WFDC3 sensitizes colorectal cancer to chemotherapy by regulating ATM/ATR kinase signaling pathway

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Chemoresistance remains a significant challenge in colorectal cancer (CRC) treatment.
• WFDC3 was previously identified as a tumor suppressor inhibiting CRC metastasis.
• The role of WFDC3 in chemotherapy response was previously unknown.

Purpose of the Study:

• To investigate the function of WFDC3 in colorectal cancer chemoresistance.
• To determine if WFDC3 expression correlates with oxaliplatin efficacy in CRC patients.
• To elucidate the molecular mechanisms by which WFDC3 influences oxaliplatin sensitivity.

Main Methods:

• Analysis of WFDC3 expression in CRC patients treated with oxaliplatin.
• In vitro studies involving WFDC3 overexpression and knockdown in CRC cells.
• In vivo tumor growth suppression assays.
• Investigation of DNA damage and ATM/ATR signaling pathways.

Main Results:

• High WFDC3 expression correlated with better prognosis in oxaliplatin-treated CRC patients.
• WFDC3 overexpression increased oxaliplatin sensitivity, while knockdown induced resistance.
• WFDC3 enhanced oxaliplatin-induced DNA damage by inhibiting ATM/ATR signaling.
• Combination therapy with oxaliplatin and ATM/ATR inhibitors partially overcame chemoresistance in low WFDC3 CRC cells.

Conclusions:

• WFDC3 acts as a biomarker for predicting oxaliplatin sensitivity in colorectal cancer.
• WFDC3 modulates oxaliplatin efficacy through the ATM/ATR kinase signaling pathway.
• Combining oxaliplatin with ATM or ATR inhibitors presents a potential therapeutic strategy for improving CRC outcomes.