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Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis
Chaehwa Park1, Won-Seog Kim, Yunseon Choi
1Department of Medicine, and Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Seoul, South Korea.
Abstract:
Transforming growth factor beta (TGF-beta) type-II receptor mutations have been reported in several epithelial-type human malignancies. To elucidate the role of TGF-beta RII in lung cancer progression, we prepared gene-modified clones of the human lung cancer cell line NCI-H23. NCI-H23, a human non-small-cell lung adenocarcinoma cell line which has a frameshift mutation in, and reduced expression of, the TGF-beta type-II receptor (TGF-beta RII), exhibits resistance to growth inhibition by TGF-beta(1) in vitro. Transfection of NCI-H23 with a retroviral vector expressing wild-type TGF-beta RII restored the responsiveness of cells to exogenous TGF-beta(1) with reduced cell proliferation. Immunocytochemical analysis demonstrated nuclear translocation of Smad3 after TGF-beta(1) treatment in RII-restored NCI-H23 cells. Underphosphorylation of the retinoblastoma protein accompanying p21 up-regulation was observed after TGF-beta(1) treatment of NCI-H23-RII cells. Receptor restoration also changed the levels of VEGF mRNA induced by TGF-beta(1). However, impairment of TGF-beta signalling did not alter microvessel formation in vivo in transplanted tumours. Instead, in vivo tumorigenesis experiments revealed a remarkable difference in the number and sizes of the tumours derived from NCI-H23-RII cells and dominant negative NCI-H23-dnRII cells (P < 0.01). Collectively, these observations suggest that impairment of TGF-beta signal transduction contributes significantly to tumour progression, mainly by cell proliferation rather than by modulation of angiogenesis in human NCI-H23 lung carcinoma cells.
Insights
Mutations in the transforming growth factor beta (TGF-beta) type-II receptor impair lung cancer cell growth inhibition. Restoring TGF-beta RII function reduces NCI-H23 lung carcinoma cell proliferation and tumor growth.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Transforming growth factor beta (TGF-beta) type-II receptor (TGF-beta RII) mutations are implicated in human epithelial cancers.
- The NCI-H23 lung adenocarcinoma cell line exhibits reduced TGF-beta RII expression and TGF-beta(1) resistance.
- Understanding TGF-beta RII's role is crucial for lung cancer progression insights.
Purpose of the Study:
- To investigate the role of TGF-beta RII in the progression of human non-small-cell lung cancer.
- To determine how restoring TGF-beta RII function affects NCI-H23 cell behavior and tumor development.
Main Methods:
- Gene-modified clones of the NCI-H23 human lung cancer cell line were created.
- Transfection with a retroviral vector expressing wild-type TGF-beta RII was performed.
- Immunocytochemistry, Western blotting, and in vivo tumorigenesis experiments were utilized.
Main Results:
- Restoration of TGF-beta RII in NCI-H23 cells re-sensitized them to TGF-beta(1)-induced growth inhibition.
- TGF-beta(1) treatment led to Smad3 nuclear translocation and retinoblastoma protein underphosphorylation.
- Impaired TGF-beta signaling affected cell proliferation but not angiogenesis in vivo, though tumor development differed significantly between restored and dominant-negative clones.
Conclusions:
- Impairment of TGF-beta signal transduction significantly contributes to lung carcinoma progression, primarily through enhanced cell proliferation.
- TGF-beta RII restoration effectively reduces NCI-H23 lung cancer cell proliferation and tumor growth in vivo.
- These findings highlight TGF-beta RII as a potential therapeutic target in lung cancer.