Functional relationship between CFTR and RAC3 expression for maintaining cancer cell stemness in human colorectal...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cystic fibrosis transmembrane conductance regulator (CFTR) mutations are linked to increased colorectal cancer risk.
• The role of CFTR in colorectal cancer development among patients without cystic fibrosis remains uninvestigated.
• RAC3, a nuclear receptor coactivator, is overexpressed in tumors and maintains cancer stemness.

Purpose of the Study:

• To investigate the functional relationship between CFTR and RAC3 in maintaining cancer stemness in human colorectal cancer.
• To explore the role of CFTR in colorectal cancer patients without cystic fibrosis.

Main Methods:

• Cancer stemness was assessed using stem cell markers, clonogenic growth, and fluorochrome retention assays in HCT116 cells with CFTR or RAC3 knockdown.
• Pathway enrichment and network analyses were performed on human colorectal cancer samples (TCGA) and Caco-2 cells, comparing CD133+ vs. CD133- populations and CFTRwt vs. CFTRmut cells.

Main Results:

• The CD133+ side population showed higher RAC3 and CFTR expression than the CD133- population.
• RAC3 overexpression elevated CFTR expression, while CFTR downregulation reduced cancer stemness.
• Colorectal cancer samples from patients without cystic fibrosis exhibited increased CFTR and RAC3 mRNA levels compared to those with CFTR mutations.

Conclusions:

• CFTR may have a non-tumor suppressor role in colorectal cancer development and maintenance.
• CFTR influences cancer stemness through RAC3 and the expression of inflammatory and nuclear receptor-modulating genes.
• These findings suggest CFTR's involvement in colorectal cancer pathogenesis beyond its association with cystic fibrosis.