Egr-1 於大腸癌幹細胞之功能研究

Abstract

癌幹細胞具有較強的抗化療藥物以及轉移能力，因此不易治療根除，被認為是導致癌症復發及轉移的原因。Egr-1 為轉錄因子可以調控細胞的增生及凋亡，也會促使幹細胞的分化。而在癌症的研究中發現 Egr-1 同時作為促癌基因和抑癌基因，但是目前還不清楚 Egr-1 對於癌幹細胞的影響。本篇研究在大腸癌細胞株 DLD1 中過量表現及削弱 Egr-1，並藉由球體及群落形成檢測、群落抗藥性試驗、邊緣族群分析、大腸癌幹細胞標記表現量檢測以及轉移能力分析，發現 Egr-1 會透過抑制癌幹細胞的自我更新，降低其族群數量，以及促使分化。此外，我發現給予大腸癌細胞株 DLD1，常山植物的萃取物處理後，會促進 Egr-1 蛋白質的表現，並且也會降低癌幹細胞的族群數量及特性，代表著常山萃取物可能是透過促進 Egr-1 來達成抑制癌幹細胞的功效。未來可以利用這些藥物，使病患腫瘤組織中，癌幹細胞群減少甚至消失，進而降低癌症的復發以及轉移，增加治療的成功率。

Cancer stem cells (CSCs) are the small population cells in tumor and have the ability of self-renewal to maintain themselves and differentiation into various non-stem cancer cells. CSCs are responsible for tumor progression, drug resistance, metastasis and cancer recurrence. Early growth response-1 (Egr-1), a zinc finger transcription factor, is involved in regulation of cell proliferation, apoptosis and stem cell differentiation. In cancer, Egr-1 has a dual role as both an oncogene and a tumor suppressor. Therefore, Egr-1 may play an important role in CSCs. In this study, I demonstrated that Egr-1 could inhibited self-renewal ability of CSCs to form spheres and colonies. The ratio of side population and colorectal CSCs markers were reduced. In addition, Egr-1 could also suppress drug resistance and migration of CSCs. These data demonstrated that Egr-1 could reduce the number of CSCs in cancer through inhibition of self-renewal and inducing CSCs differentiation. Furthermore, after treatment of Dichroa febrifuga extract, Egr-1 protein expression was upregulated in colorectal cancer cells, and the abilities of CSCs, such as self-renewal and drug resistance, were inhibited. These evidences revealed that Dichroa febrifuga extract had an antitumor effect may associate with the induction of Egr-1. Therefore, Dichroa febrifuga extract might be useful for decreasing or even eliminating CSCs in tumor mass. This method might be a CSCs target therapy to prevent tumor recurrence and metastasis.