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Decreased expression of TGF‐β cell surface receptors during progression of human oral squamous cell carcinoma
Author(s) -
Paterson Ian C.,
Matthews John B.,
Huntley Suzy,
Robinson C. Max,
Fahey Mark,
Parkinson E. Kenneth,
Prime Stephen S.
Publication year - 2001
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/1096-9896(2000)9999:9999<::aid-path822>3.0.co;2-v
Subject(s) - epithelium , biology , lymph node , receptor , pathology , cell culture , transforming growth factor , cancer research , cell , microbiology and biotechnology , medicine , endocrinology , genetics
This study examined the immunocytochemical expression of the transforming growth factor‐β (TGF‐β) isoforms TGF‐β1, TGF‐β2, and TGF‐β3, together with the TGF‐β cell surface receptors TβR‐I and TβR‐II, in patient‐matched tissue pairs of normal human oral epithelium, primary squamous cell carcinomas, and metastatic lymph node tumour deposits. There were no significant differences in the intensity of TGF‐β isoform specific staining between the normal oral epithelium, the primary tumours, and the lymph node metastases. By contrast, there was significantly less TβR‐II in the metastases than in the primary tumour and between the primary tumour and the normal oral epithelium. Similar trends were evident with TβR‐I, but not at a statistically significant level. This study also examined the structure of TβR‐I and TβR‐II in normal human oral keratinocytes in vitro and in 14 human oral carcinoma cell lines with known responses to TGF‐β1. No structural abnormalities of TβR‐II were present in the normal keratinocytes or in 13 of 14 malignant cell lines; in one line, there were both normal and mutant forms of TβR‐II, the latter being in the form of a frameshift mutation with the insertion of a single adenine base (bases 709–718, codons 125–128), predicting a truncated receptor having no kinase domain. No defects were present in TβR‐I. The structures of TβR‐I and TβR‐II did not correlate with growth inhibition by TGF‐β1. The data suggest that decreased expression of TGF‐β receptors, rather than structural defects of these genes, may be important in oral epithelial tumour progression. In order to examine the functional significance of a specific decrease in TβR‐II expression, a dominant‐negative TβR‐II construct (dnTβR‐II) was transfected into a human oral carcinoma cell line with a normal TGF‐β receptor profile and known to be markedly inhibited by TGF‐β1. In those clones that overexpressed the dnTβR‐II, growth inhibition and Smad binding activity were decreased, whilst the regulation of Fra‐1 and collagenase‐1 remained unchanged following treatment with TGF‐β1. The results demonstrate that a decrease in TβR‐II relative to TβR‐I leads to selective gene regulation with loss of growth inhibition but continued transcription of AP‐1‐dependent genes that are involved in the regulation of the extracellular matrix. Copyright © 2001 John Wiley & Sons, Ltd.