Skip to main content

Advertisement

SpringerLink
Log in

AXL is required for hypoxia-mediated hypoxia-inducible factor-1 alpha function in glioblastoma

  • Original Article
  • Published:
Toxicological Research Aims and scope Submit manuscript

Abstract

Glioblastoma (GBM) is the most aggressive type of central nervous system tumor. Molecular targeting may be important when developing efficient GBM treatment strategies. Sequencing of GBMs revealed that the receptor tyrosine kinase (RTK)/RAS/phosphatidylinositol-3-kinase pathway was altered in 88% of samples. Interestingly, AXL, a member of RTK, was proposed as a promising target in glioma therapy. However, the molecular mechanism of AXL modulation of GBM genesis and proliferation is still unclear. In this study, we investigated the expression and localization of hypoxia-inducible factor-1 alpha (HIF-1α) by AXL in GBM. Both AXL mRNA and protein are overexpressed in GBM. Short-interfering RNA knockdown of AXL in U251-MG cells reduced viability and migration. However, serum withdrawal reduced AXL expression, abolishing the effect on viability. AXL is also involved in hypoxia regulation. In hypoxic conditions, the reduction of AXL decreased the level and nuclear localization of HIF-1α. The co-expression of HIF-1α and AXL was found in human GBM samples but not normal tissue. This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic.

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

Adapted from cBioPortal: http://www.cbioportal.org/index.do. b Human glioma tissue arrays were immuno-histochemically analyzed in terms of AXL staining. Representative images from samples from two patients are shown. Scale bars: 100 μm. c Human glioma tissue arrays were immunohistochemically analyzed in terms of HIF-1α staining. Representative images from samples from two patients are shown. Scale bars: 100 μm. d the co-expression of AXL mRNA and HIF-1α mRNA from 142 queried glioblastoma (GBM) samples in the TCGA database. e The co-expression of AXL mRNA and HIF-1α mRNA from 182 ovarian serous cystadenocarcinoma queried samples. Adapted from cBioPortal: http://www.cbioportal.org /index.do. f The working model of the role of AXL in GBM survival. Under the control of the tumor microenvironment, such as the nutrient supply and hypoxia conditions, AXL translocates to the nucleus. The inhibition of HIF-1α degradation and the nuclear trans-localization of HIF-1α by hypoxia trigger the expression of AXL. Nuclear HIF-1α promotes the proliferation and survival genes in GBM

Similar content being viewed by others

Data availability

The proper data availability was provided in the figure legends and material and methods section (Fig. 5 legends, M&M).

References

  1. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 16:896–913. https://doi.org/10.1093/neuonc/nou087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ostrom QT, Cote DJ, Ascha M, Kruchko C, Barnholtz-Sloan JS (2018) Adult glioma incidence and survival by race or ethnicity in the united states from 2000 to 2014. JAMA Oncol 4:1254–1262. https://doi.org/10.1001/jamaoncol.2018.1789

    Article  PubMed  PubMed Central  Google Scholar 

  3. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23:1231–1251. https://doi.org/10.1093/neuonc/noab106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zakharova G, Efimov V, Raevskiy M, Rumiantsev P, Gudkov A, Belogurova-Ovchinnikova O, Sorokin M, Buzdin A (2022) Reclassification of TCGA diffuse glioma profiles linked to transcriptomic, epigenetic, genomic and clinical data, according to the 2021 WHO CNS tumor classification. Int J Mol Sci 24:157. https://doi.org/10.3390/ijms24010157

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mohammed S, Dinesan M, Ajayakumar T (2022) Survival and quality of life analysis in glioblastoma multiforme with adjuvant chemoradiotherapy: a retrospective study. Rep Pract Oncol Radiother 27:1026–1036. https://doi.org/10.5603/RPOR.a2022.0113

    Article  PubMed  PubMed Central  Google Scholar 

  6. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O’Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L, Network TR (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477. https://doi.org/10.1016/j.cell.2013.09.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, Cancer Genome Atlas Research N (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110. https://doi.org/10.1016/j.ccr.2009.12.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J, Kallop D, Ludlam MJ, Pei L (2009) Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene 28:3442–3455. https://doi.org/10.1038/onc.2009.212

    Article  CAS  PubMed  Google Scholar 

  9. Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N, Knyazeva T, Barbieri V, Reindl M, Muigg A, Kostron H, Stockhammer G, Ullrich A (2008) Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res 14:130–138. https://doi.org/10.1158/1078-0432.CCR-07-0862

    Article  CAS  PubMed  Google Scholar 

  10. Onken J, Torka R, Korsing S, Radke J, Krementeskaia I, Nieminen M, Bai X, Ullrich A, Heppner F, Vajkoczy P (2016) Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo. Oncotarget 7:9876–9889. https://doi.org/10.18632/oncotarget.7130

    Article  PubMed  PubMed Central  Google Scholar 

  11. O’Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET (1991) AXL, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol 11:5016–5031. https://doi.org/10.1128/mcb.11.10.5016-5031.1991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Craven RJ, Xu LH, Weiner TM, Fridell YW, Dent GA, Srivastava S, Varnum B, Liu ET, Cance WG (1995) Receptor tyrosine kinases expressed in metastatic colon cancer. Int J Cancer 60:791–797. https://doi.org/10.1002/ijc.2910600611

    Article  CAS  PubMed  Google Scholar 

  13. Ito T, Ito M, Naito S, Ohtsuru A, Nagayama Y, Kanematsu T, Yamashita S, Sekine I (1999) Expression of the AXL receptor tyrosine kinase in human thyroid carcinoma. Thyroid 9:563–567. https://doi.org/10.1089/thy.1999.9.563

    Article  CAS  PubMed  Google Scholar 

  14. Berclaz G, Altermatt HJ, Rohrbach V, Kieffer I, Dreher E, Andres AC (2001) Estrogen dependent expression of the receptor tyrosine kinase AXL in normal and malignant human breast. Ann Oncol 12:819–824. https://doi.org/10.1023/a:1011126330233

    Article  CAS  PubMed  Google Scholar 

  15. Sun W, Fujimoto J, Tamaya T (2004) Coexpression of Gas6/AXL in human ovarian cancers. Oncology 66:450–457. https://doi.org/10.1159/000079499

    Article  CAS  PubMed  Google Scholar 

  16. Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW (2005) Expression of AXL in lung adenocarcinoma and correlation with tumor progression. Neoplasia 7:1058–1064. https://doi.org/10.1593/neo.05640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Giles KM, Kalinowski FC, Candy PA, Epis MR, Zhang PM, Redfern AD, Stuart LM, Goodall GJ, Leedman PJ (2013) AXL mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib. Mol Cancer Ther 12:2541–2558. https://doi.org/10.1158/1535-7163.MCT-13-0170

    Article  CAS  PubMed  Google Scholar 

  18. Sainaghi PP, Castello L, Bergamasco L, Galletti M, Bellosta P, Avanzi GC (2005) Gas6 induces proliferation in prostate carcinoma cell lines expressing the AXL receptor. J Cell Physiol 204:36–44. https://doi.org/10.1002/jcp.20265

    Article  CAS  PubMed  Google Scholar 

  19. Falcone I, Conciatori F, Bazzichetto C, Bria E, Carbognin L, Malaguti P, Ferretti G, Cognetti F, Milella M, Ciuffreda L (2020) AXL receptor in breast cancer: molecular involvement and therapeutic limitations. Int J Mol Sci 21. https://doi.org/10.3390/ijms21228419

  20. He L, Lei Y, Hou J, Wu J and Lv G (2020) Implications of the receptor tyrosine kinase Axl in gastric cancer progression. Onco Targets Ther 13:5901–5911. https://doi.org/10.2147/ott.S257606

  21. Chung BI, Malkowicz SB, Nguyen TB, Libertino JA, McGarvey TW (2003) Expression of the proto-oncogene AXL in renal cell carcinoma. DNA Cell Biol 22:533–540. https://doi.org/10.1089/10445490360708946

    Article  CAS  PubMed  Google Scholar 

  22. Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, Wisner L, Iorio M, Shakalya K, Garewal H, Nagle R, Bearss D (2007) A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 26:3909–3919. https://doi.org/10.1038/sj.onc.1210173

    Article  CAS  PubMed  Google Scholar 

  23. Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, Lai GM, Chuang SE (2008) Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett 268:314–324. https://doi.org/10.1016/j.canlet.2008.04.017

    Article  CAS  PubMed  Google Scholar 

  24. Stone L (2017) Kidney cancer: AXL expression predicts prognosis. Nat Rev Urol 14:700. https://doi.org/10.1038/nrurol.2017.186

    Article  PubMed  Google Scholar 

  25. Ghiso E, Migliore C, Ciciriello V, Morando E, Petrelli A, Corso S, De Luca E, Gatti G, Volante M, Giordano S (2017) YAP-dependent AXL overexpression mediates resistance to EGFR inhibitors in NSCLC. Neoplasia 19:1012–1021. https://doi.org/10.1016/j.neo.2017.10.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kanlikilicer P, Ozpolat B, Aslan B, Bayraktar R, Gurbuz N, Rodriguez-Aguayo C, Bayraktar E, Denizli M, Gonzalez-Villasana V, Ivan C, Lokesh GLR, Amero P, Catuogno S, Haemmerle M, Wu SY, Mitra R, Gorenstein DG, Volk DE, de Franciscis V, Sood AK and Lopez-Berestein G (2017) Therapeutic targeting of AXL receptor tyrosine kinase inhibits tumor growth and intraperitoneal metastasis in ovarian cancer models. Mol Ther Nucleic Acids 9:251–262. https://doi.org/10.1016/j.omtn.2017.06.023

  27. Bao B, Azmi AS, Ali S, Ahmad A, Li Y, Banerjee S, Kong D, Sarkar FH (2012) The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochim Biophys Acta 1826:272–296. https://doi.org/10.1016/j.bbcan.2012.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Masoud GN, Li W (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5:378–389. https://doi.org/10.1016/j.apsb.2015.05.007

  29. Liu ZJ, Semenza GL, Zhang HF (2015) Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B 16:32–43. https://doi.org/10.1631/jzus.B1400221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613. https://doi.org/10.1128/MCB.16.9.4604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70. https://doi.org/10.1016/s0092-8674(00)81683-9

    Article  CAS  PubMed  Google Scholar 

  32. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364. https://doi.org/10.1016/S0092-8674(00)80108-7

    Article  CAS  PubMed  Google Scholar 

  33. Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE (1997) Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 3:1222–1227. https://doi.org/10.1038/nm1197-1222

    Article  CAS  PubMed  Google Scholar 

  34. Nalwoga H, Ahmed L, Arnes JB, Wabinga H, Akslen LA (2016) Strong expression of hypoxia-inducible factor-1α (HIF-1α) is associated with AXL expression and features of aggressive tumors in African breast cancer. PLoS One 11:e0146823. https://doi.org/10.1371/journal.pone.0146823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goyette MA, Elkholi IE, Apcher C, Kuasne H, Rothlin CV, Muller WJ, Richard DE, Park M, Gratton JP, Côté JF (2021) Targeting AXL favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels. Proc Natl Acad Sci USA 118:e2023868118. https://doi.org/10.1073/pnas.2023868118

    Article  PubMed  PubMed Central  Google Scholar 

  36. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 25:5675–5686. https://doi.org/10.1128/mcb.25.13.5675-5686.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, Kaelin WG Jr (2011) Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov 1:222–235. https://doi.org/10.1158/2159-8290.cd-11-0098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mazumder S, Higgins PJ, Samarakoon R (2023) Downstream targets of VHL/HIF-α signaling in renal clear cell carcinoma progression: mechanisms and therapeutic relevance. Cancers (Basel) 15:1316. https://doi.org/10.3390/cancers15041316

    Article  CAS  PubMed  Google Scholar 

  39. Na AY, Yang EJ, Jeon JM, Ki SH, Song KS, Lee S (2018) Protective effect of isoliquiritigenin against ethanol-induced hepatic steatosis by regulating the SIRT1-AMPK pathway. Toxicol Res 34:23–29. https://doi.org/10.5487/TR.2018.34.1.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tran Q, Jung JH, Park J, Lee H, Hong Y, Cho H, Kim M, Park S, Kwon SH, Kim SH, Thomas G, Kim KP, Cho MH, Park J (2018) S6 kinase 1 plays a key role in mitochondrial morphology and cellular energy flow. Cell Signal 48:13–24. https://doi.org/10.1016/j.cellsig.2018.04.002

    Article  CAS  PubMed  Google Scholar 

  41. Na CH, Hong JH, Kim WS, Shanta SR, Bang JY, Park D, Kim HK, Kim KP (2015) Identification of protein markers specific for papillary renal cell carcinoma using imaging mass spectrometry. Mol Cells 38:624–629. https://doi.org/10.14348/molcells.2015.0013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nalwoga H, Ahmed L, Arnes JB, Wabinga H, Akslen LA (2016) Strong expression of hypoxia-inducible factor-1alpha (HIF-1alpha) is associated with AXL expression and features of aggressive tumors in African breast cancer. PLoS One 11:e0146823. https://doi.org/10.1371/journal.pone.0146823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fernandes G, Fernandes BC, Valente V, Dos Santos JL (2018) Recent advances in the discovery of small molecules targeting glioblastoma. Eur J Med Chem 164:8–26. https://doi.org/10.1016/j.ejmech.2018.12.033

    Article  CAS  PubMed  Google Scholar 

  44. Geraldo LHM, Garcia C, da Fonseca ACC, Dubois LGF, de Sampaio ESTCL, Matias D, de Camargo Magalhaes ES, do Amaral RF, da Rosa BG, Grimaldi I, Leser FS, Janeiro JM, Macharia L, Wanjiru C, Pereira CM, Moura-Neto V, Freitas C, Lima FRS (2019) Glioblastoma therapy in the age of molecular medicine. Trends Cancer 5:46–65. https://doi.org/10.1016/j.trecan.2018.11.002

    Article  CAS  PubMed  Google Scholar 

  45. Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Luthar N, Toulany M, Gill PS, Salgia R, Kimple RJ, Wheeler DL (2014) AXL mediates resistance to cetuximab therapy. Cancer Res 74:5152–5164. https://doi.org/10.1158/0008-5472.Can-14-0294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zuo Q, Liu J, Huang L, Qin Y, Hawley T, Seo C, Merlino G, Yu Y (2018) AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma. Oncogene 37:3275–3289. https://doi.org/10.1038/s41388-018-0205-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mishra A, Wang J, Shiozawa Y, McGee S, Kim J, Jung Y, Joseph J, Berry JE, Havens A, Pienta KJ, Taichman RS (2012) Hypoxia stabilizes GAS6/AXL signaling in metastatic prostate cancer. Mol Cancer Res 10:703–712. https://doi.org/10.1158/1541-7786.MCR-11-0569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mattila PK, Lappalainen P (2008) Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol 9:446–454. https://doi.org/10.1038/nrm2406

    Article  CAS  PubMed  Google Scholar 

  49. Obacz J, Avril T, Le Reste PJ, Urra H, Quillien V, Hetz C, Chevet E (2017) Endoplasmic reticulum proteostasis in glioblastoma-from molecular mechanisms to therapeutic perspectives. Sci Signal 10:eaal2323. https://doi.org/10.1126/scisignal.aal2323

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by a research fund from Chungnam National University (grant to S.H. Kim) and by the Brain Korea 21 PLUS Project for Medical Science, Chungnam National University School of Medicine. This study was also supported by a research fund from Mongolian Foundation for Science and Technology (ShU/x/So-2017/06)

Funding

This work was financially supported by a research fund from Chungnam National University (grant to S.H. Kim) for initial screening and by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (NRF-2021R1A2C1008492, NRF-2020R1F1A1049801, NRF-2021R1C1C200845611) for the evaluation of AXL function in cell experiments. This study was also supported by a research fund from Mongolian Foundation for Science and Technology (ShU/x/So-2017/06) for bioinformatical analysis.

Author information

Author notes

  1. Thuy Trang T. Vo, Quangdon Tran and Youngeun Hong equally contributed to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea

    Thuy-Trang T. Vo, Quangdon Tran, Youngeun Hong, Hyunji Lee, Hyeonjeong Cho, Minhee Kim, Sungjin Park, Chaeyeong Kim, Jisoo Park & Jongsun Park

  2. Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea

    Thuy-Trang T. Vo, Quangdon Tran, Youngeun Hong, Hyunji Lee, Hyeonjeong Cho, Minhee Kim, Sungjin Park, Chaeyeong Kim, Jisoo Park & Jongsun Park

  3. Department of Graduate Education, Graduate School, Mongolian National University of Medical Sciences, Ulaanbaatar, 14210, Mongolia

    Choinyam Bayarmunkh & Damdindorj Boldbaatar

  4. Department of Physiology, Mongolian National University of Medical Sciences, Ulaanbaatar, 14210, Mongolia

    Choinyam Bayarmunkh & Damdindorj Boldbaatar

  5. College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea

    So Hee Kwon

  6. Department of Life Science, Hyehwa Liberal Arts College, LINC Plus Project Group, Daejeon University, Daejeon, 34520, Republic of Korea

    Jisoo Park

  7. Department of Neurosurgery, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea

    Seon-Hwan Kim

Authors
  1. Thuy-Trang T. Vo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Quangdon Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Youngeun Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyunji Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyeonjeong Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Minhee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sungjin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chaeyeong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Choinyam Bayarmunkh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Damdindorj Boldbaatar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. So Hee Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jisoo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Seon-Hwan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jongsun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Contributes to conception and design: QT, GK, JiP, YH and HL. Acquisition of data, or analysis and interpretation of data: QT, YH, HL, SK, JoP and JiP. Contributions to assist the exam and acquisition of data: CB, DB, CK, SP, SHK and SK. All authors agreed to be accountable for all aspects of the work and all authors read and approved the final manuscript.

Corresponding authors

Correspondence to Seon-Hwan Kim or Jongsun Park.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (JPG 29 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vo, TT.T., Tran, Q., Hong, Y. et al. AXL is required for hypoxia-mediated hypoxia-inducible factor-1 alpha function in glioblastoma. Toxicol Res. 39, 669–679 (2023). https://doi.org/10.1007/s43188-023-00195-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43188-023-00195-z

Keywords

Search

Navigation