2017-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648204摘要：卵巢癌在婦女惡性腫瘤中是死亡率排名第一位的疾病。卵巢癌的發生率在最近十年逐年上升，卵巢癌在台灣地區婦女惡化腫瘤發生率排名為第九位的疾病。以上數據顯示卵巢癌實在是一個值得重視的疾病。雖然積極的減積手術和化學治療藥品已被廣泛地使用，近二十法年來卵巢癌病人的總存活只有稍為地改變。近年來研究發現治療癌症的常規方法雖可清除普通的腫瘤細胞，但很難殺死腫瘤幹細胞。腫瘤幹細胞的生命力頑強，它的存在有可能導致手術、放射治療與化學治療後的腫瘤復發，同時也是腫瘤轉移的元兇。研究卵巢癌幹細胞的形成、進展和其轉移的機制將有助於我們了解這個疾病和發展未來新的卵巢癌治療方針。在先期的研究結果中，我們已經建立一株嶄新的出人類卵巢癌細胞CA5171，並加以培養為腫瘤幹細胞(Chiang YC, et al, Reprod Sci 2015;22:725)。這些卵巢癌幹細胞具抑制化療藥物誘發細胞死亡的能力。接著我們再以微矩陣分析將卵巢癌幹細胞與卵巢癌細胞進行基因表現差異，發現CHI3L1 在卵巢癌幹細胞與母體細胞相比有3 倍以上的表現。在臨床檢體中，我們也已經證實病患癌症組織中大量表現，並抑制化療藥物所誘發之細胞凋亡，此外CHI3L1的高度表現則有著較差的預後(Chiang YC, et al, Oncotarget 2015;6:39740)。這些現象與卵巢癌幹細胞的生物特性十分吻合。然而CHI3L1 是否會誘發卵巢癌幹細胞的生成及可能的機制則仍尚未被釐清。為了進一步探討CHI3L1 在卵巢癌幹細胞生成的角色與可能機制，我們設計了這個三年的計畫來回答上述的問題。我們將探討包括：第一，CHI3L1 與卵巢癌幹細胞的生成是否具關連性。第二，探討CHI3L1 影響卵巢癌幹細胞的生物性特徵如抗藥性及促癌發生的可能作用機制。第三，利用動物的研究模式確認在先前體外觀察到CHI3L1 影響卵巢癌幹細胞的生物特性的現象，並且評估逆轉CHI3L1 的訊息傳遞路徑後對降低卵巢癌幹細胞的生物性特的方法和機轉。本計畫在利用相關的分子生物指標及進一步釐清相關的基因影響癌症發生的作用機轉以及對CHI3L1 的生物功能特性作詳細的探討，並提供將來嶄新的卵巢癌標靶治療的策略與理論基礎。<br> Abstract: Ovarian cancer has the highest mortality rate of gynecologic malignancies. The incidence ofovarian cancer has increased over the past decade and it has become the ninth cause ofmalignancies of women in Taiwan. From the above-mentioned data, ovarian cancer indeed is adisease that should be respected. Despite the widespread use of aggressive cytoreductive surgeriesand the introduction of chemotherapy regimens, the overall survival has changed little over thelast two decades. Recent studies have revealed that that although conventional methods of cancertreatment could destroy the common tumor cells, however, it is difficult to kill cancer stem cells.Cancer stem cells demonstrate tenacious vitality that might enhance tumor recurrence ormetastasis after cancer treatment, including surgery, radiation therapy and chemotherapy. To studythe mechanisms of cancer stem cells generation and formation, progression, and metastasis ofovarian cancer will help us understand this disease and develop new treatment strategies forovarian cancer in the future.We have generated a novel human ovarian cancer cell line CA5171 and keep culturing thesecells to be cancer stem cells. These cancer stem cells could inhibit chemotherapeutic drugsinducing cell death (Chiang YC, et al, Reprod Sci 2015;22:725). We further analyzed the genesexpression profiles between CA5171 parental and stem cells. Evidences revealed that CHI3L1expression levels increased more than 3-fold in cancer stem cells compared with parental cells.Clinical evidences also demonstrated CHI3L1 could be over-expressed in cancer tissues andsuppressed chemotherapy-induced apoptosis. Besides, high CHI3L1in cancerous tissue alsosuggested poor prognosis in ovarian cancer patients (Chiang YC, et al, Oncotarget 2015;6:39740).These phenomena were highly similar to the biological properties of cancer stem cells. However,whether CHI3L1 expression might affect cancer stem cells generation and the detail mechanismhas not been investigated yet.To explore the role and possible mechanism of CHI3L1 on ovarian cancer stem cellsgeneration, we have proposed this three-year project to elucidate the following issues: First, wewill investigate the correlation of CHI3L1 expression and ovarian cancer stem cell generations.Second, we will investigate the possible mechanisms of CHI3L1 in affecting ovarian cancer stemcells properties including drug-resistance and tumorigenesis. Third, we will utilize in vivo animalmodels to elucidate whether the in vitro phenomena between CHI3L1 and ovarian cancer stemcells can also be observed in vivo. We will also evaluate the methods and mechanisms to inhibitpossible signal transduction pathways to reverse the CHI3L1-promoting cancer stem cellproperties. The results will provide a molecular biomarker and further related genetic informationto evaluate the possible mechanisms to classify ovarian cancer tumorigenesis. These results mightalso offer a novel strategy and theory of target therapy for ovarian cancer in the future.