Pan-Cancer Analysis of CLDN3 and Its Contribution to 5-FU Resistance in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Bioinformatics

Background:

• The role and regulation of Claudin 3 (CLDN3) in cancer, particularly colorectal cancer (CRC), are not fully understood.
• Aberrant CLDN3 expression is implicated in various cancers, but its precise mechanisms and clinical significance require further elucidation.

Purpose of the Study:

• To investigate the aberrant expression patterns and regulatory mechanisms of CLDN3 in cancers.
• To evaluate the functional role of CLDN3 in colorectal cancer (CRC) proliferation, migration, and chemoresistance.
• To explore the interaction between CLDN3 and TRIM28 and its implications for CRC therapy.

Main Methods:

• Bioinformatic analysis using R software to assess CLDN3 expression and genomic alterations.
• In vitro assays in CRC cells: proliferation, wound healing, cell cycle, and apoptosis assays.
• Co-immunoprecipitation (CO-IP), immunofluorescence, and Western blotting to study CLDN3-TRIM28 interaction and SUMOylation.

Main Results:

• CLDN3 is significantly overexpressed in multiple cancers, driven by genomic alterations and promoter hypomethylation.
• CLDN3 knockdown reduced CRC cell proliferation and migration; CLDN3 overexpression decreased sensitivity to 5-fluorouracil (5-FU).
• TRIM28 directly interacts with CLDN3, mediating its SUMOylation and degradation, establishing the TRIM28/CLDN3 axis.

Conclusions:

• CLDN3 plays a crucial role in promoting CRC growth and chemoresistance.
• The interaction between CLDN3 and TRIM28 influences CLDN3 protein stability and function.
• The TRIM28/CLDN3 axis represents a potential therapeutic target for colorectal cancer treatment.