FOXO3 在大腸癌幹細胞之功能研究

Abstract

癌幹細胞具有較強的抗藥性和轉移能力，而且會促進腫瘤的進程。FOXO3 為一轉錄因子。由於它會抑制細胞週期和促進細胞凋亡，所以 FOXO3 一直以來被視為抑癌基因。然而有些研究卻發現 FOXO3 也有助於腫瘤，而且 FOXO3 負責維持成體幹細胞的自我更新能力。目前還不清楚為何 FOXO3 在癌症裡有矛盾的功能，也不清楚 FOXO3 對於癌幹細胞的影響。在這篇研究裡，我發現缺乏特定轉譯後修飾的 FOXO3 會促進癌幹細胞的特性。相比於癌細胞而言，癌幹細胞的 FOXO3 的表現量較高。抑制 FOXO3 表現會降低癌幹細胞的特性，證明了 FOXO3 的確對癌幹細胞很重要。而且，本篇研究還發現了癌幹細胞裡 FOXO3 的功能會受到特定後轉譯修飾調控。轉譯後修飾會調控 FOXO3 對目標基因的專一性。失去特定修飾型態的 FOXO3 會促進自我更新、抗藥性和轉移能力，而有此轉譯後修飾的 FOXO3 則沒有這樣的功能。而且，基因表現分析結果發現缺乏此轉譯後修飾的 FOXO3 可能還會增進氧化自由基的清除和 DNA 修復能力，而有此轉譯後修飾的 FOXO3 則可能會促使細胞凋亡。因此，我們的結果證明了，FOXO3 的確會維持癌幹細胞的特性，而且 FOXO3 的不同功能會受到蛋白質的後轉譯修飾調控。FOXO3 的後轉譯修飾酵素在未來也許可以當作癌症標靶治療的目標。這篇研究顯示著在癌症裡基因的重要性並不能只由表現量決定，還跟蛋白質的後轉譯修飾有關。

Cancer stem cells (CSCs) are responsible for tumor progression, drug resistance and metastasis in malignant diseases. FOXO3, a transcription factor, has been regarded as a tumor suppressor due to its cell-cycle arrest and apoptosis-inducing abilities. Nevertheless, some studies indicated that FOXO3 may be an oncogene and FOXO3 maintains self-renewal in adult stem cells. The paradoxical roles of FOXO3 in cancers and the roles of FOXO3 in CSCs remain to be clarified. Here I show that without specific posttranslational modifications, FOXO3 promotes colorectal CSC properties. Higher FOXO3 expression was observed in CSCs and inhibition of FOXO3 reduced CSC properties, suggesting that FOXO3 is essential for colorectal CSCs. Moreover, I discovered that the functions of FOXO3 in CSCs are regulated by posttranslational modifications. Posttranslational modifications on FOXO3 regulated its target specificity. Without specific posttranslational modifications, FOXO3 promoted self-renewal, drug resistance and migration, while modified FOXO3 could not. Also, different gene expression profiles showed that without specific posttranslational modifications, FOXO3 might enhance ROS detoxification and DNA repair, while modified FOXO3 might induce apoptosis. Therefore, my results suggest that FOXO3 is indispensable for the maintenance of CSCs and the differential functions of FOXO3 in CSCs are regulated by protein modifications. Specific FOXO3 modulating enzymes could be target molecules for cancer therapy in the future. This study shows that the roles of genes in cancers could not be determined only by gene expression levels but also their protein posttranslational modifications.