Transmembrane Protein TMEM59L Modulates 5-FU Resistance via PTPRN-Mediated DNA Damage Repair in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Chemotherapy resistance in colorectal cancer (CRC) is a significant clinical challenge.
• Enhanced DNA damage repair (DDR) is a key mechanism mediating resistance to chemotherapeutic agents like 5-fluorouracil (5-FU).
• The role of transmembrane protein TMEM59L in CRC chemoresistance and its association with DDR remains largely unexplored.

Purpose of the Study:

• To investigate the role of TMEM59L in regulating PTPRN-mediated DNA damage repair (DDR).
• To determine the impact of the TMEM59L/PTPRN axis on 5-fluorouracil (5-FU) sensitivity in colorectal cancer (CRC).
• To identify potential therapeutic targets for overcoming chemoresistance in CRC.

Main Methods:

• Bioinformatics analysis of TMEM59L/PTPRN expression and prognosis in CRC cohorts.
• In vitro gain- and loss-of-function experiments in CRC cell lines and 5-FU-resistant derivatives.
• Assessment of cell proliferation, migration, invasion, apoptosis, DNA damage, and reactive oxygen species (ROS).
• In vivo xenograft studies in nude mice to validate the TMEM59L/PTPRN axis.

Main Results:

• TMEM59L expression was elevated in metastatic CRC lesions and correlated with poor patient survival.
• TMEM59L overexpression promoted malignant behaviors, epithelial-mesenchymal transition (EMT), and 5-FU resistance.
• TMEM59L knockdown sensitized CRC cells to 5-FU by increasing ROS, DNA damage, and apoptosis, mediated through PTPRN.
• In vivo studies confirmed that TMEM59L knockdown enhanced 5-FU's antitumor effect.

Conclusions:

• The TMEM59L/PTPRN axis is a critical regulator of DNA damage repair (DDR) and 5-fluorouracil (5-FU) resistance in colorectal cancer (CRC).
• TMEM59L confers chemoresistance by enhancing DNA repair and reducing ROS-mediated apoptosis through PTPRN.
• Targeting the TMEM59L/PTPRN pathway presents a promising therapeutic strategy to overcome 5-FU resistance in CRC.