RCN3 functions as a tumor promoter in colorectal cancer by modulating the GRP78-PI3K-AKT signaling pathway.

Colorectal cancer (CRC) remains a significant global health concern, highlighting the urgent need for novel therapeutic targets and prognostic biomarkers. This study investigates the role of Reticulocalbin-3 (RCN3) in CRC development, focusing on its regulatory influence on calcium ion homeostasis and transport proteins, critical factors in cancer progression. We employed bioinformatics databases, qRT-PCR, Western blotting, and immunohistochemistry to evaluate RCN3 expression levels, revealing that RCN3 is upregulated in CRC tissues and correlates with poorer patient outcomes. Functional assays demonstrated that alterations in RCN3 expression significantly accelerated cell proliferation, migration, and invasion of CRC cells both in vitro and in vivo. Mechanistically, the interaction of RCN3's EF-hand domains 3 and 4 with glucose-regulated protein 78 (GRP78) promotes its translocation to the cellular membrane, inducing endoplasmic reticulum stress through elevated intracellular calcium levels. Furthermore, RCN3 was found to regulate the PI3K-AKT-mTOR-S6 signaling pathway by enhancing the phosphorylation of key proteins, thereby emphasizing its multifaceted role in CRC pathogenesis. In conclusion, these findings suggest that RCN3 not only contributes to CRC progression but also holds promise as a potential therapeutic target and biomarker for improving patient outcomes in CRC management.