TGF-β alterations in oral squamous cell carcinoma. Narrative review

  • Jorge Candia Facultad de Odontología, Universidad Andrés Bello.
  • Carolina Somarriva Facultad de Odontología, Universidad Andrés Bello.
  • Diego Fonseca Facultad de Odontología, Universidad Andrés Bello.
  • Fernando Parada Facultad de Odontología, Universidad Andrés Bello.
  • Jorge Briceño Facultad de Odontología, Universidad Andrés Bello.
  • Alejandra Fernández Facultad de Odontología, Universidad Andrés Bello. Centro de Investigaciones Biomédicas, Universidad de Los Andes.


The transforming growth factor beta (TGF-β) is a cytokine that plays crucial roles in the regulation of angiogenesis, immune response, proliferation, migration and apoptosis of cells. In addition, it can inhibit cell progression and stimulate apoptosis in early stages of cancer. TGF-β is a multifunctional homodimeric protein secreted by various cell lines, which have three different isoforms: TGF-β1, TGF-β2 and TGF-β3. In normal conditions, TGF-β1 activates some tumor suppressor cell signaling pathways that inhibit proliferation and are involved in cell migration, differentiation and apoptosis. However, in more advanced stages of cancer, when TGF-β1 is altered, it acts as a promoter of tumorigenesis and may cause: 1) increased TGF-β1, 2) overexpression of TGF-β1 receptors (TβR), 3) TβR mutations, and 4) downregulation of TβR. In oral squamous cell carcinoma, the path is altered especially at the level of transmembrane receptors, with the TβR-II and TβR-III subtypes being the most affected. However, there is little information on the prognostic role it plays in the various types of cancers. It is important to study the signaling pathways of TGF-β in order to develop techniques that may help detect their alterations and restore their normal operation. The objective of this review is to describe the alterations of TGF-β in oral squamous cell carcinoma.

Author Biography

Jorge Candia, Facultad de Odontología, Universidad Andrés Bello.
Editor de Journal of Oral Research.Asesor en Metodología de la Investigación.


1. Fernández A, Córdova P, Badenier O, Esguep A. Epidemiological characterization of oral cancer. Literature review. J Oral Res. 2015;4(2):137–45.
2. Gonçalves AS, Arantes DA, Bernardes VF, Jaeger F, Silva JM, Silva TA, Aguiar MC, Batista AC. Immunosuppressive mediators of oral squamous cell carcinoma in tumour samples and saliva. Hum Immunol. 2015;76(1):52–8.
3. Prime SS, Davies M, Pring M, Paterson IC. The role of TGF-beta in epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II). Crit Rev Oral Biol Med. 2004;15(6):337–47.
4. Chen ZY, Wang PW, Shieh DB, Chiu KY, Liou YM. Involvement of gelsolin in TGF-beta 1 induced epithelial to mesenchymal transition in breast cancer cells. J Biomed Sci. 2015:22–90.
5. Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci. 2003;116(Pt 2):217–24.
6. Miyazono K, Ehata S, Koinuma D. Tumor-promoting functions of transforming growth factor-β in progression of cancer. Ups J Med Sci. 2012;117(2):143–52.
7. Papageorgis P, Stylianopoulos T. Role of TGFβ in regulation of the tumor microenvironment and drug delivery (review). Int J Oncol. 2015;46(3):933–43.
8. Krstić J, Trivanović D, Mojsilović S, Santibanez JF. Transforming Growth Factor-Beta and Oxidative Stress Interplay: Implications in Tumorigenesis and Cancer Progression. Oxid Med Cell Longev. 2015;2015:654594.
9. Finnson KW, Arany PR, Philip A. Transforming Growth Factor Beta Signaling in Cutaneous Wound Healing: Lessons Learned from Animal Studies. Adv Wound Care (New Rochelle). 2013;2(5):225–37.
10. Nana AW, Yang PM, Lin HY. Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression. Asian Pac J Cancer Prev. 2015;16(16):6813–23.
11. Kamath VV, Krishnamurthy S, Satelur KP, Rajkumar K. Transforming growth factor-β1 and TGF-β2 act synergistically in the fibrotic pathway in oral submucous fibrosis: An immunohistochemical observation. Indian J Med Paediatr Oncol. 2015;36(2):111–6.
12. Tirado-Rodriguez B, Ortega E, Segura-Medina P, Huerta-Yepez S. TGF- β: an important mediator of allergic disease and a molecule with dual activity in cancer development. J Immunol Res. 2014;2014:31848.
13. Liu S, de Boeck M, van Dam H, Ten Dijke P. Regulation of the TGF-β pathway by deubiquitinases in cancer. Int J Biochem Cell Biol. 2016;76:135–45.
14. Papageorgis P, Stylianopoulos T. Role of TGFβ in regulation of the tumor microenvironment and drug delivery (review). Int J Oncol. 2015;46(3):933–43.
15. Cichon MA, Radisky DC. Extracellular matrix as a contextual determinant of transforming growth factor-β signaling in epithelial-mesenchymal transition and in cancer. Cell Adh Migr. 2014;8(6):588–94.
16. Kurakula K, Goumans MJ, Ten Dijke P. Regulatory RNAs controlling vascular (dys)function by affecting TGF-ß family signalling. EXCLI J. 2015;14:832–50.
17. Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harb Perspect Biol. 2016;8(5):pii:a021873.
18. Papageorgis P. TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis. J Oncol. 2015;2015:587193.
19. Santarpia M, González-Cao M, Viteri S, Karachaliou N, Altavilla G, Rosell R. Programmed cell death protein-1/programmed cell death ligand-1 pathway inhibition and predictive biomarkers: understanding transforming growth factor-beta role. Transl Lung Cancer Res. 2015;4(6):782–42.
20. Wegner K, Bachmann A, Schad JU, Lucarelli P, Sahle S, Nickel P, Meyer C, Klingmüller U, Dooley S, Kummer U. Dynamics and feedback loops in the transforming growth factor β signaling pathway. Biophys Chem. 2012;162:22–34.
21. Sheen YY, Kim MJ, Park SA, Park SY, Nam JS. Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy. Biomol Ther (Seoul). 2013;21(5):323–31.
22. Zhao B, Chen YG. Regulation of TGF-β Signal Transduction. Scientifica (Cairo). 2014;2014:874065.
23. Augustyniak E, Trzeciak T, Richter M, Kaczmarczyk J, Suchorska W. The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration. Int Orthop. 2015;39(5):955–1003.
24. Lin 1 RL, Zhao LJ. Mechanistic basis and clinical relevance of the role of transforming growth factor-β in cancer. Cancer Biol Med. 2015;12(4):385–93.
25. Rothenberg SM, Ellisen LW. The molecular pathogenesis of head and neck squamous cell carcinoma. J Clin Invest. 2012;122(6):1951–7.
26. Meng W, Xia Q, Wu L, Chen S, He X, Zhang L, Gao Q, Zhou H. Downregulation of TGF-beta receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts. BMC Cancer. 2011:11–88.
27. Gaur P, Mittal M, Mohanti BK, Das SN. Functional genetic variants of TGF-β1 and risk of tobacco-related oral carcinoma in high-risk Asian Indians. Oral Oncol. 2011;47(12):1117–21.
28. Krisanaprakornkit S, Iamaroon A. Epithelial-mesenchymal transition in oral squamous cell carcinoma. ISRN Oncol. 2012;2012:681469.
29. Mincione G, Di Marcantonio MC, Artese L, Vianale G, Piccirelli A, Piccirilli M, Perrotti V, Rubini C, Piattelli A, Muraro R. Loss of expression of TGF-beta1, TbetaRI, and TbetaRII correlates with differentiation in human oral squamous cell carcinomas. Int J Oncol. 2008;32(2):323–31.
30. Pring M, Prime S, Parkinson EK, Paterson I. Dysregulated TGF-beta1-induced Smad signalling occurs as a result of defects in multiple components of the TGF-beta signalling pathway in human head and neck carcinoma cell lines. Int J Oncol. 2006;28(5):1279–85.
31. Gu YY, Wang H, Wang S. TGF-β1 C-509T and T869C polymorphisms and cancer risk: a meta analysis. Int J Clin Exp Med. 2015;8(10):17932–40.
32. Hsu HJ , Yang YH, Shieh TY, Chen CH, Kao YH, Yang CF, Ko EC. TGF-β1 and IL-10 single nucleotide polymorphisms as risk factors for oral cancer in Taiwanese. Kaohsiung J Med Sci. 2015;31(3):123–9.
33. Qiu W, Schönleben F, Li X, Su GH. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett. 2007;245(1-2):163–70.
34. Andl T, Le Bras GF, Richards NF, Allison GL, Loomans HA, Washington MK, Revetta F, Lee RK, Taylor C, Moses HL, Andl CD. Concerted loss of TGFβ-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma. Carcinogenesis. 2014;35(11):2602–10.
35. Ge WL, Xu JF, Hu J. Regulation of Oral Squamous Cell Carcinoma Proliferation Through Crosstalk Between SMAD7 and CYLD. Cell Physiol Biochem. 2016;38(3):1209–17.
36. Freudlsperger C, Bian Y, Contag Wise S, Burnett J, Coupar J, Yang X, Chen Z, Van Waes C. TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Oncogene. 2013;32(12):1549–59.
37. Iamaroon A, Pattamapun K, Piboonniyom SO. Aberrant expression of Smad4, a TGF-beta signaling molecule, in oral squamous cell carcinoma. J Oral Sci. 2006;48(3):105–9.
38. Li D, Xu D, Lu Z, Dong X, Wang X. Overexpression of transforming growth factor type III receptor restores TGF-β1 sensitivity in human tongue squamous cell carcinoma cells. Biosci Rep. 2015;35(4):pii:e00243.
39. Lin RL, Zhao LJ. Mechanistic basis and clinical relevance of the role of transforming growth factor-β in cancer. Cancer Biol Med. 2015;12(4):385–93.
40. Carneiro NK, Oda JM, Losi Guembarovski R, Ramos G, Oliveira BV, Cavalli IJ, de S F Ribeiro EM, Gonçalves MS, Watanabe MA. Possible association between TGF-β1 polymorphism and oral cancer. Int J Immunogenet. 2013;40(4):292–8.
41. Park I, Son HK, Che ZM, Kim J. A novel gain-of-function mutation of TGF-β receptor II promotes cancer progression via delayed receptor internalization in oral squamous cell carcinom. Cancer Lett. 2012;315(2):161–9.
42. Lee EH, Bae JY, Kim TW, Park HS, Lee EJ, Kim JH. Genetic mutation of transforming growth factor beta type II receptor in oral squamous cell carcinoma. Basic Appl Pathol. 2009;2(3):82–8.
43. Sivadas VP, George NA, Kattoor J, Kannan S. Novel mutations and expression alterations in SMAD3/TGFBR2 genes in oral carcinoma correlate with poor prognosis. Genes Chromosomes Cancer. 2013;52(11):1042–52.
44. Ge WL, Xu JF, Hu J. Regulation of Oral Squamous Cell Carcinoma Proliferation Through Crosstalk Between SMAD7 and CYLD. Cell Physiol Biochem. 2016;38(3):1209–17.
45. Quan J, Elhousiny M, Johnson NW, Gao J. Transforming growth factor-β1 treatment of oral cancer induces epithelial-mesenchymal transition and promotes bone invasion via enhanced activity of osteoclasts. Clin Exp Metastasis. 2013;30(5):659–70.
46. Hwang YS, Park KK, Chung WY. Stromal transforming growth factor-beta 1 is crucial for reinforcing the invasive potential of low invasive cancer. Arch Oral Biol. 2014;59(7):687–94.
47. Sun L, Diamond ME, Ottaviano AJ, Joseph MJ, Ananthanarayan V, Munshi HG. Transforming growth factor-beta 1 promotes matrix metalloproteinase-9-mediated oral cancer invasion through snail expression. Mol Cancer Res. 2008;6(1):10–20.
48. Qiao B, Johnson NW, Gao J. Epithelial-mesenchymal transition in oral squamous cell carcinoma triggered by transforming growth factor-beta1 is Snail family-dependent and correlates with matrix metalloproteinase-2 and -9 expressions. Int J Oncol. 2010;37(3):663–8.
49. Wu Y, Zhou BP. Snail: More than EMT. Cell Adh Migr. 2010;4(2):199–203.
50. Richter P, Umbreit C, Franz M, Berndt A, Grimm S, Uecker A, Böhmer FD, Kosmehl H, Berndt A. EGF/TGFβ1 co-stimulation of oral squamous cell carcinoma cells causes an epithelial-mesenchymal transition cell phenotype expressing laminin 332. J Oral Pathol Med. 2011;40(1):46–54.
How to Cite
CANDIA, Jorge et al. TGF-β alterations in oral squamous cell carcinoma. Narrative review. Journal of Oral Research, [S.l.], v. 5, n. 5, p. 207-214, aug. 2016. ISSN 0719-2479. Available at: <>. Date accessed: 07 july 2020. doi:


Transforming Growth Factor Beta1; Smad4 protein; Squamous cell carcinoma; Oral Cancer.

Most read articles by the same author(s)