CLEC5A suppresses cell growth and metastasis via interfering with the calcineurin/NFATc1 signaling pathway in osteosarcoma

Osteosarcoma (OS) is a prevalent primary bone malignancy characterized by a poor prognosis due to its high metastatic potential. Although the dysregulation of C-type lectin domain family 5, member A (CLEC5A) has been reported in various cancers, its role in OS progression and molecular pathogenesis remains elusive. We leveraged a comprehensive gene expression dataset (GSE21257) to elucidate the key genes in OS, both with and without metastatic involvement. Bioinformation analyses, Western blot, and RT-qPCR assays consistently demonstrated significantly lower CLEC5A expression levels in human OS cell lines and tissues. Notably, OS tissues from patients with metastasis exhibited lower CLEC5A levels compared to those without metastasis. We generated stable CLEC5A-deficient MG-63 and 143B cells with short hairpin RNA. Our findings revealed that CLEC5A knockdown enhanced OS cell proliferation and metastasis. Additionally, CLEC5A-deficient cells displayed increased calcineurin activity, which promoted the nuclear translocation of NFATc1, leading to elevated expression of MMPs. Conversely, CLEC5A overexpression suppressed OS cells growth and invasion and concurrently inhibited calcineurin activity. In summary, our study uncovers a suppressive role for CLEC5A in OS tumorigenesis and metastasis through the modulation of the calcineurin/NFATc1 signaling pathway. The deregulation of this pathway significantly impacts OS progression, highlighting its potential as a predicted and therapeutic target for metastatic OS.