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Orai1, a Direct Target of microRNA-519, Promotes Progression of Colorectal Cancer via Akt/GSK3β Signaling Pathway

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Abstract

Background

Orai1, which is involved in store-operated calcium entry, has recently been implicated in cancer progression. However, the role of Orai1 in colorectal cancer (CRC) progression remains unclear.

Methods

We used real-time PCR and western blot to measure Orai1 expression in four CRC cell lines, 60 tumor pairs, and corresponding non-tumor tissues from CRC patients. Immunohistochemistry was performed to examine Orai1 expression in CRC and corresponding non-tumor tissues. Statistical analyses were applied to evaluate the prognostic value and associations of Orai1 expression with clinical parameters. Furthermore, the Orai1 gene was overexpressed in HCT116 cell and silenced with siRNA in LOVO cell. Moreover, cell proliferation and apoptosis were measured using MTT assay and flow cytometry, and a molecular mechanism of Orai1 regulation by miR-519 was explored.

Results

Orai1 expression was higher in CRC tissues than adjacent non-cancerous tissues, and this was positively correlated in CRC patients with distant metastasis and poor prognosis. Also, increased expression of Orai1 was observed in highly invasive CRC cell lines and ectopic expression of Orai1 enhanced cell proliferation and inhibited apoptosis; silencing Orai1 suppressed cell proliferation and induced apoptosis. The Akt/GSK3β pathway contributed to Orai1 effects in CRC cells, and Orai1 was a direct target of miR-519, a microRNA not previously reported to be involved in both CRC tissues and cell lines.

Conclusions

We identified a novel CRC regulatory circuit involving the miR-519-Orai1 axis, and dysfunction of this drives diverse aspects of CRC pathogenesis.

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References

  1. Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin. 2009;59:366–378.

    Article  PubMed  Google Scholar 

  2. Chibaudel B, Tournigand C, Andre T, de Gramont A. Therapeutic strategy in unresectable metastatic colorectal cancer. Ther Adv Med Oncol. 2012;4:75–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zheng L, Zhang Y, Liu Y, et al. MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer. J Transl Med. 2015;13:252.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Prevarskaya N, Skryma R, Shuba Y. Calcium in tumour metastasis: new roles for known actors. Nat Rev Cancer. 2011;11:609–618.

    Article  CAS  PubMed  Google Scholar 

  5. Parkash J, Asotra K. Calcium wave signaling in cancer cells. Life Sci. 2010;87:587–595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roberts-Thomson SJ, Peters AA, Grice DM, Monteith GR. ORAI-mediated calcium entry: mechanism and roles, diseases and pharmacology. Pharmacol Ther. 2010;127:121–130.

    Article  CAS  PubMed  Google Scholar 

  7. Parekh AB. Store-operated CRAC channels: function in health and disease. Nat Rev Drug Discovery. 2010;9:399–410.

    Article  CAS  PubMed  Google Scholar 

  8. Song K, Zhong XG, Xia XM, et al. Orai1 forms a signal complex with SK3 channel in gallbladder smooth muscle. Biochem Biophys Res Commun. 2015;466:456–462.

    Article  CAS  PubMed  Google Scholar 

  9. Fedida-Metula S, Feldman B, Koshelev V, Levin-Gromiko U, Voronov E, Fishman D. Lipid rafts couple store-operated Ca2+ entry to constitutive activation of PKB/Akt in a Ca2+/calmodulin-, Src- and PP2A-mediated pathway and promote melanoma tumor growth. Carcinogenesis. 2012;33:740–750.

    Article  CAS  PubMed  Google Scholar 

  10. Davis FM, Azimi I, Faville RA, et al. Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Oncogene. 2014;33:2307–2316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang S, Zhang JJ, Huang XY. Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell. 2009;15:124–134.

    Article  CAS  PubMed  Google Scholar 

  12. Chen YF, Chiu WT, Chen YT, et al. Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis. Proc Natl Acad Sci USA. 2011;108:15225–15230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu H, Zhang H, Jin F, et al. Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma. Oncotarget. 2014;5:3455–3471.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhan ZY, Zhong LX, Feng M, Wang JF, Liu DB, Xiong JP. Over-expression of Orai1 mediates cell proliferation and associates with poor prognosis in human non-small cell lung carcinoma. Int J Clin Exp Pathol. 2015;8:5080–5088.

    PubMed  PubMed Central  Google Scholar 

  15. Abdelmohsen K, Kim MM, Srikantan S, et al. miR-519 suppresses tumor growth by reducing HuR levels. Cell Cycle (Georgetown, Tex.). 2010;9:1354–1359.

    Article  CAS  Google Scholar 

  16. Abdelmohsen K, Srikantan S, Tominaga K, et al. Growth inhibition by miR-519 via multiple p21-inducing pathways. Mol Cell Biol. 2012;32:2530–2548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qin Y, Wang J, Gong W, et al. UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest. Oncol Rep. 2014;31:2635–2643.

    CAS  PubMed  Google Scholar 

  18. Cvejic S, Zhu Z, Felice SJ, Berman Y, Huang XY. The endogenous ligand Stunted of the GPCR Methuselah extends lifespan in Drosophila. Nat Cell Biol. 2004;6:540–546.

    Article  CAS  PubMed  Google Scholar 

  19. Tommasi S, Pinto R, Pilato B, Paradiso A. Molecular pathways and related target therapies in liver carcinoma. Curr Pharm Des. 2007;13:3279–3287.

    Article  CAS  PubMed  Google Scholar 

  20. Liu L, Dong Z, Liang J, et al. As an independent prognostic factor, FAT10 promotes hepatitis B virus-related hepatocellular carcinoma progression via Akt/GSK3beta pathway. Oncogene. 2014;33:909–920.

    Article  CAS  PubMed  Google Scholar 

  21. Garrett CR, Coppola D, Wenham RM, et al. Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest New Drugs. 2011;29:1381–1389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang H, Li Y, Lai M. The microRNA network and tumor metastasis. Oncogene. 2010;29:937–948.

    Article  CAS  PubMed  Google Scholar 

  23. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517–529.

    Article  CAS  PubMed  Google Scholar 

  24. Chiu WT, Tang MJ, Jao HC, Shen MR. Soft substrate up-regulates the interaction of STIM1 with store-operated Ca2+ channels that lead to normal epithelial cell apoptosis. Mol Biol Cell. 2008;19:2220–2230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des. 2010;16:34–44.

    Article  CAS  PubMed  Google Scholar 

  26. Jayadev S, Petranka JG, Cheran SK, Biermann JA, Barrett JC, Murphy E. Reduced capacitative calcium entry correlates with vesicle accumulation and apoptosis. J Biol Chem. 1999;274:8261–8268.

    Article  CAS  PubMed  Google Scholar 

  27. Parekh AB, Putney JW Jr. Store-operated calcium channels. Physiol Rev. 2005;85:757–810.

    Article  CAS  PubMed  Google Scholar 

  28. Zanotto-Filho A, Braganhol E, Schroder R, et al. NFkappaB inhibitors induce cell death in glioblastomas. Biochem Pharmacol. 2011;81:412–424.

    Article  CAS  PubMed  Google Scholar 

  29. Makeyev EV, Maniatis T. Multilevel regulation of gene expression by microRNAs. Science (New York, N.Y.). 2008;319:1789–1790.

    Article  CAS  Google Scholar 

  30. Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9:189–198.

    Article  CAS  PubMed  Google Scholar 

  31. Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development (Cambridge, England). 2005;132:4653–4662.

    Article  CAS  Google Scholar 

  32. Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685–689.

    Article  PubMed  Google Scholar 

  33. Abdelmohsen K, Srikantan S, Kuwano Y, Gorospe M. miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels. Proc Natl Acad Sci USA. 2008;105:20297–20302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript. This study was supported by grants from the National Natural Science Foundation of China (No. 51320154).

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Authors and Affiliations

  1. Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Xicheng District, Beijing, 100050, China

    Wei Deng, Jin Wang, Jun Zhang, Jun Cai, Zhigang Bai & Zhongtao Zhang

  2. National Clinical Research Center of Digestive Diseases, Beijing, 100050, China

    Wei Deng, Jin Wang, Jun Zhang, Jun Cai, Zhigang Bai & Zhongtao Zhang

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  1. Wei Deng
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  2. Jin Wang
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  3. Jun Zhang
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Correspondence to Zhongtao Zhang.

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Deng, W., Wang, J., Zhang, J. et al. Orai1, a Direct Target of microRNA-519, Promotes Progression of Colorectal Cancer via Akt/GSK3β Signaling Pathway. Dig Dis Sci 61, 1553–1560 (2016). https://doi.org/10.1007/s10620-015-4029-6

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  • DOI: https://doi.org/10.1007/s10620-015-4029-6

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