/cell cycle, µ-17 on proliferation/chaperones, and µ-155 on transport/immune regulation.
• Combination therapy yielded a unique proteomic signature.
• Identified validated and novel miRNA targets (e.g., RPL31, DNM2, RPL17) whose expression correlates with better CRC patient outcomes.
• Established comprehensive mechanistic insights into µ-ASO-mediated miRNA suppression.

Conclusions:

• µ-ASOs targeting oncogenic miRNAs represent a promising therapeutic strategy for CRC.
• Distinct molecular pathways are modulated by individual and combined µ-ASO treatments.
• The identified miRNA targets provide novel biomarkers and therapeutic targets for colorectal cancer.