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

ABSTRACT

Despite advances in targeted therapies, primary and acquired resistance make the treatment of colorectal cancer (CRC) a pressing issue to be resolved. According to reports, the development of CRC is linked to miRNA dysregulation. Multiple studies have demonstrated that miR-135b-5p has an aberrant expression level between CRC tissues and adjacent tissues. However, it is unclear whether there is a correlation between miR-135b-5p and cetuximab (CTx) resistance in CRC. Use the GEO database to measure miR-135b-5p expression in CRC. Additionally, RT-qPCR was applied to ascertain the production level of miR-135b-5p in three human CRC cells and NCM460 cells. The capacity of cells to migrate and invade was examined utilizing the wound-healing and transwell assays, while the CCK-8 assay served for evaluating cell viability, as well as colony formation assays for proliferation. The expected target protein of miR-135b-5p in CRC cell cetuximab resistance has been investigated using western blot. Suppression of miR-135b-5p could increase the CTx sensitivity of CTx-resistant CRC cells, as manifested by the attenuation of proliferation, migration, and invasion ability. Mechanistic studies revealed miR-135b-5p regulates the epithelial-to-mesenchymal transition (EMT) process and Wnt/β-catenin signaling pathway through downgulating FOXN3. In short, knockdowning miR-135b-5p could increase FOXN3 expression in CRC cells, promote the EMT process, and simultaneously activate the Wnt/β-catenin signaling pathway to elevate CTx resistance in CRC cells.

KEYWORDS:

• Colorectal cancer
• cetuximab
• miR-135b-5p
• FOXN3
• tumor resistance

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Study design: CZ and CP; data collection: CP and YN; data analysis: CP, XL, and YY; cellular experiments: CP, YN, and LF; manuscript review and editing: CP, CZ, XL, and YY, figure and manuscript proofing: CP and XL and YY; funding acquisition: CZ. All the authors read, reviewed, and approved the final manuscript.

Data availability statement

The datasets used or analyzed in this study are available from the corresponding authors upon reasonable request.

Additional information

Funding

This research was funded by Nanjing Second Hospital talent lifting plan key project [Grant No. RCZD202302], Natural Science Foundation of Nanjing University of Chinese Medicine [Grant No. XRZ2021078], Medical research project general program of jiangsu Provincial Health Commission [Grant No. M2020055], and Nanjing medical science and technology development project key project [Grant No. ZKX23037].