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Title: | Lovastatin抑制口腔癌幹細胞幹性基因表現與侵襲能力 Lovastatin inhibits stemness genes and invasion of oral cancer stem cells |
Authors: | Chi-Yu Hong 洪志瑜 |
Advisor: | 郭彥彬(YEN-PING KUO) |
Keyword: | 口腔癌,癌幹細胞,洛伐他汀,甲羥戊酸途徑, oral cancer,cancer stem cell,stemness,lovastatin,mevalonate pathway, |
Publication Year : | 2019 |
Degree: | 碩士 |
Abstract: | 衛生福利部公佈的106年癌症登記報告指出,口腔癌為臺灣男性十大癌症死亡率的第五位。儘管近幾年口腔癌在診斷及治療技術上有改進,但病人五年存活率並未有顯著改善,失敗的主要原因之一為能夠自我更新的癌幹細胞(cancerstem cells, CSCs)存在,雖只佔一腫瘤小部份,但具持續分裂、分化的能力。近期的研究發現癌幹細胞對常規治療有抗藥性,導致癌症在治療後容易出現復發情形。由於癌幹細胞會表現大量的胚胎幹細胞調控蛋白,如果能夠有效抑制這些特定蛋白,便可消除癌幹細胞對化學藥物及放射治療之抗性。 Lovastatin為膽固醇
生合成途徑mevalonate途徑HMG-CoA reductase的抑制劑。近年文獻指出statin類的藥物除了有降血脂的功用外,對於惡性腫瘤如大腸癌、頭頸癌、乳癌、肺癌具有抑制增殖與轉移或促進細胞凋亡的作用。 郭教授實驗室先前已成功自口腔癌細胞株中培養出呈聚球狀(sphere)的口腔癌幹細胞。本研究是探討lovastatin做為未來抑制口腔癌幹細胞藥物的潛力。我們首先利用不同濃度的lovastatin處理SAS,經MTT結果發現,在濃度1~5M之間不影響SAS 聚球細胞存活率(IC50=10M); 且濃度1~50M之間的lovastatin不影響正常纖維母細胞的細胞存活率。接著在sphere forming assay中,lovastatin的濃度越高,形成sphere的數量與大小隨之減少。在invasion assay中,5M的lovastatin,幾乎可以完全抑制SAS 聚球細胞的侵襲。qPCR和Western blotting發現5M lovastatin 與 2.5 M的mevalonate途徑FPP synthase 抑制劑zoledronic acid幾乎可以完全抑制SAS 聚球細胞的癌幹細胞相關基因如OCT4、SOX2 、KLF4 的表現。Lovastatin 可能經由抑制ras 癌蛋白geranylgeranylation 而具有未來抑制口腔癌幹細胞藥物的潛力。 According to the 106-year cancer registration report released by the Ministry of Health and Welfare, oral cancer is the fifth leading cause of death among men in Taiwan . Despite the improvement in the diagnosis and treatment of oral cancer in recent years, the five-year survival rate of patients has not improved significantly. Treatment failure and recurrence are attributed to cancer stem cells. Cancer stem cells, a small part of cancer cells, are highly tumorigenic cancer cells that are capable of self-renewal and asymmetric division leads to differentiation into various heterogeneous cancer cells to cause tumor formation. It is worth noting that recent studies have shown that cancer stem cells are resistant to conventional treatment and drive local recurrence and metastasis. Since cancer stem cells would highly express embryonic stem cell proteins, if we can effectively inhibit these specific proteins, we would eliminate the resistance of cancer stem cells to chemical drugs and radiation therapy. Lovastatin, the HMG-CoA reductase inhibitors, not only lower serum cholesterol but also have antitumor effects in many cancer cell such as colorectal cancer, head and neck cancer, breast cancer and lung cancer in recent years. Professor Kuo’s lab has previously successfully cultured oral cancer stem cells in a sphere form from oral cancer cell lines. This study explores the potential of lovastatin for suppressing oral cancer stem cells in the future. First, we treat SAS cell line with different concentrations of lovastatin, MTT results found that the concentration of 1~5M does not affect the cell viability of SAS sp (IC50=10M), and lovastatin at a concentration of 1~50 M does not affect the cell viability of normal fibroblasts; then in the sphere forming assay, the higher the concentration of lovastatin, the formation of sphere number and size decreased; in the invasion assay, 5 M lovastatin almost completely inhibited the invasion of SAS sp, and we further treated SAS sp with lovastatin and zoledronic acid(FPP synthase inhibitor), using qPCR and western blotting we found that 5M lovastatin and 2.5M zoledronic acid inhibit the expression of stemness-associated genes such as OCT4, SOX2 and KLF4. Lovastatin have the potential to inhibit oral cancer stem cell by inhibiting the geranylgeranylation of Ras oncogene. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73799 |
DOI: | 10.6342/NTU201903808 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 口腔生物科學研究所 |
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