MiniSOX9, a dominant-negative variant in colon cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Aberrant pre-mRNA processing is implicated in human diseases, particularly cancer.
• The SOX9 transcription factor exhibits anti-oncogenic properties in the colon, with its knockout leading to intestinal hyperplasia.
• SOX9 activity is often diminished in colon cancer cells, suggesting the presence of inhibitory variants.

Purpose of the Study:

• To identify SOX9 variants that impair SOX9 activity in colon cancer cells.
• To investigate the role of a newly discovered truncated SOX9 variant, MiniSOX9, in colon cancer development.

Main Methods:

• Real-time reverse transcriptase-PCR to quantify MiniSOX9 mRNA levels in tumor and normal tissues.
• Immunohistochemistry to assess MiniSOX9 protein expression in colon cancer samples.
• Functional assays to determine MiniSOX9's effect on SOX9 activity, protein kinase Cα promoter, and Wnt pathway.

Main Results:

• A truncated SOX9 variant, MiniSOX9, resulting from intron retention, was identified.
• MiniSOX9 mRNA and protein were significantly overexpressed in human colon tumors compared to normal tissues.
• MiniSOX9 functions as a SOX9 inhibitor, represses protein kinase Cα promoter activity, and activates the canonical Wnt pathway.

Conclusions:

• MiniSOX9 is an oncogenic variant of SOX9 implicated in colon cancer progression.
• The overexpression of MiniSOX9 contributes to colon tumorigenesis by inhibiting SOX9 and activating oncogenic pathways.
• These findings offer new insights into the dual role of the SOX9 locus in colon cancer.