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Title: | Arecoline誘導口腔癌上皮細胞AKR1B10表現的訊息傳遞路徑 Signal transduction pathways of arecoline-induced AKR1B10 expression in oral epithelial cells |
Authors: | Sheng-Jiun Shie 謝昇峻 |
Advisor: | 郭彥彬(Yen-Ping Kuo) |
Keyword: | 醛酮還原?1B10,轉化生長因子,薑黃素,活性氧化物,口腔癌,檳榔鹼, Arecoline,Aldo-keto reductase 1B10,Transforming growth factor-β1,oral cancer,Curcumin,Reactive oxygen species (ROS), |
Publication Year : | 2019 |
Degree: | 碩士 |
Abstract: | 根據衛服部2017年統計,口腔癌在臺灣癌症十大死因中排名第四位。在口腔癌早期(I-II期)治療成功率相當高,但有仍然有30%的病患有復發的情形;對於口腔癌晚期的患者,即便目前化療和放療日益進步,其治療成功率也仍低於30%,而近20年間,口腔癌患者的五年存活率依舊沒有變化,因此需要繼續找尋新的診斷標誌以及標靶藥物。
我們研究發現檳榔中的主要成分檳榔鹼Arecoline可以誘導口腔癌SAS和Ca9-22細胞株中AKR1B10蛋白大量表現,我們嘗試找尋可能的訊息傳導途徑,其中包含了TGF-β1路徑,結果在SAS和Ca9-22細胞株中發現TGF-β1中和抗體和ALK5 抑制劑 (SB431542) 以及 Smad3 抑制劑 (SIS3)可以降低AKR1B10蛋白表現量,接著我們利用TGF-β1誘導SAS細胞株中AKR1B10大量表現,經由抑制劑發現路徑有PI3K、ERK、JNK以及Src;此外我們也發現薑黃素能夠抑制經由Arecoline所誘導的AKR1B10的蛋白質表現量。 我們探討AKR1B10與化療抗性中所扮演的角色,結果發現在內生性AKR1B10蛋白大量表現的HSC3細胞株中,加入AKR1B10蛋白抑制劑Dicofenac可以提高化療藥物CDDP對口腔癌SAS細胞株的毒性。 關鍵字: 檳榔鹼、口腔癌、醛酮還原酶1B10、活性氧(ROS)、薑黃素、轉化生長因子-β1 In Taiwan, oral cancer is the sixth leading cause of death from cancer in both genders and ranks the fourth in males in 2011. Although treatment of early stage oral cancer (stage I or II) is frequently successful, disease relapses still occur in about 30% patient. For patients with advanced disease, fewer than 30% of them can be cured. Despite recent advances in surgery, radiotherapy and chemotherapy, the overall 5-year survival rate for patients with oral cancer has not changed during the past two decades. Thererfore, continued investigation of new diagnostic markers and chemotherapeutic agents is needed. We found Aldo-keto reductase 1B10 (AKR1B10) is induced by an areca nut alkaloid, arecoline. Arecoline induce AKR1B10 synthesis in a dose- and time- depend Manner in SAS and Ca9-22 cell. We aimed to examine the possible signal transduction pathways involved in TGF-β1-induced AKR1B10 expression in SAS and Ca9-22 cell, we found the effect that Arecoline induces AKR1B10 activation was inhibited by TGF-β1 neutralizing antibody, ALK5 inhibitor (SB431542) and Smad3 inhibitor (SIS3).We have also shown that PI3K inhibitor (LY294002), ERK inhibitor (PD98059), JNK inhibitor (SP600125), and Src inhibitor (PP2) are involved in the TGF-β1-induced AKR1B10 in SAS cell.Furthermore, Cucurmin completely inhibited Arecoline-induced AKR1B10 synthesis and inhibition is dose-dependent. We investigate whether AKR1B10 play a role in regulating chemoresistant in SAS cells. We found inhibited AKR1B10 significantly inhibited chemoresistant in HSC3 cell. KEYWORDS: Arecoline、oral cancer、Aldo-keto reductase 1B10,AKR1B10、Reactive oxygen species (ROS)、Curcumin、Transforming growth factor-β1 |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73528 |
DOI: | 10.6342/NTU201900468 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 口腔生物科學研究所 |
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ntu-108-1.pdf Restricted Access | 2.09 MB | Adobe PDF |
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