2017-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/686808摘要：卵巢癌球體形成不僅是造成體腔傳播轉移性利基，且顯著阻礙了治療的效應。球體形成細胞表現了STAT3 信號的活化和顯現癌症幹細胞的性質。然而，STAT3 對癌細胞幹性的調控機制，以及在卵巢癌發展中的關鍵作用仍然未知。我們最近研究發現STAT3 信號中的卵巢癌球體形成和自我更新調節中起重要作用，保護癌細胞免受化療藥劑的毒殺。STAT3 訊息所引導的調節路徑為不同的細胞株的球體形成之所必需，也支持小鼠腹膜內的腫瘤生長，抑制該途徑是對治療至關重要。最近研究顯示，癌細胞能特異性改變脂質代謝，可以影響許多細胞過程，包括細胞生長，增殖，分化，惡性腫瘤和移動能力。本計劃所提出的研究是為了確定1）STAT3 是如何專一性調節到卵巢癌細胞幹性，和2）STAT3 如何特異性調節脂質代謝途徑在調節卵巢癌幹性的角色。在目標1 中，我們將研究STAT3 的活化是否在卵巢癌球狀體的形成具有中心作用。我們也將調查STAT3/ miRNA -92 /Wnt 信號調節路徑的分子觀點。在目標2，我們將測試卵巢癌球體的生長和存活需要脂肪酸（FA）供給的假說，並將探討阻斷FA 合成系統是否具有抗癌作用。我們將研究LPL，是否在富含甘油三酯的脂蛋白存在下，加速的卵巢癌球狀體的生長。本計劃所提出的研究預期新的調控機制，控制LPL 的合成，並引入了新的途徑，以癌症代謝為標靶的治療。在目標3 中，由於球體形成細胞表達活性STAT3 信號和顯示幹細胞性質，我們將測試假設如果抑制STAT3 信號有效地消除了轉移性的形成和化療後抑制的持久性。這些特性將導引出抑制該途徑的治療方法將為本計劃的重要目標。<br> Abstract: Ovarian cancer spheroids not only form the metastatic niche for transcoelomic spread, but represent asignificant impediment to efficacious treatment. Spheroid-forming cells express active STAT3 signaling anddisplay stem cell-like properties. However, it remains unknown the mechanisms underlying STAT3/cancerstemness regulation and how critical is their role in ovarian cancer progression. We recently uncovered anessential role of STAT3 signaling in regulation of ovarian cancer spheroid formation and self-renewal,protecting them from chemotherapeutic agents. STAT3-mediated regulatory circuits are required for thespheroid formation in diverse cell lines and intraperitoneal tumor growth in xenografts, supporting thatinhibition of this pathway will be vital to a cure. Recently, cancer cells show specific alterations in lipidmetabolism that can affect numerous cellular processes, including cell growth, proliferation, differentiation,malignancy and motility. The proposed research is to determine 1) how STAT3 is specifically regulated tothe ovarian cancer cell stemness, and 2) how STAT3 specifically regulates lipid metabolic pathway involvedin regulating ovarian cancer stemness.In Aim 1, we will investigate whether the activation of STAT3 plays a central role in the generation of EOCspheroids. We will also investigate the molecular basis of the STAT3/miRNA-92/Wnt signaling regulatorycircuit.In Aim 2, we will test the hypothesis that EOC spheroids require a supply of fatty acids (FA) for growth andsurvival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We willinvestigate whether LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of EOCspheroids. The proposed investigation is anticipated to identify a new regulatory mechanism for the controlof LPL synthesis and to introduce a new avenue to target cancer metabolism for therapy.In Aim 3, Since spheroid-forming cells express active STAT3 signaling and display stem cell-like properties,we will test the hypothesis if inhibition of STAT3 signaling effectively eliminates the formation of themetastatic niche and suppresses its persistence after chemotherapy. These features point to the idea that theinhibition of this pathway is vital to the discovery of a cure.