Skip to main content
SpringerLink
Log in

Involvement of acid-sensing ion channel 1α in hepatic carcinoma cell migration and invasion

  • Research Article
  • Published:
Tumor Biology

Abstract

An acidic microenvironment promotes carcinoma cell proliferation and migration. Acid-sensing ion channels (ASICs) are H+, Ca2+, and Na+-gated cation channels that are activated by changes in the extracellular pH, and ASIC1α may be associated with tumor proliferation and migration. Here, we investigated the role of ASIC1α in hepatocellular carcinoma (HCC) migration and invasion. The expression of ASIC1α was examined in 15 paired HCC and adjacent non-tumor tissues by immunohistochemistry. Reverse transcription (RT)-PCR and Western blotting were used to assess ASIC1α messenger RNA (mRNA) and protein expression in the HCC cell line SMMC-7721 cultured in different pH media or transfected with short hairpin RNA (shRNA) against ASIC1α. Cell migration ability was detected by wound healing and Transwell assays. ASIC1α expression was significantly higher in tumor tissues than in non-tumor tissues, and it was higher in HCC with postoperative metastasis than in that without metastasis. ASIC1α mRNA and protein expression was significantly higher in SMMC-7721 cells cultured at pH 6.5 than in those cultured at pH 7.4 and 6.0. shRNA-mediated silencing of ASIC1α significantly downregulated ASIC1α mRNA and protein expression compared with negative control or untransfected cells and inhibited HCC cell migration and invasion. ASIC1α is overexpressed in HCC tissues and associated with advanced clinical stage. A moderately acidic extracellular environment promoted ASIC1α expression, and silencing of ASIC1α expression inhibited the migration and invasion of HCC cells. Suppression of ASIC1α expression by RNAi attenuated the malignant phenotype of HCC cells, suggesting a novel approach for anticancer gene therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, et al. Acidic extracellular microenvironment and cancer. Cancer Cell Int. 2013;13:89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hrgovic I, Glavic Z, Kovacic Z, Mulic S, Zunic L, Hrgovic Z. Repeated administration of inhibitors for ion pumps reduce markedly tumor growth in vivo. Med Arch. 2014;68:76–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Xiong ZG, Chu XP, Simon RP. Acid sensing ion channels—novel therapeutic targets for ischemic brain injury. Front Biosci. 2007;12:1376–86.

    Article  CAS  PubMed  Google Scholar 

  4. Chu XP, Grasing KA, Wang JQ. Acid-sensing ion channels contribute to neurotoxicity. Transl Stroke Res. 2014;5:69–78.

    Article  CAS  PubMed  Google Scholar 

  5. Kellenberger S, Schild L. Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev. 2002;82:735–67.

    Article  CAS  PubMed  Google Scholar 

  6. Wemmie JA, Chen J, Askwith CC, Hruska-Hageman AM, Price MP, Nolan BC, et al. The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron. 2002;34:463–77.

    Article  CAS  PubMed  Google Scholar 

  7. Kweon HJ, Suh BC. Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation. BMB Rep. 2013;46:295–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sun X, Cao YB, Hu LF, Yang YP, Li J, Wang F, et al. ASICs mediate the modulatory effect by paeoniflorin on alpha-synuclein autophagic degradation. Brain Res. 2011;1396:77–87.

    Article  CAS  PubMed  Google Scholar 

  9. Weng XC, Zheng JQ, Li J, Xiao WB. Underlying mechanism of ASIC1a involved in acidosis-induced cytotoxicity in rat C6 glioma cells. Acta Pharmacol Sin. 2007;28:1731–6.

    Article  CAS  PubMed  Google Scholar 

  10. Jean C, Gravelle P, Fournie JJ, Laurent G. Influence of stress on extracellular matrix and integrin biology. Oncogene. 2011;30:2697–706.

    Article  CAS  PubMed  Google Scholar 

  11. Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell. 2004;118:687–98.

    Article  CAS  PubMed  Google Scholar 

  12. Xiong ZG, Chu XP, Simon RP. Ca2+-permeable acid-sensing ion channels and ischemic brain injury. J Membr Biol. 2006;209:59–68.

    Article  CAS  PubMed  Google Scholar 

  13. Li M, Inoue K, Branigan D, Kratzer E, Hansen JC, Chen JW, et al. Acid-sensing ion channels in acidosis-induced injury of human brain neurons. J Cereb Blood Flow Metab. 2010;30:1247–60.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hey JG, Chu XP, Seeds J, Simon RP, Xiong ZG. Extracellular zinc protects against acidosis-induced injury of cells expressing Ca2+-permeable acid-sensing ion channels. Stroke. 2007;38:670–3.

    Article  CAS  PubMed  Google Scholar 

  15. Lee S, Mele M, Vahl P, Christiansen PM, Jensen VE, Boedtkjer E: Na,HCO -cotransport is functionally upregulated during human breast carcinogenesis and required for the inverted ph gradient across the plasma membrane. Pflugers Arch. 2014

  16. Sun X, Zhao D, Li YL, Sun Y, Lei XH, Zhang JN, et al. Regulation of ASIC1 by Ca2+/calmodulin-dependent protein kinase II in human glioblastoma multiforme. Oncol Rep. 2013;30:2852–8.

    CAS  PubMed  Google Scholar 

  17. Berdiev BK, Xia J, McLean LA, Markert JM, Gillespie GY, Mapstone TB, et al. Acid-sensing ion channels in malignant gliomas. J Biol Chem. 2003;278:15023–34.

    Article  CAS  PubMed  Google Scholar 

  18. Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, et al. Cox-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer. 2000;89:2637–45.

    Article  CAS  PubMed  Google Scholar 

  19. Cuddapah VA, Sontheimer H. Ion channels and transporters [corrected] in cancer. 2. Ion channels and the control of cancer cell migration. Am J Physiol Cell Physiol. 2011;301:C541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang Y, Wu X, Li Q, Zhang S, Li SJ. Human voltage-gated proton channel Hv1: a new potential biomarker for diagnosis and prognosis of colorectal cancer. PLoS One. 2013;8:e70550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yuan FL, Chen FH, Lu WG, Li X, Wu FR, Li JP, et al. Acid-sensing ion channel 1a mediates acid-induced increases in intracellular calcium in rat articular chondrocytes. Mol Cell Biochem. 2010;340:153–9.

    Article  CAS  PubMed  Google Scholar 

  22. Leanza L, Biasutto L, Manago A, Gulbins E, Zoratti M, Szabo I. Intracellular ion channels and cancer. Front Physiol. 2013;4:227.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Guo YC, Chang CM, Hsu WL, Chiu SJ, Tsai YT, Chou YH, et al. Indomethacin inhibits cancer cell migration via attenuation of cellular calcium mobilization. Molecules. 2013;18:6584–96.

    Article  CAS  PubMed  Google Scholar 

  24. Le GJ, Ouadid-Ahidouch H, Soriani O, Besson P, Ahidouch A, Vandier C. Voltage-gated ion channels, new targets in anti-cancer research. Recent Patents Anticancer Drug Discov. 2007;2:189–202.

    Article  Google Scholar 

  25. Brackenbury WJ. Voltage-gated sodium channels and metastatic disease. Channels (Austin). 2012;6:352–61.

    Article  CAS  Google Scholar 

  26. Prevarskaya N, Skryma R, Bidaux G, Flourakis M, Shuba Y. Ion channels in death and differentiation of prostate cancer cells. Cell Death Differ. 2007;14:1295–304.

    Article  CAS  PubMed  Google Scholar 

  27. Brackenbury WJ, Djamgoz MB, Isom LL. An emerging role for voltage-gated Na + channels in cellular migration: regulation of central nervous system development and potentiation of invasive cancers. Neuroscientist. 2008;14:571–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Andersen AP, Moreira JM, Pedersen SF. Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130098.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Waldmann R, Champigny G, Lingueglia E, De Weille JR, Heurteaux C, Lazdunski M. H(+)-gated cation channels. Ann N Y Acad Sci. 1999;868:67–76.

    Article  CAS  PubMed  Google Scholar 

  30. Thongon N, Ketkeaw P, Nuekchob C. The roles of acid-sensing ion channel 1a and ovarian cancer G protein-coupled receptor 1 on passive Mg2+ transport across intestinal epithelium-like Caco-2 monolayers. J Physiol Sci. 2014;64:129–39.

    Article  CAS  PubMed  Google Scholar 

  31. Rothberg JM, Bailey KM, Wojtkowiak JW, Ben-Nun Y, Bogyo M, Weber E, et al. Acid-mediated tumor proteolysis: contribution of cysteine cathepsins. Neoplasia. 2013;15:1125–37.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Vukovic V, Tannock IF. Influence of low ph on cytotoxicity of paclitaxel, mitoxantrone and topotecan. Br J Cancer. 1997;75:1167–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Karuri AR, Dobrowsky E, Tannock IF. Selective cellular acidification and toxicity of weak organic acids in an acidic microenvironment. Br J Cancer. 1993;68:1080–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kapoor N, Bartoszewski R, Qadri YJ, Bebok Z, Bubien JK, Fuller CM, et al. Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration. J Biol Chem. 2009;284:24526–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kapoor N, Lee W, Clark E, Bartoszewski R, McNicholas CM, Latham CB, et al. Interaction of ASIC1 and ENaC subunits in human glioma cells and rat astrocytes. Am J Physiol Cell Physiol. 2011;300:C1246–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rooj AK, McNicholas CM, Bartoszewski R, Bebok Z, Benos DJ, Fuller CM. Glioma-specific cation conductance regulates migration and cell cycle progression. J Biol Chem. 2012;287:4053–65.

    Article  CAS  PubMed  Google Scholar 

  37. Grifoni SC, Jernigan NL, Hamilton G, Drummond HA. ASIC proteins regulate smooth muscle cell migration. Microvasc Res. 2008;75:202–10.

    Article  CAS  PubMed  Google Scholar 

  38. Arun T, Tomassini V, Sbardella E, de Ruiter MB, Matthews L, Leite MI, et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain. 2013;136:106–15.

    Article  PubMed  Google Scholar 

  39. Diochot S, Baron A, Salinas M, Douguet D, Scarzello S, Dabert-Gay AS, et al. Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature. 2012;490:552–5.

    Article  CAS  PubMed  Google Scholar 

  40. Eisenhut M, Wallace H. Ion channels in inflammation. Pflugers Arch. 2011;461:401–21.

    Article  CAS  PubMed  Google Scholar 

  41. Yuan FL, Chen FH, Lu WG, Li X. Acid-sensing ion channels 3: a potential therapeutic target for pain treatment in arthritis. Mol Biol Rep. 2010;37:3233–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 81301805 and No. 81270011) and the joint research project of hospital management center in Wuxi (No. YGZX1305 and No. YGZX1107). In addition, we are grateful for the guidance of Professor QH Ye.

Author information

Authors and Affiliations

  1. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China

    Cheng Jin, Qing-Hai Ye, Ying-Hong Shi & Zhen-Hai Lin

  2. Department of Hepatobiliary Pancreatic Center, The Third Hospital Affiliated to Nantong University, Wuxi, 214041, Jiangsu, China

    Cheng Jin, Feng-Lai Yuan, Yuan-Long Gu, Jian-Ping Li, Xiao-Min Shen &  Bo-Liu

Authors
  1. Cheng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qing-Hai Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng-Lai Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuan-Long Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian-Ping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying-Hong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Min Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bo-Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhen-Hai Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qing-Hai Ye.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jin, C., Ye, QH., Yuan, FL. et al. Involvement of acid-sensing ion channel 1α in hepatic carcinoma cell migration and invasion. Tumor Biol. 36, 4309–4317 (2015). https://doi.org/10.1007/s13277-015-3070-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3070-6

Keywords

Search

Navigation