Skip to main content

Advertisement

SpringerLink
Log in

High expression of CD9 and Epidermal Growth Factor Receptor promotes the development of tongue cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Tongue cancer is distinguished by aggressive behavior, a high risk of recurrence, lymph, and distant metastases. Hypoxia-Induced Factor 1 α functions as a CD9 transcription factor. CD9 is a transmembrane protein that may be found on the cell membrane. It can modulate the expression of the Epidermal Growth Factor Receptor (EGFR) pathway. ELISA was used to measure serum CD9, p-EGFR, and p-Akt levels in 70 tongue cancer patients and 35 healthy controls. RT-PCR was used to analyze the gene expression of the related genes. The gene as well as protein expression of CD9, EGFR/p-EGFR, and Akt/p-Akt was significantly higher in case subjects when compared with the controls. The expression of CD9 was higher in case subjects who were smokers/alcoholics when to control subjects who were smokers/alcoholics. Overexpression of CD9 due to hypoxic conditions leads to the activation of EGFR-signaling pathway resulting in cancer progression, resistance to chemotherapy. Hence, CD9 could be a potential target to suppress cancer progression.

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

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Ganly I, Patel S, Shah J. Early stage squamous cell cancer of the oral tongue-clinicopathologic features affecting outcome. Cancer. 2012;118(1):101–11.

    Article  PubMed  Google Scholar 

  2. Campbell BR, Netterville JL, Sinard RJ, Mannion K, Rohde SL, Langerman A, et al. Early onset oral tongue cancer in the United States: a literature review. Oral Oncol [Internet]. 2018 Dec 1 [cited 2023 Oct 30]; 87:1. Available from: /pmc/articles/PMC7039330/

  3. Zushi Y, Noguchi K, Urade M. An in vitro multistep carcinogenesis model for both HPV-positive and -negative human oral squamous cell carcinomas. Japanese J Oral Maxillofac Surg. 2013;59(3):159–71.

    Article  Google Scholar 

  4. Mithani SK, Mydlarz WK, Grumbine FL, Smith IM, Califano JA. Molecular genetics of premalignant oral lesions. Oral Dis. 2007;13(2):126–33.

    Article  CAS  PubMed  Google Scholar 

  5. Tota JE, Anderson WF, Coffey C, Califano J, Cozen W, Ferris RL, et al. Rising incidence of oral tongue cancer among white men and women in the United States, 1973–2012. Oral Oncol. 2017;67:146–52. https://doi.org/10.1016/j.oraloncology.2017.02.019.

    Article  PubMed  Google Scholar 

  6. Mohamed KM, Le A, Duong H, Wu Y, Zhang Q, Messadi DV. Correlation between VEGF and HIF-1α expression in human oral squamous cell carcinoma. Exp Mol Pathol. 2004;76(2):143–52.

    Article  CAS  PubMed  Google Scholar 

  7. Hoff CM, Grau C, Overgaard J. Effect of smoking on oxygen delivery and outcome in patients treated with radiotherapy for head and neck squamous cell carcinoma - a prospective study. Radiother Oncol. 2012;103(1):38–44. https://doi.org/10.1016/j.radonc.2012.01.011.

    Article  PubMed  Google Scholar 

  8. Rouger-Gaudichon J, Cousin E, Jakobczyk H, Debaize L, Rio AG, Forestier A, et al. Hypoxia regulates CD9 expression and dissemination of B lymphoblasts. Leuk Res [Internet]. 2022 Dec 1 [cited 2023 Oct 30] 123. Available from: https://pubmed.ncbi.nlm.nih.gov/36335655/

  9. Wright MD, Moseley GW, van Spriel AB. Tetraspanin microdomains in immune cell signalling and malignant disease. Tissue Antigens. 2004;64:533–42.

    Article  CAS  PubMed  Google Scholar 

  10. Hemler ME. Targeting of tetraspanin proteins-potential benefits and strategies. Nat Rev Drug Discov. 2008;7:747–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. H T Maecker1, S C Todd SL. The tetraspanin superfamily: molecular facilitators - PubMed. [cited 2023 Oct 30]; Available from: https://pubmed.ncbi.nlm.nih.gov/9194523/

  12. Wang JC, Bégin LR, Bérubé NG, Chevalier S, Aprikian AG, Gourdeau H, et al. Down-regulation of CD9 expression during prostate carcinoma progression is associated with CD9 mRNA modifications. Clin Cancer Res. 2007;13(8):2354–61.

    Article  CAS  PubMed  Google Scholar 

  13. Tang M, Yin G, Wang F, Liu H, Zhou S, Ni J, et al. Downregulation of CD9 promotes pancreatic cancer growth and metastasis through upregulation of epidermal growth factor on the cell surface. Oncol Rep. 2015;34(1):350–8.

    Article  CAS  PubMed  Google Scholar 

  14. Amornphimoltham P, Sriuranpong V, Patel V, Benavides F, Conti CJ, Sauk J, et al. Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01. Clin Cancer Res. 2004;10(12):4029–37.

    Article  CAS  PubMed  Google Scholar 

  15. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001;25(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  16. Herr MJ, Mabry SE, Jennings LK. Tetraspanin CD9 regulates cell contraction and actin arrangement via RhoA in human vascular smooth muscle cells. PLoS ONE. 2014;9(9):e10699.

    Article  Google Scholar 

  17. Nagaoka T, Kitaura K, Miyata Y, Kumagai K, Kaneda G, Kanazawa H, et al. Downregulation of epidermal growth factor receptor family receptors and ligands in a mutant K-ras group of patients with colorectal cancer. Mol Med Rep. 2016;13(4):3514–20.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang J, Zhang LL, Shen L, Xu XM, Yu HG. Regulation of AKT gene expression by cisplatin. Oncol Lett. 2013;5(3):756–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Manjappa AB, Rao S, Shetty S, Shetty V, Asode AS, Molahalli SS, et al. Characterization of human articular cartilage derived mesenchymal progenitor cells from osteoarthritis patients. J Adv Biotechnol Exp Ther. 2021;4(2):200–9.

    Article  Google Scholar 

  20. Lin Li, Shao-Hua Chen, Yu Zhang, Chao-Hui Yu, Shu-Dan Li YML. Is the hypoxia-inducible factor-1 alpha mRNA expression activated by ethanol-induced injury, the mechanism underlying alcoholic liver disease? - PubMed [Internet]. [cited 2023 Oct 30]. Available from: https://pubmed.ncbi.nlm.nih.gov/17085342/

  21. Michaud SE, Ménard C, Guy LG, Gennaro G, Rivard A. Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure: impairment of the HIF-1alpha/VEGF pathway. FASEB J. 2003;17(9):1150–2.

    Article  CAS  PubMed  Google Scholar 

  22. Lin PY, Yu CH, Wang JT, Chen HH, Cheng SJ, Kuo MYP, et al. Expression of hypoxia-inducible factor-1α is significantly associated with the progression and prognosis of oral squamous cell carcinomas in Taiwan. J Oral Pathol Med. 2008;37(1):18–25.

    Article  PubMed  Google Scholar 

  23. Jiang L, Hochwald S, Deng S, Zhu Y, Tan C, Zhong Q, et al. Evaluation of EGF, EGFR, and E-cadherin as potential biomarkers for gastrointestinal cancers. Front Lab Med. 2017;1(3):135–40. https://doi.org/10.1016/j.flm.2017.08.001.

    Article  Google Scholar 

  24. Tsalikidis C, Papachristou F, Pitiakoudis M, Asimakopoulos B, Trypsianis G, Bolanaki E, et al. Soluble E-cadherin as a diagnostic and prognostic marker in gastric carcinoma. Folia Med (Plovdiv). 2013;55(3–4):26–32.

    Article  CAS  PubMed  Google Scholar 

  25. Shernan GH, Michael RV, Kirk RS, Laura FN, Gabrielle M, Fiona H, Todd ED, Gregory MV, Arne S, Margaret LM, Sarah AC, Bruce RB, Angela P-M, and,. Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease. Biol Blood Marrow Transplant. 2016;176(1):139–48.

    Google Scholar 

  26. Maramotti S, Paci M, Manzotti G, Rapicetta C, Gugnoni M, Galeone C, et al. Soluble epidermal growth factor receptors (sEGFRs) in cancer: Biological aspects and clinical relevance. Int J Mol Sci. 2016;17(4):593.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Heng H, Lingling G, Cun W, Yan L, Huiying M, Long C, Jie Q, Binbin L, Yinkun LCL. Lower serum soluble-EGFR is a potential biomarker for metastasis of HCC demonstrated by N-glycoproteomic analysis - PubMed [Internet]. [cited 2023 Oct 30]. Available from: https://pubmed.ncbi.nlm.nih.gov/26105696/

  28. Adamczyk KA, Klein-Scory S, Tehrani MM, Warnken U, Schmiegel W, Schnölzer M, et al. Characterization of soluble and exosomal forms of the EGFR released from pancreatic cancer cells. Life Sci. 2011;89(9–10):304–12. https://doi.org/10.1016/j.lfs.2011.06.020.

    Article  CAS  PubMed  Google Scholar 

  29. Singh B, Carpenter G, Coffey RJ. EGF receptor ligands: recent advances. Research. 2016;5:2270.

    Google Scholar 

  30. Fisher DA, Lakshmanan J. Metabolism and effects of epidermal growth factor and related growth factors in mammals. Endocr Rev. 1990;11:418–42.

    Article  CAS  PubMed  Google Scholar 

  31. Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel). 2017;9(5):52. https://doi.org/10.3390/cancers9050052.PMID:28513565;PMCID:PMC5447962.

    Article  PubMed  Google Scholar 

  32. Sato K-I. Cellular functions regulated by phosphorylation of EGFR on Tyr845. Int J Mol Sci. 2013;14:10761–90.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Morrison DK. MAP kinase pathways. Perspect Biol. 2012;4:a011254.

    Google Scholar 

  34. Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49–139.

    Article  CAS  PubMed  Google Scholar 

  35. Dibble CC, Cantley LC. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 2015;25:545–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Qi JC, Wang J, Mandadi S, Tanaka K, Roufogalis BD, Madigan MC, et al. Human and mouse mast cells use the tetraspanin CD9 as an alternate interleukin-16 receptor. Blood. 2006;107(1):135–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kotha J, Longhurst C, Appling W, Jennings LK. Tetraspanin CD9 regulates β1 integrin activation and enhances cell motility to fibronectin via a PI-3 kinase-dependent pathway. Exp Cell Res. 2008;314(8):1811–22.

    Article  CAS  PubMed  Google Scholar 

  39. Rappa G, Green TM, Karbanová J, Corbeil D, Lorico A. Tetraspanin CD9 determines invasiveness and tumorigenicity of human breast cancer cells. Oncotarget. 2015;6(10):7970–91.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yáñez-Mó M, Alfranca A, Cabañas C, Marazuela M, Tejedor R, Ursa MA, et al. Regulation of endothelial cell motility by complexes of retraspan molecules CD81/TAPA-1 and CD151/PETA-3 with α3β1 integrin localized at endothelial lateral junctions. J Cell Biol. 1998;141(3):791–804.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Okochi H, Kato M, Nashiro K, Yoshie O, Miyazono K, Furue M. Expression of tetra-spans transmembrane family (CD9, CD37, CD53, CD63, CD81 and CD82) in normal and neoplastic human keratinocytes: an association of CD9 with α3β1 integrin. Br J Dermatol. 1997;137(6):856–63.

    Article  CAS  PubMed  Google Scholar 

  42. Higashiyama S, Iwamoto R, Goishi K, Raab G, Taniguchi N, Klagsbrun M, et al. The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J Cell Biol. 1995;128(5):929–38.

    Article  CAS  PubMed  Google Scholar 

  43. Noi M, Ichi MK, Murakami S, Koshinuma S, Machida Y, Yamori M, et al. Expressions of ezrin, ERK, STAT3, and AKT in tongue cancer and association with tumor characteristics and patient survival. Clin Exp Dent Res. 2020;6(4):420–7.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Podergajs N, Motaln H, Rajčević U, Verbovšek U, Koršič M, Obad N, et al. Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells. Oncotarget. 2023;7(1):593–609.

    Article  Google Scholar 

  45. Murayama Y, Oritani K, Tsutsui S. Novel CD9-targeted therapies in gastric cancer. World J Gastroenterol. 2015;21(11):3206–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ullah M, Akbar A, Thakor AS. An emerging role of CD9 in stemness and chemoresistance. Oncotarget. 2019;10(40):4000–1.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Reyes R, Cardeñes B, Machado-Pineda Y, Cabañas C. Tetraspanin CD9: a key regulator of cell adhesion in the immune system. Front Immunol. 2018;9:1–9.

    Article  Google Scholar 

Download references

Acknowledgements

The authors are extremely grateful to NITTE (Deemed to be University) for providing the required facilities for the study.

Author information

Authors and Affiliations

  1. Department of Biochemistry, KS Hegde Medical Academy, NITTE (Deemed to be University), Mangalore, Karnataka, 575018, India

    P. C. Suhasini, Praveen Kumar Shetty, P. G. Roopashree & N. Suchetha Kumari

  2. Department of ENT, KS Hegde Medical Academy, NITTE (Deemed to be University), Mangalore, Karnataka, 575018, India

    Vadisha Bhat

  3. Cellomics, Lipdomics and Molecular Genetics division, Central Research Laboratory, KS Hegde Medical Academy, NITTE (Deemed to be University), Mangalore, Karnataka, 575018, India

    Shilpa S Shetty

Authors
  1. P. C. Suhasini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vadisha Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shilpa S Shetty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Praveen Kumar Shetty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. G. Roopashree
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Suchetha Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: SPC, SKN, PKS; Methodology: SPC, SSS, RPG; Formal analysis and investigation: SPC, RPG; Writing–original draft preparation: SPC; Writing–review and editing: VB, PKS; Supervision: SKN.

Corresponding author

Correspondence to N. Suchetha Kumari.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of NITTE (Deemed to be University) (Ref. NU/CEC/2020/0336). Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

Suhasini, P.C., Bhat, V., Shetty, S. et al. High expression of CD9 and Epidermal Growth Factor Receptor promotes the development of tongue cancer. Med Oncol 41, 86 (2024). https://doi.org/10.1007/s12032-024-02311-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-024-02311-x

Keywords

Search

Navigation