Tumor suppression through the interaction between CNTN4 and PTPRG attenuates EGFR signaling in colorectal cancer

Chromosome 3 harbors numerous tumor suppressor genes (TSGs) linked to cancer development and progression. We conducted fine deletion mapping on 179 colorectal cancer (CRC) tumors, and herewith revealed a 3.1 Mb minimal deletion region (MDR) at 3p26.1–p26.3 affecting 31.6% of cases. Allelic loss of the MDR is associated with younger age, distant metastasis, and poorer overall survival. Contactin-4 (CNTN4) is located within the MDR, and its expression was downregulated in 11 of 12 CRC cell lines and 42.3% of colorectal carcinomas. The finding was further verified via the datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases. Ectopic expression of CNTN4 inhibited CRC cell proliferation and anchorage-dependent/independent growth, and promoted apoptosis in vitro. In the xenograft tumor model, CNTN4 suppressed tumor growth through down-regulation of uPA-mediated angiogenesis. Mechanistically, CNTN4 inhibits the EGFR/ERK/c-MYC signaling pathway by directly interacting with PTPRG. CNTN4, a functional tumor suppressor, exhibits early dysregulation, suggesting its potential as a novel prognostic biomarker for CRC initiation and progression.