RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis
Abstract 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 stud...
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doaj-c05f06ff3805491988776a3367203b032021-04-04T11:05:13ZengNature Publishing GroupCell Death and Disease2041-48892021-04-0112411810.1038/s41419-021-03642-7RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axisQian Liang0Yun Wang1Yingsi Lu2Qingqing Zhu3Wenlin Xie4Nannan Tang5Lifen Huang6Tailai An7Di Zhang8Anqi Yan9Shaoyu Liu10Liping Ye11Chengming Zhu12Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen UniversityDepartment of Pathology, The Seventh Affiliated Hospital, Sun Yat-sen UniversityDivision of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-sen UniversityDivision of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-sen UniversityCenter of Digestive Diseases, The Seventh Affiliated Hospital, Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen UniversityZhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen UniversityAbstract 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 (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.https://doi.org/10.1038/s41419-021-03642-7 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Qian Liang Yun Wang Yingsi Lu Qingqing Zhu Wenlin Xie Nannan Tang Lifen Huang Tailai An Di Zhang Anqi Yan Shaoyu Liu Liping Ye Chengming Zhu |
spellingShingle |
Qian Liang Yun Wang Yingsi Lu Qingqing Zhu Wenlin Xie Nannan Tang Lifen Huang Tailai An Di Zhang Anqi Yan Shaoyu Liu Liping Ye Chengming Zhu RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis Cell Death and Disease |
author_facet |
Qian Liang Yun Wang Yingsi Lu Qingqing Zhu Wenlin Xie Nannan Tang Lifen Huang Tailai An Di Zhang Anqi Yan Shaoyu Liu Liping Ye Chengming Zhu |
author_sort |
Qian Liang |
title |
RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis |
title_short |
RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis |
title_full |
RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis |
title_fullStr |
RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis |
title_full_unstemmed |
RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis |
title_sort |
rank promotes colorectal cancer migration and invasion by activating the ca2+-calcineurin/nfatc1-acp5 axis |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-04-01 |
description |
Abstract 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 (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. |
url |
https://doi.org/10.1038/s41419-021-03642-7 |
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