Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Department of Pathology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Cell Death Dis. 2021 Apr 1;12(4):336. 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) oscillation. The RANK-mediated intracellular Ca 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-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.
肿瘤坏死因子（TNF）受体超家族成员 11a（TNFRSF11a，也称为 RANK）被证明在肿瘤转移中发挥重要作用。然而，RANK 在结直肠癌（CRC）转移中的具体功能及其潜在机制尚不清楚。在本研究中，我们发现 RANK 在 CRC 组织中的表达明显高于匹配的非癌组织。RANK 表达的增加与 CRC 患者的转移、更高的 TNM 分期和更差的预后呈正相关。RANK 的过表达促进了 CRC 细胞在体外和体内的转移，而 RANK 的敲低则降低了细胞的迁移和侵袭。在机制上，RANK 的过表达显著上调了 CRC 细胞中抗酒石酸酸性磷酸酶 5（TRAP/ACP5）的表达。在 RANK 过表达的 CRC 细胞中沉默 ACP5 减弱了 RANK 诱导的迁移和侵袭，而过表达 ACP5 则增加了 RANK 沉默细胞的迁移和侵袭。ACP5 的表达受钙调神经磷酸酶/活化 T 细胞核因子 c1（NFATC1）轴的转录调控。钙调神经磷酸酶/NFATC1 的抑制显著降低了 ACP5 的表达，并减弱了 RANK 诱导的细胞迁移和侵袭。此外，RANK 诱导磷脂酶 C-γ（PLCγ）介导的肌醇 1,4,5-三磷酸受体（IP3R）轴和基质相互作用分子 1（STIM1）引发钙（Ca）振荡。RANK 介导的细胞内 Ca 动员刺激钙调神经磷酸酶使 NFATC1 去磷酸化并诱导 NFATC1 核转位。PLCγ-IP3R 轴和 STIM1 的阻断均挽救了 RANK 诱导的 NFATC1 核转位、ACP5 的表达和细胞转移。我们的研究揭示了 RANK 在人类 CRC 细胞中的功能性表达，并证明了 RANK 通过调节 CRC 转移诱导 Ca-钙调神经磷酸酶/NFATC1-ACP5 轴，这可能适合治疗靶向。
