RANK promotes colorectal cancer migration and invasion by activating the Ca(2+)-calcineurin/NFATC1-ACP5 axis.
RANK promotes colorectal cancer migration and invasion by activating the Ca(2+)-calcineurin/NFATC1-ACP5 axis.
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RANK通过激活Ca2-钙调神经磷酸酶/NFATC1-ACP5轴促进结直肠癌迁移和侵袭
DOI：
10.1038/s41419-021-03642-7
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发表时间：
2021-04-01
影响因子：
9
通讯作者：
Zhu C
中科院分区：
文献类型：
--
作者：
Liang Q;Wang Y;Lu Y;Zhu Q;Xie W;Tang N;Huang L;An T;Zhang D;Yan A;Liu S;Ye L;Zhu C
肿瘤坏死因子受体超家族成员11a(TNFRSF11a，又称RANK)在肿瘤转移中起重要作用。然而，RANK在结直肠癌转移中的具体作用及其机制尚不清楚。在这项研究中，我们发现RANK在结直肠癌组织中的表达明显高于在配对的非癌组织中的表达。RANK表达升高与大肠癌转移、TNM分期高、预后差呈正相关。RANK过表达促进了结直肠癌细胞的体内外转移，而RANK基因敲除则减少了细胞的迁移和侵袭。机制上，RANK过表达显著上调耐酒石酸酸性磷酸酶5(TRAP/ACP5)在大肠癌细胞中的表达。在RANK过表达的CRC细胞中沉默ACP5可减弱RANK诱导的迁移和侵袭，而过表达ACP5则增加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C_1(NFATC_1)轴的转录调控。抑制钙调神经磷酸酶/NFATC1显著降低ACP5的表达，并减弱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)引起钙振荡。RANK介导的细胞内Ca~(2+)动员刺激钙调神经磷酸酶去磷酸化NFATC1并诱导NFATC1核转位。阻断PLCγ-IP3R轴和STIM1均可挽救RANK诱导的NFATC1核转位、ACP5表达和细胞转移。我们的研究揭示了RANK在人结直肠癌细胞中的功能表达，并证明RANK诱导了钙-钙调神经磷酸酶/NFATC1-ACP5轴在调控结直肠癌转移中的作用，这可能是治疗的靶向。
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 ofRANKpromoted CRC cell metastasis in vitro and in vivo, while knockdown ofRANKdecreased cell migration and invasion. Mechanistically,RANKoverexpression significantly upregulated the expression of tartrate-resistant acid phosphatase 5 (TRAP/ACP5) in CRC cells. Silencing ofACP5inRANK-overexpressing CRC cells attenuated RANK-induced migration and invasion, whereas overexpression ofACP5increased the migration and invasion ofRANK-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 (Ca2+) oscillation. The RANK-mediated intracellular Ca2+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 Ca2+-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.
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影响因子：
3.8
作者：
Honig A;Rieger L;Kapp M;Krockenberger M;Eck M;Dietl J;Kämmerer U
通讯作者：
Kämmerer U
影响因子：
4
作者：
Renema N;Navet B;Heymann MF;Lezot F;Heymann D
通讯作者：
Heymann D
影响因子：
64.8
作者：
Jones, DH;Nakashima, T;Penninger, JM
通讯作者：
Penninger, JM
影响因子：
6.5
作者：
Kupas, Verena;Weishaupt, Carsten;Loser, Karin
通讯作者：
Loser, Karin
影响因子：
5.2
作者：
Maurizi A;Rucci N
通讯作者：
Rucci N