Reticulocalbin3: A Ca(2+) homeostasis regulator that promotes esophageal squamous cell carcinoma progression and cisplatin resistance

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. There is a critical need to identify new mechanisms that contribute to ESCC progression. Reticulocalbin3 (RCN3) is mainly located in the endoplasmic reticulum and Ca(2+)‐binding protein containing EF‐hands. The function of RCN3 in tumor progression has not been clarified. We observed that the expression level of RCN3 was higher in ESCC tissues than in paired normal tissues. Overexpression of RCN3 was positively associated with tumor size, lymph node metastasis, TNM stage, lymphatic vessel infiltration, and poor outcome in patients with ESCC. Increased malignant phenotypes were observed in RCN3 overexpressing ESCC cells, whereas the opposite effects were achieved in RCN3‐silenced cells. Reticulocalbin3 promoted the expression of MMP‐2 and MMP‐9 by regulating the inositol 1,4,5‐trisphosphate receptor 1 (IP3R1)–Ca(2+)–calcium/calmodulin‐dependent protein kinase II–c‐Jun signaling pathway. Reticulocalbin3 induced cisplatin resistance by regulating IP3R1/Ca(2+) to maintain intracellular Ca(2+) homeostasis and reduced reactive oxygen species in ESCC cells. Finally, the expression of RCN3 was regulated by hypoxia inducible factor‐1α. Collectively, these data strongly support that RCN3 regulates Ca(2+) homeostasis by targeting IP3R1 to promote the progression and platinum resistance of ESCC. Our studies suggest that RCN3 could serve as predictive factor of poor prognosis and potential therapeutic target for ESCC patients.