LRCH4 drives tumor cell proliferation by regulating the GSK3B/MEK/ERK axis in colorectal cancer

Abstract Leucine-rich repeat-containing protein 4 (LRCH4), a member of the LRCH family, has emerged as a potential prognostic biomarker in several cancers, including colorectal cancer (CRC). While other proteins in this family have been implicated in tumorigenesis, the specific role of LRCH4 in CRC remains poorly understood. This study aimed to elucidate the clinical significance and biological function of LRCH4 in CRC. Bioinformatics analysis of The Cancer Genome Atlas data revealed that LRCH4 was significantly upregulated in CRC tissues, and its high expression correlated with poor patient prognosis. Gene set enrichment analysis suggested its potential involvement in the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) signaling pathway. Using mass spectrometry and co-immunoprecipitation assays, we identified glycogen synthase kinase 3B (GSK3B) as a novel binding partner of LRCH4. Functional experiments demonstrated that LRCH4 binds to GSK3B and inhibits its phosphorylation, thereby activating downstream MEK/ERK signaling to promote cell proliferation. An in vivo xenograft model confirmed that the knockdown of LRCH4 expression suppressed tumor growth. Furthermore, immunohistochemical analysis of clinical samples validated the negative correlation between high LRCH4 expression and patient survival rate. In conclusion, our findings establish LRCH4 as a key oncoprotein that drives CRC proliferation by directly modulating the GSK3B pathway, highlighting its potential as both a prognostic biomarker and a promising therapeutic target.