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

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, highlighting the need for a deeper understanding of its molecular mechanisms to drive the development of novel therapeutic approaches. In this study, the findings indicated a significant reduction in PDZ Domain Containing Family Member 1 (GIPC1) expression in CRC tissues, which correlated with poor prognosis in patients with CRC at pathological stages T1 and T2. GIPC1 acted as a tumor suppressor gene that inhibited CRC cell proliferation, colony formation, migration, and invasion. Additionally, it enhanced CRC cell sensitivity to first-line chemotherapies such as 5-fluorouracil (5-FU), oxaliplatin (OXA), and irinotecan (CPT-11). Mechanistically, GIPC1 reduced the ubiquitination level of tetratricopeptide repeat domain 7B (TTC7B) by downregulating the E3 ubiquitin ligase TRIM21, thereby stabilizing TTC7B's expression and inhibiting the downstream mTOR/NF-κB signaling cascade. Moreover, in vivo studies confirmed the inhibitory role of GIPC1 in CRC growth and found that GIPC1-loaded lipid nanoparticles (GIPC1-LNPs) combined with 5-FU treatment had a more significant antitumor effect. In conclusion, this study reveals the GIPC1/TRIM21/TTC7B/mTOR/NF-κB tumor-suppressive axis in CRC and highlights the potential of GIPC1 for early diagnosis and overcoming chemoresistance in CRC patients.