Transforming Growth factor-β1 Suppresses Bone Morphogenetic protein-2-induced Mesenchymal-Epithelial Transition in HSC-4 Human Oral Squamous Cell Carcinoma Cells via Smad1/5/9 Pathway Suppression

Oncol Rep. 2017 Feb;37(2):713-720. doi: 10.3892/or.2016.5338. Epub 2016 Dec 28.

Abstract

Squamous cell carcinoma is the most common cancer in the oral cavity. We previously demonstrated that transforming growth factor-β1 (TGF-β1) promotes the epithelial-mesenchymal transition (EMT) of human oral squamous cell carcinoma (hOSCC) cells; however, it remains to be clarified whether the TGF-β superfamily member bone morphogenetic protein (BMP) affects this process in hOSCC cells. Here, we examined the independent and collective effects of TGF-β1 and BMP-2 on EMT and mesenchymal‑epithelial transition (MET) in a panel of four hOSCC cell lines. Notably, we found that HSC-4 cells were the most responsive to BMP-2 stimulation, which resulted in the upregulation of Smad1/5/9 target genes such as the MET inducers ID1 and cytokeratin 9 (CK9). Furthermore, BMP-2 downregulated the mesenchymal marker N-cadherin and the EMT inducer Snail, but upregulated epithelial CK9 expression, indicating that BMP-2 prefers to induce MET rather than EMT. Moreover, TGF-β1 dampened BMP-2-induced epithelial gene expression by inhibiting Smad1/5/9 expression and phosphorylation. Functional analysis revealed that TGF-β1 and BMP-2 significantly enhanced HSC-4 cell migration and proliferation, respectively. Collectively, these data suggest that TGF-β positively regulates hOSCC invasion in the primary tumor, whereas BMP-2 facilitates cancer cell colonization at secondary metastatic sites. Thus, the invasive and metastatic characteristics of hOSCC appear to be reciprocally regulated by BMP and TGF-β.

MeSH terms

  • Apoptosis / drug effects
  • Blotting, Western
  • Bone Morphogenetic Protein 2 / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Epithelial-Mesenchymal Transition / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mouth Neoplasms / drug therapy
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / metabolism
  • Mouth Neoplasms / pathology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad Proteins / genetics
  • Smad Proteins / metabolism*
  • Smad1 Protein / genetics
  • Smad1 Protein / metabolism
  • Smad5 Protein / genetics
  • Smad5 Protein / metabolism
  • Smad8 Protein / genetics
  • Smad8 Protein / metabolism
  • Transforming Growth Factor beta1 / pharmacology*
  • Tumor Cells, Cultured

Substances

  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • RNA, Messenger
  • SMAD1 protein, human
  • SMAD5 protein, human
  • SMAD9 protein, human
  • Smad Proteins
  • Smad1 Protein
  • Smad5 Protein
  • Smad8 Protein
  • Transforming Growth Factor beta1