The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis

• Published in: Journal of experimental & clinical cancer research 2017-09, Vol.36 (1), p.130-130, Article 130
• Main Authors: Zhou, Zhi-Hang, Song, Jin-Wen, Li, Wen, Liu, Xue, Cao, Liu, Wan, Lu-Ming, Tan, Ying-Xia, Ji, Shou-Ping, Liang, Yu-Mei, Gong, Feng
• Format: Article
• Language: English
• Subjects: Acid Sensing Ion Channels - metabolism; Acidosis; Acidosis - metabolism; Acids; Aged; Angiogenesis; Animals; Apoptosis; ASIC2; Binding Sites; Breast cancer; Calcineurin - metabolism; Calcium - metabolism; Cell cycle; Cell Line, Tumor; Cell Proliferation; Colorectal cancer; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Complications and side effects; Development and progression; Female; Gene Expression Regulation, Neoplastic; Genetic aspects; HCT116 Cells; HT29 Cells; Humans; Inflammatory bowel disease; Ion channels; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - secondary; Lung cancer; Male; Medical prognosis; Metastasis; Mice; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasm Transplantation; Nervous system; NFAT1; NFATC Transcription Factors - chemistry; NFATC Transcription Factors - metabolism; Physiological aspects; Physiology; Proteins; rho GTP-Binding Proteins - metabolism; Rodents; Signal Transduction; Studies; Transcription factors; Tumor Microenvironment
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-017-0599-9

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. 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. 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. 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.