Abstract
BackgroundTransforming growth factor-β (TGF-β) signaling is a double-edged sword in cancer development and progression. TGF-β 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-β receptor II (TβRII) in human oral squamous cell carcinoma (OSCC) samples. In the present study we analyzed I227T/N236D mutation of TβRII, which was detected in the metastatic lymph node of an OSCC patient.MethodsThe effect of I227T/N236D TβRII mutation on transcriptional activities was measured using DR26 cells, which lack functional TβRII. HSC2 human OSCC cells stably expressing wild-type and I227T/N236D mutant TβRII were generated and used to examine the effect of I227T/N236D TβRII mutation on xenograft tumor growth, in vitro cell proliferation, apoptosis, migration, and invasion.ResultsThe I227T/N236D mutation of TβRII upregulated TGF-β 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.ConclusionsThese results suggest that enhanced EGFR signaling via upregulated TGF-β 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 TβRII in OSCC progression.
Highlights
Transforming growth factor-β (TGF-β) signaling is a double-edged sword in cancer development and progression
Analysis of canonical TGF-β signaling by I227T/N236D TGF-β receptor II (TβRII) We have previously identified various mutations of TβRII in human oral squamous cell carcinoma (OSCC) samples [12]
Since I227T/N236D mutation was detected only in the metastatic lymph node, but not in the primary tumor, of an OSCC patient, we speculated this mutation could have been linked to functional alterations of TβRII leading to OSCC progression
Summary
Transforming growth factor-β (TGF-β) signaling is a double-edged sword in cancer development and progression. Phosphorylated R-Smads recruit Smad, and translocate to the nucleus to activate transcription of downstream target genes [4, 7, 8] In addition to this canonical TGF-β signaling pathway, TGF-β activates Smad-independent non-canonical pathways, including PI3K/ AKT, mitogen-activated protein kinases (MAPKs), NF-κB, Rho/Rac, Cdc, FAK, Src, and Abl [4, 9]. Overexpression of TGF-β1 correlates with progression of carcinomas, including breast, colon, esophageal, gastric, lung, ovarian, and pancreatic cancers. Weak or no TGF-β signaling due to mutations of TβRII, have been found in gliomas, biliary, breast, colon, esophageal, gastric, lung, ovarian, esophageal, pancreatic, prostate, and head and neck cancers [7, 11, 12]. It is largely unclear how abnormal TGF-β signaling contributes to carcinogenesis of OSCC
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