RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis

• Published in: Cell death & disease Vol. 12; no. 4; p. 336
• Main Authors: Liang, Qian, Wang, Yun, Lu, Yingsi, Zhu, Qingqing, Xie, Wenlin, Tang, Nannan, Huang, Lifen, An, Tailai, Zhang, Di, Yan, Anqi, Liu, Shaoyu, Ye, Liping, Zhu, Chengming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/1; 13/109; 13/51; 631/67/322; 692/699/67/322; 96; 96/1; 96/109; Acid phosphatase (tartrate-resistant); Antibodies; Biochemistry; Biomedical and Life Sciences; Calcineurin; Calcium (intracellular); Calcium mobilization; Cell adhesion & migration; Cell Biology; Cell Culture; Cell migration; Colorectal cancer; Colorectal carcinoma; Immunology; Inositol 1,4,5-trisphosphate receptors; Life Sciences; Metastases; Metastasis; NF-AT protein; Nuclear transport; Osteoprotegerin; Phospholipase C; STIM1 protein; Therapeutic targets; Transcription factors; Tumor necrosis factor; Tumor necrosis factor-TNF
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03642-7

The tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, also known as RANK) was demonstrated to play an important role in tumor metastasis. However, the specific function of RANK in colorectal cancer (CRC) metastasis and the underlying mechanism are unknown. In this study, we found that RANK expression was markedly upregulated in CRC tissues compared with that in matched noncancerous tissues. Increased RANK expression correlated positively with metastasis, higher TNM stage, and worse prognosis in patients with CRC. Overexpression of
RANK
promoted CRC cell metastasis in vitro and in vivo, while knockdown of
RANK
decreased cell migration and invasion. Mechanistically,
RANK
overexpression significantly upregulated the expression of tartrate-resistant acid phosphatase 5 (
TRAP/ACP5
) in CRC cells. Silencing of
ACP5
in
RANK
-overexpressing CRC cells attenuated RANK-induced migration and invasion, whereas overexpression of
ACP5
increased the migration and invasion of
RANK-
silencing cells. The ACP5 expression was transcriptionally regulated by calcineurin/nuclear factor of activated T cells c1 (NFATC1) axis. The inhibition of calcineurin/NFATC1 significantly decreased ACP5 expression, and attenuated RANK-induced cell migration and invasion. Furthermore, RANK induced phospholipase C-gamma (PLCγ)-mediated inositol-1,4,5-trisphosphate receptor (IP3R) axis and stromal interaction molecule 1 (STIM1) to evoke calcium (Ca
2+
) oscillation. The RANK-mediated intracellular Ca
2+
mobilization stimulated calcineurin to dephosphorylate NFATC1 and induce NFATC1 nuclear translocation. Both blockage of PLCγ-IP3R axis and STIM1 rescued RANK-induced NFATC1 nuclear translocation, ACP5 expression, and cell metastasis. Our study revealed the functional expression of RANK in human CRC cells and demonstrated that RANK induced the Ca
2+
-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.