Genetic and transcriptomic alterations underlying aggressiveness in 5-fluorouracil-resistant HCT116 cells

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• 5-fluorouracil (5-FU) resistance is a major challenge in colorectal cancer (CRC) treatment.
• Genetic factors contribute to chemoresistance, tumor recurrence, and increased cancer aggressiveness.

Purpose of the Study:

• To characterize the transcriptomic profiles of 5-FU-resistant CRC cells.
• To understand the molecular mechanisms underlying chemoresistance and aggressive tumor behavior in CRC.

Main Methods:

• Induction of 5-FU resistance in HCT116 colon cancer cells through progressive drug exposure.
• Assessment of chemoresistance and invasiveness using MTT, clonogenic, and scratch assays.
• Transcriptomic profiling via next-generation sequencing (NGS).

Main Results:

• 5-FU-resistant cells displayed cross-resistance and enhanced invasion, with upregulated matrix metalloproteinases (MMP-2, MMP-9).
• Overexpression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cell adhesion genes (NXPE1, NCAM1) was observed.
• Upregulation of specific microRNAs (miR-6789, miR-5006, miR-7107) and activation of the PI3K-AKT pathway were identified.

Conclusions:

• Transcriptomic alterations in 5-FU-resistant CRC cells are associated with aggressive phenotypes.
• Upregulated genes and non-coding RNAs, potentially via the PI3K-AKT pathway, contribute to chemoresistance and invasiveness.
• These findings offer potential targets for developing novel therapies to overcome 5-FU resistance in CRC.