A novel TGF-beta receptor II mutation (I227T/N236D) promotes aggressive phenotype of oral squamous cell carcinoma via enhanced EGFR signaling.

BACKGROUND: Transforming growth factor-beta (TGF-beta) signaling is a double-edged sword in cancer development and progression. TGF-beta signaling plays a tumor suppressive role during the early stages of tumor development but promotes tumor progression in later stages. We have previously identified various mutations of TGF-beta receptor II (TbetaRII) in human oral squamous cell carcinoma (OSCC) samples. In the present study we analyzed I227T/N236D mutation of TbetaRII, which was detected in the metastatic lymph node of an OSCC patient. METHODS: The effect of I227T/N236D TbetaRII mutation on transcriptional activities was measured using DR26 cells, which lack functional TbetaRII. HSC2 human OSCC cells stably expressing wild-type and I227T/N236D mutant TbetaRII were generated and used to examine the effect of I227T/N236D TbetaRII mutation on xenograft tumor growth, in vitro cell proliferation, apoptosis, migration, and invasion. RESULTS: The I227T/N236D mutation of TbetaRII upregulated TGF-beta signaling and promoted xenograft tumor growth when compared with the wild-type, without affecting the in vitro proliferative capacities. To delineate the differences in proliferative capacities in vivo and in vitro, the apoptotic and survival signals were analyzed following curcumin treatment. Concomitant with apoptotic induction, epidermal growth factor receptor (EGFR) activation was observed upon curcumin treatment, which was further activated in I227T/N236D mutant transfectant cells when compared with wild-type cells. Enhanced EGFR activation correlated with cell survival and apoptotic resistance. Enhanced migratory and invasive capabilities of I227T/N236D mutant cells also depended on EGFR signaling. CONCLUSIONS: These results suggest that enhanced EGFR signaling via upregulated TGF-beta signaling shifted the balance toward survival and promoted cell migration and invasion in I227T/N236D mutant cells, elucidating the role of I227T/N236D mutation of TbetaRII in OSCC progression.