GIPC1 Restrains the Progression and Chemoresistance of Colorectal Cancer by Regulating TTC7B/mTOR/NF-κB Axis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Colorectal cancer (CRC) is a major cause of cancer mortality, necessitating research into its molecular underpinnings for new treatments.
• Understanding the molecular mechanisms of CRC is crucial for developing effective therapeutic strategies and improving patient outcomes.

Purpose of the Study:

• To investigate the role of PDZ Domain Containing Family Member 1 (GIPC1) in colorectal cancer.
• To elucidate the molecular mechanisms by which GIPC1 influences CRC progression and chemoresistance.
• To evaluate the therapeutic potential of GIPC1 in CRC treatment.

Main Methods:

• Analysis of GIPC1 expression in CRC tissues and correlation with patient prognosis.
• In vitro studies assessing GIPC1's effects on CRC cell proliferation, colony formation, migration, and invasion.
• Investigation of GIPC1's impact on CRC cell sensitivity to chemotherapies (5-FU, OXA, CPT-11).
• Mechanistic studies involving E3 ubiquitin ligase TRIM21, TTC7B ubiquitination, and mTOR/NF-κB signaling.
• In vivo studies using GIPC1-loaded lipid nanoparticles (GIPC1-LNPs) combined with 5-FU.

Main Results:

• Reduced GIPC1 expression was observed in CRC tissues and correlated with poor prognosis in early pathological stages (T1, T2).
• GIPC1 suppressed CRC cell proliferation, colony formation, migration, and invasion, acting as a tumor suppressor.
• GIPC1 enhanced CRC cell sensitivity to 5-FU, OXA, and CPT-11.
• GIPC1 stabilized TTC7B by downregulating TRIM21, inhibiting the mTOR/NF-κB pathway.
• GIPC1-LNPs combined with 5-FU demonstrated significant antitumor effects in vivo.

Conclusions:

• GIPC1 functions as a tumor suppressor in CRC through the GIPC1/TRIM21/TTC7B/mTOR/NF-κB axis.
• GIPC1 holds potential as a biomarker for early diagnosis and a therapeutic target for overcoming chemoresistance in colorectal cancer.