The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis
Abstract Background The tumor acidic microenvironment, a common biochemical event in solid tumors, offers evolutional advantage for tumors cells and even enhances their aggressive phenotype. However, little is known about the molecular mechanism underlying the acidic microenvironment-induced invasio...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-09-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-017-0599-9 |
| _version_ | 1818146581589786624 |
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| author | Zhi-hang Zhou Jin-wen Song Wen Li Xue Liu Liu Cao Lu-ming Wan Ying-xia Tan Shou-ping Ji Yu-mei Liang Feng Gong |
| author_facet | Zhi-hang Zhou Jin-wen Song Wen Li Xue Liu Liu Cao Lu-ming Wan Ying-xia Tan Shou-ping Ji Yu-mei Liang Feng Gong |
| author_sort | Zhi-hang Zhou |
| collection | DOAJ |
| description | Abstract Background The tumor acidic microenvironment, a common biochemical event in solid tumors, offers evolutional advantage for tumors cells and even enhances their aggressive phenotype. However, little is known about the molecular mechanism underlying the acidic microenvironment-induced invasion and metastasis. Methods We examined the expression of the acid-sending ion channel (ASIC) family members after acidic exposure using RT-PCR and immunofluoresence. Gene manipulation was applied to reveal the potential of ASIC2 on invasion, proliferation, colony formation of colorectal cancer (CRC). We assessed the in vivo tumor growth by subcutaneous transplantation and metastasis by spleen xenografts. Chromatin immunoprecipitation-sequencing was used to uncover the binding sites of NFAT1. Finally, we examined the expression of ASIC2 in CRC tissues using immunohistochemistry. Results Acidic exposure led to up-regulation of the acid-sensing ion channel, ASIC2, in colorectal cancer (CRC) cells. ASIC2 overexpression in CRC cell lines, SW480 and HCT116, significantly enhanced cell proliferation in vitro and in vivo, while ASIC2 knockdown had the reverse effect. Importantly, ASIC2 promoted CRC cell invasion under acidosis in vitro and liver metastasis in vivo. Mechanistically, ASIC2 activated the calcineurin/NFAT1 signaling pathway under acidosis. Inhibition of the calcineurin/NFAT pathway by cyclosporine A (CsA) profoundly attenuated ASIC2-induced invasion under acidosis. ChIP-seq assay revealed that the nuclear factor, NFAT1, binds to genes clustered in pathways involved in Rho GTPase signaling and calcium signaling. Furthermore, immunohistochemistry showed that ASIC2 expression is increased in CRC samples compared to that in adjacent tissues, and ASIC2 expression correlates with T-stage, distant metastasis, recurrence, and poor prognosis. Conclusion ASIC2 promotes metastasis of CRC cells by activating the calcineurin/NFAT1 pathway under acidosis and high expression of ASIC2 predicts poor outcomes of patients with CRC. |
| first_indexed | 2024-12-11T12:21:38Z |
| format | Article |
| id | doaj.art-b21594645ca9477db9e5174ceb1896bd |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-11T12:21:38Z |
| publishDate | 2017-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-b21594645ca9477db9e5174ceb1896bd2022-12-22T01:07:31ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-09-0136111210.1186/s13046-017-0599-9The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axisZhi-hang Zhou0Jin-wen Song1Wen Li2Xue Liu3Liu Cao4Lu-ming Wan5Ying-xia Tan6Shou-ping Ji7Yu-mei Liang8Feng Gong9Department of Pathology, the 309th hospital of PLADepartment of Tissue Engineering, Beijing Institute of Transfusion MedicineDepartment of Tissue Engineering, Beijing Institute of Transfusion MedicineDepartment of Pathology, Basic Science School, Jining Medical UniversityDepartment of Surgery, the 15th hospital of PLADepartment of Tissue Engineering, Beijing Institute of Transfusion MedicineDepartment of Tissue Engineering, Beijing Institute of Transfusion MedicineDepartment of Tissue Engineering, Beijing Institute of Transfusion MedicineDepartment of Pathology, the 309th hospital of PLADepartment of Tissue Engineering, Beijing Institute of Transfusion MedicineAbstract Background The tumor acidic microenvironment, a common biochemical event in solid tumors, offers evolutional advantage for tumors cells and even enhances their aggressive phenotype. However, little is known about the molecular mechanism underlying the acidic microenvironment-induced invasion and metastasis. Methods We examined the expression of the acid-sending ion channel (ASIC) family members after acidic exposure using RT-PCR and immunofluoresence. Gene manipulation was applied to reveal the potential of ASIC2 on invasion, proliferation, colony formation of colorectal cancer (CRC). We assessed the in vivo tumor growth by subcutaneous transplantation and metastasis by spleen xenografts. Chromatin immunoprecipitation-sequencing was used to uncover the binding sites of NFAT1. Finally, we examined the expression of ASIC2 in CRC tissues using immunohistochemistry. Results Acidic exposure led to up-regulation of the acid-sensing ion channel, ASIC2, in colorectal cancer (CRC) cells. ASIC2 overexpression in CRC cell lines, SW480 and HCT116, significantly enhanced cell proliferation in vitro and in vivo, while ASIC2 knockdown had the reverse effect. Importantly, ASIC2 promoted CRC cell invasion under acidosis in vitro and liver metastasis in vivo. Mechanistically, ASIC2 activated the calcineurin/NFAT1 signaling pathway under acidosis. Inhibition of the calcineurin/NFAT pathway by cyclosporine A (CsA) profoundly attenuated ASIC2-induced invasion under acidosis. ChIP-seq assay revealed that the nuclear factor, NFAT1, binds to genes clustered in pathways involved in Rho GTPase signaling and calcium signaling. Furthermore, immunohistochemistry showed that ASIC2 expression is increased in CRC samples compared to that in adjacent tissues, and ASIC2 expression correlates with T-stage, distant metastasis, recurrence, and poor prognosis. Conclusion ASIC2 promotes metastasis of CRC cells by activating the calcineurin/NFAT1 pathway under acidosis and high expression of ASIC2 predicts poor outcomes of patients with CRC.http://link.springer.com/article/10.1186/s13046-017-0599-9Colorectal cancerAcidosisASIC2NFAT1Metastasis |
| spellingShingle | Zhi-hang Zhou Jin-wen Song Wen Li Xue Liu Liu Cao Lu-ming Wan Ying-xia Tan Shou-ping Ji Yu-mei Liang Feng Gong The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis Journal of Experimental & Clinical Cancer Research Colorectal cancer Acidosis ASIC2 NFAT1 Metastasis |
| title | The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis |
| title_full | The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis |
| title_fullStr | The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis |
| title_full_unstemmed | The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis |
| title_short | The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis |
| title_sort | acid sensing ion channel asic2 promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin nfat1 axis |
| topic | Colorectal cancer Acidosis ASIC2 NFAT1 Metastasis |
| url | http://link.springer.com/article/10.1186/s13046-017-0599-9 |
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