The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis
| Autor: | Liu Cao, Shou-Ping Ji, Yu-mei Liang, Lu-Ming Wan, Ying-Xia Tan, Jin-Wen Song, Feng Gong, Zhi-hang Zhou, Xue Liu, Wen Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
rho GTP-Binding Proteins 0301 basic medicine Cancer Research Metastasis Mice 0302 clinical medicine NFAT Pathway ASIC2 Tumor Microenvironment Gene knockdown Calcineurin Liver Neoplasms Middle Aged lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Female Signal transduction Colorectal Neoplasms Acidosis HT29 Cells Signal Transduction Biology lcsh:RC254-282 03 medical and health sciences Cell Line Tumor medicine Animals Humans Neoplasm Invasiveness Aged Cell Proliferation Neoplasm Staging Binding Sites NFATC Transcription Factors Cell growth Research NFAT1 HCT116 Cells medicine.disease Colorectal cancer Acid Sensing Ion Channels Transplantation 030104 developmental biology Apoptosis Cancer research Calcium Neoplasm Transplantation |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 36, Iss 1, Pp 1-12 (2017) Journal of Experimental & Clinical Cancer Research : CR |
| ISSN: | 1756-9966 |
| DOI: | 10.1186/s13046-017-0599-9 |
| Popis: | 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. Electronic supplementary material The online version of this article (10.1186/s13046-017-0599-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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