Study the effects of sorafenib in TGF-β signaling

碩士 === 國立中山大學 === 生物科學系研究所 === 106 === The multi-kinase inhibitor sorafenib is the FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other solid tumors. Previous studies have showed that Transforming Growth Factor-β (TGF-β) signaling may help tumor progression in HCC...

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Main Authors: Shi-Wei Wang, 王士瑋
Other Authors: Chun-Lin Chen
Format: Others
Language:zh-TW
Published: 2018
Online Access:http://ndltd.ncl.edu.tw/handle/4jjrv6
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spelling ndltd-TW-106NSYS51120102019-10-31T05:22:28Z http://ndltd.ncl.edu.tw/handle/4jjrv6 Study the effects of sorafenib in TGF-β signaling 研究索拉非尼(sorafenib)影響TGF-β訊息傳遞的機制 Shi-Wei Wang 王士瑋 碩士 國立中山大學 生物科學系研究所 106 The multi-kinase inhibitor sorafenib is the FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other solid tumors. Previous studies have showed that Transforming Growth Factor-β (TGF-β) signaling may help tumor progression in HCC. Both autocrine and paracrine TGF-β promote tumor growth, enhance metastasis ability and malignancy by inducing epithelial -mesenchymal transition (EMT). Sorafenib is thought to suppress tumor progression by inhibiting TGF-β induced EMT and tissue fibrosis. However HCC is resistant to sorafenib in patients and causes relapse, of which the detailed mechanism remains unknown. In this study, we found that sorafenib specific decreased cell surface TGF-β type II receptor in HCCs and hepatocytes (Hep-G2, Clone9) by increasing TβRII internalization through lipid-raft/caveolae-mediate endocytosis and then degrade in lysosome. Sorafenib-induced downregulation and degradation of TβRII can be protected by caveolae and lysosome inhibitor. On the other hands, sorafenib just affected TβRII localization in lipid-raft/caveolae but not in non-lipid raft on hepatic stellate cells (HSCs) so that TGF-β still induced smad2/3 signaling pathway in HSCs . Our result showed that sorafenib mainly induced TβRII internalization through lipid-raft/caveolae-mediate endocytosis and caused degradation of TGF-β type II receptor for suppression of TGF-β signaling. By gathering TβRII in lipid-raft or using TGF-β receptor kinase inhibitor may provide a direction of sorafenib treat with HCC and TGF-β related diseases. Chun-Lin Chen 陳俊霖 2018 學位論文 ; thesis 59 zh-TW
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language zh-TW
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description 碩士 === 國立中山大學 === 生物科學系研究所 === 106 === The multi-kinase inhibitor sorafenib is the FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other solid tumors. Previous studies have showed that Transforming Growth Factor-β (TGF-β) signaling may help tumor progression in HCC. Both autocrine and paracrine TGF-β promote tumor growth, enhance metastasis ability and malignancy by inducing epithelial -mesenchymal transition (EMT). Sorafenib is thought to suppress tumor progression by inhibiting TGF-β induced EMT and tissue fibrosis. However HCC is resistant to sorafenib in patients and causes relapse, of which the detailed mechanism remains unknown. In this study, we found that sorafenib specific decreased cell surface TGF-β type II receptor in HCCs and hepatocytes (Hep-G2, Clone9) by increasing TβRII internalization through lipid-raft/caveolae-mediate endocytosis and then degrade in lysosome. Sorafenib-induced downregulation and degradation of TβRII can be protected by caveolae and lysosome inhibitor. On the other hands, sorafenib just affected TβRII localization in lipid-raft/caveolae but not in non-lipid raft on hepatic stellate cells (HSCs) so that TGF-β still induced smad2/3 signaling pathway in HSCs . Our result showed that sorafenib mainly induced TβRII internalization through lipid-raft/caveolae-mediate endocytosis and caused degradation of TGF-β type II receptor for suppression of TGF-β signaling. By gathering TβRII in lipid-raft or using TGF-β receptor kinase inhibitor may provide a direction of sorafenib treat with HCC and TGF-β related diseases.
author2 Chun-Lin Chen
author_facet Chun-Lin Chen
Shi-Wei Wang
王士瑋
author Shi-Wei Wang
王士瑋
spellingShingle Shi-Wei Wang
王士瑋
Study the effects of sorafenib in TGF-β signaling
author_sort Shi-Wei Wang
title Study the effects of sorafenib in TGF-β signaling
title_short Study the effects of sorafenib in TGF-β signaling
title_full Study the effects of sorafenib in TGF-β signaling
title_fullStr Study the effects of sorafenib in TGF-β signaling
title_full_unstemmed Study the effects of sorafenib in TGF-β signaling
title_sort study the effects of sorafenib in tgf-β signaling
publishDate 2018
url http://ndltd.ncl.edu.tw/handle/4jjrv6
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AT wángshìwěi yánjiūsuǒlāfēinísorafenibyǐngxiǎngtgfbxùnxīchuándìdejīzhì
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