請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60508
標題: | 中草藥: NTNU05抗肝癌之研究 Mechanisms of anti-hepatocellular carcinoma of Chinese Herbal Medicine: NTNU05 |
作者: | Kang-Hsu Fan 范綱緒 |
指導教授: | 林榮耀(Jung-Yaw Lin) |
關鍵字: | 肝細胞癌,中草藥,細胞爬行,血管新生,血管內皮生長因子-A,mTOR, Hepatocellular carcinoma,Chinese Herbal Medicine,Migration,Angiogenesis,VEGFA,mTOR, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | 肝細胞癌(Hepatocellular carcinoma)是全球發生率及死亡率極高的癌症之一,在台灣也高居十大癌症死亡原因的第二名。可能造成肝細胞癌形成的致病機轉有很多,如長期感染B型或C型肝炎病毒、酒精性肝炎以及長期攝取受黃麴毒素感染的食物等等。目前治療肝細胞癌最有效的方式是手術切除,然後針對那些無法經由手術治療的患者,化學療法成為另一個選擇。目前在臨床上已經有許多小分子藥物被開發,並且應用於肝細胞癌的治療,像是Sorafenib。但由於肝癌細胞具有高度轉移性,導致復發率居高不下。基於此點,研發抗肝細胞癌轉移的藥物成為一個急切的課題。
科學界近年積極探究中草藥的治病機轉,探索中藥治療肝癌之路。本研究以Huh7肝細胞癌細胞株來檢測中草藥對於抗肝細胞癌之效果。在篩選多數中草藥之後,發現NTNU05可以不毒殺細胞的方式抑制細胞爬行。進一步分析此抗細胞轉移的細胞機制,發現NTNU05可以透過阻礙FAK/Src之訊息傳遞路徑而抑制Rac1的活化,進而抑制肌絲蛋白重組,最後導致Huh7細胞爬行能力下降。NTNU05亦可抑制AKT/mTOR之訊息傳遞路徑,最終導致VEGFA的表現量減少而抑制血管新生。此外,NTNU05可以穩定E-cadherin和beta-catenin之複合體,並抑制Snail以及Slug的進核,而抑制Huh7細胞轉變為間葉細胞(mesenchyme)型態。本研究也利用異種移植(xenograft)腫瘤小鼠模式,將Huh7細胞注射到嚴重免疫不全症小鼠(NOD-SCID)之皮下,探討NTNU05在活體(in vivo)的抗癌效果。發現NTNU05可以顯著抑制腫瘤生長;除此之外,透過免疫組織化學染色法鑑定(IHC),CD31(血管上皮之標記)亦顯著減少,顯示NTNU05在活體中亦可透過抑制血管新生之方式進而抑制腫瘤生長。 本研究亦探究NTNU05有效成分之-NTNU05-1之抗癌能力。發現NTNU05-1亦可以透過抑制Rho GTPases和mTOR相關訊息傳遞路徑而達到抑制Huh7細胞之爬行和血管新生。根據以上的實驗結果,本研究證明中草藥NTNU05以及其有效成分-NTNU05-1具有抑制肝細胞癌轉移及血管新生的能力,在往後肝細胞癌的治療甚至預防上,具有相當大的發展潛力。 Hepatocellular carcinoma (HCC) is one of the most malignant human cancers over the world, and now, it is the second cause of cancer deaths in Taiwan. It is usually caused by hepatitis virus infection, alatoxin-B1-contained food intake, and chromic alcohol consumption. Multiple therapeutic strategies have been developed so far, such as some small molecular compounds like Sorafinib, which is used in clinical treatment. However, the cure rate of HCC remains poor due to the high metastatic effect with the high recurrence rate. Therefore. it is an urgent need for investigation of a novel anti-metastasis drug for therapy of HCC. Recently, Chinese Herbal Medicines (CHMs) are wildly used on the prevention and treatment against HCC. In this study, we found that CHM NTNU05 water-extracts, which are usually used to treat rheumatoid arthritis by its anti-inflammatiotory activity has an inhibitory effect on Huh7 cells migration, demonstrated by transwell migration/invasion assays. We further showed that aqueous extracts of NTNU05 could inhibit Huh7 cells migration/invasion by suppressing the FAK/SRC/Rac1, resulting in disrupting the F-actin rearrangement. NTNU05 also inhibited AKT/mTOR pathway, leading to the decrement of VEGFA. In addition, aqueous extracts of NTNU05 could promote the formation of E-cadherin and beta-catenin complex, the adhesive structures between adjacent cells, and decreased the translocation of Snail/Slug to nucleus. We further showed that NTNU05 also had inhibitory effects on tumor growth and angiogenesis in vivo by a mouse xenograft model. Furthermore, we found that NTNU05-1, one of the active components of NTNU05, contributed its anti-migration and angiogenesis activities to NTNU05 through inhibition of RhoGTPases and mTOR-related pathway. Taken together, NTNU05 and NTNU05-1 may be potential chemotherapeutic agents for HCC. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60508 |
全文授權: | 有償授權 |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-102-1.pdf 目前未授權公開取用 | 7.04 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。