MiR-135b-5p promotes cetuximab resistance in colorectal cancer by regulating FOXN3

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Colorectal cancer (CRC) treatment faces challenges due to primary and acquired resistance to targeted therapies.
• MicroRNA (miRNA) dysregulation is implicated in CRC development, with miR-135b-5p showing aberrant expression in CRC tissues.
• The specific role of miR-135b-5p in cetuximab (CTx) resistance in CRC remains unclear.

Purpose of the Study:

• To investigate the correlation between miR-135b-5p expression and cetuximab resistance in colorectal cancer.
• To elucidate the underlying molecular mechanisms by which miR-135b-5p influences CRC cell behavior and drug resistance.

Main Methods:

• Analysis of miR-135b-5p expression using the GEO database and RT-qPCR in CRC cell lines.
• Assessment of cell proliferation, viability, migration, and invasion using CCK-8, colony formation, wound-healing, and transwell assays.
• Investigation of target protein interactions via Western blot, focusing on the epithelial-to-mesenchymal transition (EMT) and Wnt/β-catenin signaling pathways.

Main Results:

• Suppression of miR-135b-5p significantly increased cetuximab sensitivity in resistant CRC cells, reducing proliferation, migration, and invasion.
• miR-135b-5p was found to regulate the EMT process and Wnt/β-catenin signaling pathway by downregulating FOXN3.
• Knockdown of miR-135b-5p led to increased FOXN3 expression, promoting EMT and activating the Wnt/β-catenin pathway, thereby enhancing CTx resistance.

Conclusions:

• miR-135b-5p plays a crucial role in mediating cetuximab resistance in colorectal cancer.
• Targeting miR-135b-5p presents a potential therapeutic strategy to overcome cetuximab resistance in CRC.
• The findings highlight the regulatory role of miR-135b-5p in EMT and Wnt/β-catenin signaling in the context of CRC drug resistance.