Abstract
Abstract Disclosure: S. Kuwabara: None. H. Kameda: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. Y. Ishi: None. H. Motegi: None. M. Fujimura: None. T. Atsumi: None. Objective: It has been well recognized that the Wnt/β-catenin pathway regulates cell proliferation, and that translocation of β-catenin from the cytoplasm to the nucleus promotes cell proliferation. There have been, however, limited reports on the Wnt/β-catenin pathway in growth hormone-producing pituitary tumors (GHomas), and we aimed to investigate the impact of the Wnt/β-catenin pathway on cell proliferation in GHomas. Methods: We performed three types of experiments with patient pathological specimens, disease model cell lines, and primary culture of GHoma cells. 1.The intracellular localization of β-catenin was evaluated using immunofluorescence staining of pathological specimens from GHoma patients and subsequently its association with clinical data was analyzed. 2.The Wnt/β-catenin inhibitor iCRT14 was administered to rat GHoma cells GH1, using the WST-1 assay to measure cell viability and real-time PCR to assess GH and cell cycle genes expression. 3. The Wnt/β-catenin inhibitor iCRT14 was added to cultured cells obtained from GHoma patients to evaluate cell viability and gene expression. Results: 1. Samples from 26 cases (42%) exhibited strong dot-like expression of β-catenin in the nucleus (dot pattern (DP) group), and samples from 36 cases (58%) showed β-catenin expression in the cytoplasm or cell membrane (non-DP group). Tumors in the DP group had a larger size than non-DP group (diameters 18.3±9.2 vs. 13.4±7.4 mm, p<0.05), and the postoperative remission rate was lower (23 vs. 50%, p<0.05). 2. Viability evaluation using WST-1 assay showed a maximum decrease of 25%. Gene expression showed concentration-dependent reduction in GH gene expression by up to 40% (p<0.05) and cyclin D1 gene up to 50% (p<0.05) following iCRT14 administration. 3. Among 6 cases, 3 showed a tendency toward cell growth inhibition, and 4 showed a tendency toward decreased cyclin D1 gene expression. Conclusion: It is suggested that the Wnt/β-catenin pathway is activated in the DP group because of the nucleus accumulation of β-catenin, and given the larger tumor size and lower postoperative remission rate in DP group, the Wnt/β-catenin pathway may stimulate cell proliferation in GHomas. In addition, cyclin D1-mediated effects were considered. Wnt/β-catenin pathway could play a role in GHomas growth, therefore this pathway would be a potential therapeutic target for treating affected patients. Presentation: 6/3/2024
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