Down-regulation of transforming growth factor-beta type II receptor (TGF-betaRII) protein and mRNA expression in cervical cancer

Mol Cancer. 2008 Jan 9;7:3. doi: 10.1186/1476-4598-7-3.

Abstract

Background: Cervical carcinogenesis is a multistep process initiated by "high risk" human papillomaviruses (HR-HPV), most commonly HPV16. The infection per se is, however, not sufficient to induce malignant conversion. Transforming Growth Factor beta (TGF-beta) inhibits epithelial proliferation and altered expression of TGF-beta or its receptors may be important in carcinogenesis. One cofactor candidate to initiate neoplasia in cervical cancer is the prolonged exposure to sex hormones. Interestingly, previous studies demonstrated that estrogens suppress TGF-beta induced gene expression. To examine the expression of TGF-beta2, TGF-betaRII, p15 and c-myc we used in situ RT-PCR, real-time PCR and immunohistochemistry in transgenic mice expressing the oncogene E7 of HPV16 under control of the human Keratin-14 promoter (K14-E7 transgenic mice) and nontransgenic control mice treated for 6 months with slow release pellets of 17beta-estradiol.

Results: Estrogen-induced carcinogenesis was accompanied by an increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-E7 mice. TGF-beta2 mRNA and protein levels increased in K14-E7 transgenic mice as compared with nontransgenic mice and further increased after hormone-treatment in both nontransgenic and transgenic mice. In contrast, TGF-betaRII mRNA and protein levels were decreased in K14-E7 transgenic mice compared to nontransgenic mice and these levels were further decreased after hormone treatment in transgenic mice. We also observed that c-myc mRNA levels were high in K14-E7 mice irrespective of estrogen treatment and were increased in estrogen-treated nontransgenic mice. Finally we found that p15 mRNA levels were not increased in K14-E7 mice.

Conclusion: These results suggest that the synergy between estrogen and E7 in inducing cervical cancer may in part reflect the ability of both factors to modulate TGF-beta signal transduction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p15 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Down-Regulation
  • Female
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Oncogene Proteins, Viral / genetics
  • Oncogenes
  • Papillomavirus E7 Proteins
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA, Messenger / biosynthesis*
  • RNA, Messenger / genetics
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / biosynthesis*
  • Receptors, Transforming Growth Factor beta / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta2 / biosynthesis
  • Transforming Growth Factor beta2 / genetics
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology

Substances

  • Cdkn2b protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p15
  • Myc protein, mouse
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta2
  • oncogene protein E7, Human papillomavirus type 16
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II