2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/661631摘要：細胞循環調控的異常是癌症的典型特徵之一。在許多種癌症﹝包括肝細胞癌﹞都發現細胞循環調控蛋白cyclins有過度表現的現象，這種過度表現也常與晚期疾病以及病患預後不良相關。雖然已經有針對cyclins或是與cyclin相關之磷酸激酶之分子靶向治療藥物在研發中，但是這些藥物在癌症治療所扮演的角色仍待驗證。分子靶向治療藥物sorafenib是目前針對晚期肝細胞癌病患的標準治療藥物。雖然sorafenib最初是針對Raf 磷酸激酶所開發出來的抑制劑，但是我們以及其他研究者近來的研究均指出：sorafenib有許多「標靶外作用」﹝off-target effects﹞在sorafenib的抗癌作用扮演重要角色，對於癌細胞產生sorafenib抗藥性的作用機轉也有重要影響(Ou DL, et al. Cancer Res 2010)。我們在尋找sorafenib可能的標靶外作用標的時，發現sorafenib在肝癌細胞的抗癌作用可能部分來自sorafenib對於細胞循環的調控，且此一作用與sorafenib對於Raf/MEK/ERK訊息傳遞路徑的抑制能力無關 (Fan HH et al. Mol Cancer Ther 2009 (suppl))。我們發現(1) sorafenib可以抑制肝癌細胞內cyclin E1的表現；(2) 肝癌細胞對sorafenib產生抗藥性時，細胞內cyclin E1 表現會增加，而且sorafenib抑制cyclin E1表現的作用在具有抗藥性的肝癌細胞中也會顯著降低； (3) 使用siRNA抑制細胞內cyclin E1表現可以扭轉肝癌細胞對sorafenib的抗藥性。我們的上述發現顯示，肝癌細胞內cyclin E1之表現及其治療後的反應可能可以做為肝癌病患接受sorafenib或其他藥物治療的療效預測指標，也可能作為未來藥物研發的可能標的。本計畫將著重於探討cyclin E1及相關訊息傳遞路徑對於sorafenib在肝細胞癌療效所扮演的角色，以及做為療效預測指標的可能性。特定目標包括：(1) 澄清sorafenib在肝癌細胞中如何調控cyclin E1及相關訊息傳遞路徑，以及對於各項細胞功能之影響；(2) 探討調控cyclin E1 表現對於sorafenib或其他不同作用機轉的分子靶向治療藥物對於肝細胞癌療效的影響；(3) 探討肝癌病患腫瘤組織中cyclin E1及相關蛋白質表現對於疾病預後以及預測藥物治療效果的價值。本計畫的長期目標是建立一個開發肝細胞癌分子靶向治療新治療標的以及療效預測指標的研究平台，以促進未來肝細胞癌相關臨床試驗的推展。<br> Abstract: Dysregulation of cell cycle control is a hallmark of cancer. Over-expression of cyclins has been reported in many types of cancers, including hepatocellular carcinoma (HCC), and the over-expression is usually associated with advanced-stage disease and poor prognosis. Although molecular targeted agents targeting cyclins and cycline-dependent kinases have been developed, their roles in cancer therapy remain to be established.The molecular targeted agent sorafenib is the current standard systemic therapy for patients with advanced hepatocellular carcinoma (HCC). Although sorafenib was originally designed as a specific Raf kinase inhibitor, we and other investigators have found many off-target effects of sorafenib that may have significant implications in the anti-tumor effects and resistance mechanisms of sorafenib in HCC cells (Ou DL, et al. Cancer Res 2010). In an attempt to identify novel targets of sorafenib in HCC, we found that sorafenib may exert its anti-tumor effects partly through cell cycle regulation, an effect independent of sorafenib’s inhibitory effects on Raf/MEK/ERK signaling (Fan HH et al. Mol Cancer Ther 2009 (suppl)). We found that (1) sorafenib can down-regulate cyclin E1 expression in HCC cells; (2) resistance of HCC cells to sorafenib is associated with higher basal levels of cyclin E1 expression and failure of down-regulation by sorafenib; (3) knockdown of cyclin E1 expression by siRNA can reverse the resistance of HCC cells to sorafenib. The above data suggest that cyclin E1 expression in HCC cells may serve both as a predictive biomarker for treatment efficacy and as a potential therapeutic target.The present project will focus on the role of cyclin E1 and related signaling pathways in mediating the anti-tumor effects of sorafenib in HCC and to identify predictive biomarkers for treatment efficacy. Our specific aims are (1) to clarify the functional significance and regulatory mechanisms of cyclin E1 expression and related signaling pathways by sorafenib in HCC; (2) to examine the implications of cyclin E1 modulation on treatment efficacy of sorafenib and other molecular targeted agents in HCC; (3) to explore the prognostic and predictive values of cyline E1 and related proteins in HCC patients.The long-term objective is to establish a pre-clinical platform to explore predictive biomarkers and novel targets for molecular targeted therapy in HCC to facilitate future clinical trials in HCC.肝細胞癌標靶治療細胞凋亡細胞週期調控hepatocellular carcinomamolecular targeted therapyapoptosiscell cycle control