轉錄因子HBP1經由REACTIVE OXYGEN SPECIES(ROS)的生成調控而達到對口腔癌中生長因子的訊息傳遞之抑制

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 健康照護學院 > 營養學系暨碩士班 > 研究計畫 > Item 310903500/11825

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題名:	轉錄因子HBP1經由REACTIVE OXYGEN SPECIES(ROS)的生成調控而達到對口腔癌中生長因子的訊息傳遞之抑制
作者:	黃俊瑩(Huang, Chun-Yin)
貢獻者:	健康照護學院營養學系
日期:	2008-07-31
上傳時間:	2009-09-01 15:26:04 (UTC+8)
摘要:	上皮生長因子的受器(EGFR)在口腔癌細胞上經常有過度表達的現象，而這種現象更直接關係到癌細胞惡化的程度。當接合子，如上皮生長因子(EGF)，接合到EGFR 後會引發受器上一些Tyrosine 的自發性磷酸化，更藉此催化一連串的訊息傳遞路徑，最終可能導致癌細胞的增生。同時，研究發現EGFR 可與β-Catenin 直接接觸，並磷酸化β-Catenin 上的特定Tyrosine，而這將使得E-Cadherin 所調控的細胞密合遭到破壞，最終的結果將提高癌細胞的活動性、侵略性及移轉性。因此，針對EGFR、β-Catenin 訊息路徑中特定目標的抑制將會是防止癌細胞惡化的重要關鍵。另外，HBPI 為一種基因轉錄抑制蛋白，而且與細胞分化有重要之關連。同時，HBPI 也被發現對細胞的生長和Wnt 的訊息傳遞系統有著抑制的作用。以上在在顯示HBPI 可能有抑制腫瘤生成及惡化之功能。除此，細胞內ROS(反應性過氧物)的調節與細胞生長和腫瘤相關的訊息傳遞系統有著相當的關係。研究發現，HBPI 可以藉由對 p47phox 基因(NDAPH Oxidase 酶系的一個調解單位)的抑製表達而減低了胞內ROS 的產生及對細胞週期的抑制。所以，我們的研究假設就如圖中所示的，HBP1 將經由對p47phox 基因的抑制而減低ROS 的生成，而藉此提高特定PTP 的活性，而達到對口腔癌中EGFR / B-Catenin 訊息傳遞的抑制。為了證明我們的假設，我們將引用RNAi 的技術降解口腔癌細胞的HBP1 以觀察對其EGFR /β-Catenin 的訊息傳遞及細胞的侵略性及移轉性之影響。本研究將提供更紮實的分子基礎以對人類口腔癌的診斷及治療有更進一步的貢獻。 The EGF receptor (EGFR), the biological receptor of EGF and TGF-α is frequently over-expressed in oral cancers. The binding of the ligands to EGFR causes auto-phosphorylation of certain tyrosines on EGFR and thereby triggers a cascade of signal transduction events. Increased expression of EGF receptor in oral cancers is associated with aggressiveness of the tumors. The EGFR also directly interacts with β-catenin and the EGFR-induced tyrosine phosphorylation ofβ-catenin causes dysfunction of the E-cadherin–mediated cell adhesion in cancer, resulting in increased cell motility, invasion, and metastasis. Therefore, targeted blockage of the EGFR-β-catenin signaling pathway is critical in the prevention of tumor aggressiveness. The transcriptional repressor HBP1 is a documented G1 inhibitor in both cell culture and animal models. HBP1 represses a number of growth regulatory genes (e.g. N-Myc, c-Myc, and Cyclin D1). More importantly, HBP1 is shown to be an inhibitor of the Wnt/β-catenin signaling pathway, which is involved in many cancer types. Several studies have linked the production of reactive oxygen species (ROS) by the NADPH oxidase to cellular growth control. In many cases, activation of the NADPH oxidase and subsequent ROS generation is required for growth factor signaling and mitogenesis in non-immune cells. It has been recently demonstrated that HBP1 regulates the gene for the p47phox regulatory subunit of the NADPH oxidase. Current work would focus on the hypothesis that HBP1 represses growth-factor dependent signal transduction through inhibition of growth factor-induced ROS generation, increased PTP activity and a concomitant decrease in ligand-induced EGFR-β-catenin signal transduction in oral cancers. To test this hypothesis, we will use the RNAi technique to knockdown HBP1 in oral cancer cell lines and assay for the EGFR-β-catenin signaling, the epithelial-mesenchymal transitions(EMT), and cell migration and invasiveness. These investigations should provide a molecular foundation for new biomarkers in the design of specific clinical diagnosis strategies.
顯示於類別:	[營養學系暨碩士班 ] 研究計畫

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