Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

microRNA-200a downregulation in human glioma leads to Gαi1 over-expression, Akt activation, and cell proliferation

Oncogene volume 37, pages 2890–2902 (2018)Cite this article

Subjects

Abstract

We previously identified a pivotal role for G protein α inhibitory subunit 1 (Gαi1) in mediating PI3K-Akt signaling by receptor tyrosine kinases (RTKs). Here, we examined the expression and biological function of Gαi1 in human glioma. Gαi1 mRNA and protein expression were significantly upregulated in human glioma tissues, which correlated with downregulation of an anti-Gαi1 miRNA: microRNA-200a (“miR-200a”). Forced-expression of miR-200a in established (A172/U251MG lines) and primary (patient-derived) human glioma cells resulted in Gαi1 downregulation, Akt inactivation and proliferation inhibition. Reduction of Gαi1 expression by shRNA, dominant negative mutant interference, or complete Gαi1 depletion inhibited Akt activation and cell proliferation. Notably, miR-200a was unable to inhibit glioma cell proliferation when Gαi1 was silenced or mutated. Co-immunoprecipitation studies, in human glioma cells and tissues, show that Gαi1 forms a complex with multiple RTKs (EGFR, PDGFRα, and FGFR) and the adapter protein Gab1. In vivo, the growth of subcutaneous and orthotopic glioma xenografts in nude mice was largely inhibited by expression of Gαi1 shRNA or miRNA-200a. Collectively, miR-200a downregulation in human glioma leads to Gαi1 over-expression, Akt activation and glioma cell proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Westphal M, Lamszus K. The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat Rev Neurosci. 2011;12:495–508.

    Article  CAS  PubMed  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  3. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  4. Khasraw M, Lassman AB. Neuro-oncology: late neurocognitive decline after radiotherapy for low-grade glioma. Nat Rev Neurol. 2009;5:646–7.

    Article  PubMed  Google Scholar 

  5. Pollack IF. Neuro-oncology: Therapeutic benefits of reirradiation for recurrent brain tumors. Nat Rev Neurol. 2010;6:533–5.

    Article  PubMed  Google Scholar 

  6. Wang Y, Jiang T. Understanding high grade glioma: molecular mechanism, therapy and comprehensive management. Cancer Lett. 2013;331:139–46.

    Article  CAS  PubMed  Google Scholar 

  7. Bostrom J, Cobbers JM, Wolter M, Tabatabai G, Weber RG, Lichter P, et al. Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res. 1998;58:29–33.

    CAS  PubMed  Google Scholar 

  8. Huang TT, Sarkaria SM, Cloughesy TF, Mischel PS. Targeted therapy for malignant glioma patients: lessons learned and the road ahead. Neurotherapeutics. 2009;6:500–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lefranc F, Rynkowski M, DeWitte O, Kiss R. Present and potential future adjuvant issues in high-grade astrocytic glioma treatment. Adv Tech Stand Neurosurg. 2009;34:3–35.

    Article  CAS  PubMed  Google Scholar 

  10. Li X, Wu C, Chen N, Gu H, Yen A, Cao L, et al. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 2016;7:33440–50.

    PubMed  PubMed Central  Google Scholar 

  11. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318:287–90.

    Article  CAS  PubMed  Google Scholar 

  12. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell. 2011;20:810–7.

    Article  CAS  PubMed  Google Scholar 

  13. Lo HW. EGFR-targeted therapy in malignant glioma: novel aspects and mechanisms of drug resistance. Curr Mol Pharmacol. 2010;3:37–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7:261–9.

    Article  CAS  PubMed  Google Scholar 

  15. Cao C, Huang X, Han Y, Wan Y, Birnbaumer L, Feng GS, et al. Galpha(i1) and Galpha(i3) are required for epidermal growth factor-mediated activation of the Akt-mTORC1 pathway. Sci Signal. 2009;2:ra17.

    PubMed  PubMed Central  Google Scholar 

  16. Zhang YM, Zhang ZQ, Liu YY, Zhou X, Shi XH, Jiang Q, et al. Requirement of Galphai1/3-Gab1 signaling complex for keratinocyte growth factor-induced PI3K-AKT-mTORC1 activation. J Invest Dermatol. 2015;135:181–91.

    Article  CAS  PubMed  Google Scholar 

  17. Li ZW, Cai S, Liu Y, Yang CL, Tian Y, Chen G, et al. Over-expression of Galphai3 in human glioma is required for Akt-mTOR activation and cell growth. Oncotarget. 2016.

  18. Cai S, Li Y, Bai JY, Zhang ZQ, Wang Y, Qiao YB, et al. Galphai3 nuclear translocation causes irradiation resistance in human glioma cells. Oncotarget. 2017;8:35061–8.

    PubMed  PubMed Central  Google Scholar 

  19. Wang Z, Dela Cruz R, Ji F, Guo S, Zhang J, Wang Y, et al. G(i)alpha proteins exhibit functional differences in the activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells. Cell Commun Signal. 2014;12:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li X, Wang D, Chen Z, Lu E, Wang Z, Duan J, et al. Galphai1 and Galphai3 regulate macrophage polarization by forming a complex containing CD14 and Gab1. Proc Natl Acad Sci USA. 2015;112:4731–6.

    Article  CAS  PubMed  Google Scholar 

  21. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med. 2008;14:1097–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Huang AL, Ostrowski MC, Berard D, Hager GL. Glucocorticoid regulation of the Ha-MuSV p21 gene conferred by sequences from mouse mammary tumor virus. Cell. 1981;27:245–55.

    Article  CAS  PubMed  Google Scholar 

  23. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.

    Article  CAS  Google Scholar 

  24. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010;9:1956–67.

    Article  CAS  PubMed  Google Scholar 

  25. Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, et al. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res. 2007;13:4261–70.

    Article  CAS  PubMed  Google Scholar 

  26. Liu M, Hu C, Xu Q, Chen L, Ma K, Xu N, et al. Methylseleninic acid activates Keap1/Nrf2 pathway via up-regulating miR-200a in human oesophageal squamous cell carcinoma cells. Biosci Rep. 2015;35. art:e00256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Faivre S, Regnauld K, Bruyneel E, Nguyen QD, Mareel M, Emami S, et al. Suppression of cellular invasion by activated G-protein subunits Galphao, Galphai1, Galphai2, and Galphai3 and sequestration of Gbetagamma. Mol Pharmacol. 2001;60:363–72.

    Article  CAS  PubMed  Google Scholar 

  28. Agnihotri S, Gajadhar AS, Ternamian C, Gorlia T, Diefes KL, Mischel PS, et al. Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients. J Clin Invest. 2012;122:253–66.

    Article  CAS  PubMed  Google Scholar 

  29. Shashidhar S, Lorente G, Nagavarapu U, Nelson A, Kuo J, Cummins J, et al. GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion. Oncogene. 2005;24:1673–82.

    Article  CAS  PubMed  Google Scholar 

  30. Andradas C, Caffarel MM, Perez-Gomez E, Salazar M, Lorente M, Velasco G, et al. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene. 2011;30:245–52.

    Article  CAS  PubMed  Google Scholar 

  31. Furman MA, Shulman K. Cyclic AMP and adenyl cyclase in brain tumors. J Neurosurg. 1977;46:477–83.

    Article  CAS  PubMed  Google Scholar 

  32. He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, et al. The G protein alpha subunit Galphas is a tumor suppressor in Sonic hedgehog-driven medulloblastoma. Nat Med. 2014;20:1035–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gong YQ, Huang W, Li KR, Liu YY, Cao GF, Cao C, et al. SC79 protects retinal pigment epithelium cells from UV radiation via activating Akt-Nrf2 signaling. Oncotarget. 2016;7:60123–32.

    PubMed  PubMed Central  Google Scholar 

  34. Li KR, Yang SQ, Gong YQ, Yang H, Li XM, Zhao YX, et al. 3H-1,2-dithiole-3-thione protects retinal pigment epithelium cells against Ultra-violet radiation via activation of Akt-mTORC1-dependent Nrf2-HO-1 signaling. Sci Rep. 2016;6:25525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang H, Liu YY, Jiang Q, Li KR, Zhao YX, Cao C, et al. Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling. Free Radic Biol Med. 2014;69:219–28.

    Article  CAS  PubMed  Google Scholar 

  36. Schmittgen TD, Zakrajsek BA. Effect of experimental treatment on housekeeping gene expression: validation by real-time, quantitative RT-PCR. J Biochem Biophys Methods. 2000;46:69–81.

    Article  CAS  PubMed  Google Scholar 

  37. Fan JB, Ruan JW, Liu W, Zhu LQ, Zhu XH, Yi H, et al. miR-135b expression downregulates Ppm1e to activate AMPK signaling and protect osteoblastic cells from dexamethasone. Oncotarget. 2016;7:70613–22.

    PubMed  PubMed Central  Google Scholar 

  38. Cao C, Rioult-Pedotti MS, Migani P, Yu CJ, Tiwari R, Parang K, et al. Impairment of TrkB-PSD-95 signaling in Angelman syndrome. PLoS Biol. 2013;11:e1001478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang D, Xia H, Zhang W, Fang B. The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor. Tumour Biol. 2016;37:1327–36.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by grants from the National Natural Science Foundation of China (81502162, 81771457, 81371055, and 81570859, 81302195, 31371139 and 81502162, 81571282, 81472786, and 81773192); Grants from Natural Science Foundation of Jiangsu Province (BK20130301, BK20170060, and BK20171248), and by Clinical Special Project of Suzhou (LCZX201601). We thank Dr. John Marshall for English edits and proof-reading of the manuscript.

Author information

Authors and Affiliations

  1. Clinical Research and Lab Center, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan, China

    Yuan-yuan Liu

  2. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China

    Yuan-yuan Liu, Long Cheng, Zhi-qing Zhang & Cong Cao

  3. Department of Radiotherapy and Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan, China

    Min-Bin Chen

  4. Department of Interventional Radiology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China

    Long Cheng

  5. Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China

    Zheng-quan Yu & Gang Chen

  6. The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, China

    Qin Jiang & Cong Cao

  7. North District, The Municipal Hospital of Suzhou, Suzhou, China

    Cong Cao

Authors
  1. Yuan-yuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min-Bin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Long Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi-qing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng-quan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qin Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Qin Jiang, Gang Chen or Cong Cao.

Ethics declarations

Conflict of interest

The autthors declare that they have no conflict of interest.

Additional information

Co-first authors: Yuan-yuan Liu, Min-Bin Chen, Long Cheng, Zhi-qing Zhang.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Yy., Chen, MB., Cheng, L. et al. microRNA-200a downregulation in human glioma leads to Gαi1 over-expression, Akt activation, and cell proliferation. Oncogene 37, 2890–2902 (2018). https://doi.org/10.1038/s41388-018-0184-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0184-5

This article is cited by

Search

Advanced search

Quick links