The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers

doi:10.3390/cancers10080247

Review

. 2018 Jul 27;10(8):247.

doi: 10.3390/cancers10080247.

The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers

Sharmila Velapasamy¹, Christopher W Dawson², Lawrence S Young³, Ian C Paterson^{4

5}, Lee Fah Yap^{6

7}

Affiliations

¹ Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. vsharmila84@gmail.com.
² Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham B15 2TT, UK. c.w.dawson@bham.ac.uk.
³ Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK. L.S.Young@warwick.ac.uk.
⁴ Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. ipaterson@um.edu.my.
⁵ Oral Cancer Research and Coordinating Centre, University of Malaya, 50603 Kuala Lumpur, Malaysia. ipaterson@um.edu.my.
⁶ Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. yapleefah@um.edu.my.
⁷ Oral Cancer Research and Coordinating Centre, University of Malaya, 50603 Kuala Lumpur, Malaysia. yapleefah@um.edu.my.

PMID: 30060514
PMCID: PMC6115974
DOI: 10.3390/cancers10080247

Review

The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers

Sharmila Velapasamy et al. Cancers (Basel). 2018.

. 2018 Jul 27;10(8):247.

doi: 10.3390/cancers10080247.

Authors

Sharmila Velapasamy¹, Christopher W Dawson², Lawrence S Young³, Ian C Paterson^{4

5}, Lee Fah Yap^{6

7}

Affiliations

¹ Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. vsharmila84@gmail.com.
² Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham B15 2TT, UK. c.w.dawson@bham.ac.uk.
³ Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK. L.S.Young@warwick.ac.uk.
⁴ Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. ipaterson@um.edu.my.
⁵ Oral Cancer Research and Coordinating Centre, University of Malaya, 50603 Kuala Lumpur, Malaysia. ipaterson@um.edu.my.
⁶ Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. yapleefah@um.edu.my.
⁷ Oral Cancer Research and Coordinating Centre, University of Malaya, 50603 Kuala Lumpur, Malaysia. yapleefah@um.edu.my.

PMID: 30060514
PMCID: PMC6115974
DOI: 10.3390/cancers10080247

Abstract

The transforming growth factor-β (TGF-β) signalling pathway plays a critical role in carcinogenesis. It has a biphasic action by initially suppressing tumorigenesis but promoting tumour progression in the later stages of disease. Consequently, the functional outcome of TGF-β signalling is strongly context-dependent and is influenced by various factors including cell, tissue and cancer type. Disruption of this pathway can be caused by various means, including genetic and environmental factors. A number of human viruses have been shown to modulate TGF-β signalling during tumorigenesis. In this review, we describe how this pathway is perturbed in Epstein-Barr virus (EBV)-associated cancers and how EBV interferes with TGF-β signal transduction. The role of TGF-β in regulating the EBV life cycle in tumour cells is also discussed.

Keywords: B-cell lymphoma; Epstein-Barr virus; TGF-β signalling; gastric cancer; nasopharyngeal carcinoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
The TGF-β signalling pathway. Binding of an activated TGF-β ligand to TGFR-2 recruits and activates TGFR-1. This, in turn, phosphorylates Smad2 and/or Smad3 (R-Smads), which then form complexes with Smad4 (Co-Smad) and translocate into nucleus to regulate the transcription of various _target genes. Smad7 (I-Smad) inhibits the pathway through various mechanisms, including mediating the degradation of TGFR-1, inhibiting phosphorylation of Smad2/Smad3 or inhibiting the formation of the Smad2/3-Samd4 complex. In addition to the canonical Smad-dependent signalling, activated TGF-β receptors can trigger other signalling pathways including ERK-MAPK, p38-MAPK, PI3K-Akt and JNK.

**Figure 2**
Modulation of TGF-β signalling by EBV. EBV infection or EBV-encoded latent proteins (LMP1 and EBNA1) can stimulate the expression and secretion of TGF-β1 in epithelial cells. However, cancer cells often do not respond to the cytostatic effects of TGF-β, partly through the repression of signal transduction by the EBV-encoded proteins (EBNA1, LMP1, LMP2A and BARF1) through various mechanisms. The cancer cells often sustain a functional TGF-β core machinery and the excessive production of TGF-β drives aggressive malignant phenotypes. TGF-β signalling also appears to be crucial in regulating the balance between latent and lytic cycles in EBV-infected cells. TGF-β facilitates lytic reactivation in EBV-infected cells by stimulating the expression of *BZLF1*/Zta via both Smad-dependent and Smad-independent pathways. Zta induces the production of TGF-β1 which in turn, together with Zta, suppress the transcription of *EBNA1* from Qp to disrupt EBV latency.

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References

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1. Siegel P.M., Massague J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat. Rev. Cancer. 2003;3:807–821. doi: 10.1038/nrc1208. - DOI - PubMed
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1. Takehara K., LeRoy E.C., Grotendorst G.R. TGF-β inhibition of endothelial cell proliferation: Alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. Cell. 1987;49:415–422. doi: 10.1016/0092-8674(87)90294-7. - DOI - PubMed
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[1] Derynck R., Zhang Y.E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature. 2003;425:577–584. doi: 10.1038/nature02006. - DOI - PubMed

[2] Derynck R., Zhang Y.E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature. 2003;425:577–584. doi: 10.1038/nature02006. - DOI - PubMed

[3] Siegel P.M., Massague J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat. Rev. Cancer. 2003;3:807–821. doi: 10.1038/nrc1208. - DOI - PubMed

[4] Siegel P.M., Massague J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat. Rev. Cancer. 2003;3:807–821. doi: 10.1038/nrc1208. - DOI - PubMed

[5] Derynck R., Akhurst R.J., Balmain A. TGF-β signaling in tumor suppression and cancer progression. Nat. Genet. 2001;29:117–129. doi: 10.1038/ng1001-117. - DOI - PubMed

[6] Derynck R., Akhurst R.J., Balmain A. TGF-β signaling in tumor suppression and cancer progression. Nat. Genet. 2001;29:117–129. doi: 10.1038/ng1001-117. - DOI - PubMed

[7] Takehara K., LeRoy E.C., Grotendorst G.R. TGF-β inhibition of endothelial cell proliferation: Alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. Cell. 1987;49:415–422. doi: 10.1016/0092-8674(87)90294-7. - DOI - PubMed

[8] Takehara K., LeRoy E.C., Grotendorst G.R. TGF-β inhibition of endothelial cell proliferation: Alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. Cell. 1987;49:415–422. doi: 10.1016/0092-8674(87)90294-7. - DOI - PubMed

[9] Moses H.L., Coffey R.J., Jr., Leof E.B., Lyons R.M., Keski-Oja J. Transforming growth factor beta regulation of cell proliferation. J. Cell. Physiol. Suppl. 1987;(Suppl. 5):1–7. doi: 10.1002/jcp.1041330403. - DOI - PubMed

[10] Moses H.L., Coffey R.J., Jr., Leof E.B., Lyons R.M., Keski-Oja J. Transforming growth factor beta regulation of cell proliferation. J. Cell. Physiol. Suppl. 1987;(Suppl. 5):1–7. doi: 10.1002/jcp.1041330403. - DOI - PubMed

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The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers

Affiliations

The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers

Authors

Affiliations

Abstract

Conflict of interest statement

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