第二型鈉葡萄糖轉運蛋白抑制劑(SGLT2i)為一類可以抑制葡萄糖經由腎臟再吸收回血管，藉此降低血糖的新型降血糖藥物。近期研究發現SGLT2i除了調節血糖的功能外，可能具有抗癌的作用。文獻指出SGLT2i對不同種類癌細胞具有抑制細胞增殖，移動能力以及促進細胞凋亡等效果，但是目前尚未有研究表明SGLT2i是否會影響癌細胞的轉移能力。因此我們將肺癌幹細胞以恩排糖(Empagliflozin)處理以了解SGLT2i對癌細胞轉移能力的影響。
從結果發現，恩排糖能夠過抑制上皮間質轉換(epithelial-mesenchymal transition, EMT)相關基因以抑制肺癌幹細胞的上皮間質轉換。接著再透過傷口癒合試驗(Wound healing assay)觀察到恩排糖也會降低肺癌幹細胞的移動能力。此外結果也發現恩排糖可以降低代表肺癌幹細胞特性(stemness)的基因，以及細胞幹性的相關基因表現。以球形成試驗(Sphere-forming assay)測試也發現恩排糖會降低肺癌幹細胞形成球體的能力。最後分析恩排糖影響的蛋白質表現情形發現，恩排糖會降低Akt/GSK3β/β-catenin路徑相關蛋白的表現量，進而降低與EMT和stemness相關轉錄因子Twist1和Snail表現量而達到抑制效果。總結上述結果，恩排糖可以透過調控Akt/GSK3β/β-catenin路徑，降低EMT和stemness相關轉錄因子，進而降低相關功能表現。

Sodium-glucose transporter-2 inhibitors (SGLT2i) are a class of antidiabetic drugs that could inhibit glucose reabsorption from the proximal tubule and lower glucose levels in blood. Besides its hypoglycaemic effects, recent studies reveal that SGLT2i may have the potential to become novel anticancer therapies. Some evidence has shown that SGLT2i can inhibit proliferation and migration and induce apoptosis in different cancer cells, but SGLT2i effect on cancer metastasis remains unclear.
To investigate the impact of SGLT2i in cancer metastasis, we treated lung cancer stem cells with Empagliflozin, an SGLT2i, to examine its influence on cancer metastasis.
Our result shows that Empagliflozin can inhibit epithelial-mesenchymal transition (EMT) by decreasing the expression of related genes. In addition, we performed wound-healing assay, and the result also showed that Empagliflozin could impair the migration ability of lung cancer cells. We also found that Empagliflozin can suppress cancer stemness by downregulating lung cancer stem cell markers CD44 and CD133, along with other stemness-related genes. The sphere-forming assay also demonstrates that Empagliflozin can attenuate the sphere-forming ability of lung cancer stem cells, which correlated with previous results. Last, we found that Empagliflozin can inhibit the expression of Akt/GSK3β/β-catenin axis-related protein in lung cancer stem cells.
Our results suggest that Empagliflozin downregulates EMT and stemness-related genes in lung cancer stem cells by downregulating the Akt/GSK3β/β-catenin axis, which indicates that SGLT2i may serve as a potential therapeutic for lung cancers.

Contents v
Chapter 1. Introduction 1
Chapter 2. Materials and Methods 10
Chapter 3. Results 17
Chapter 4. Discussion 23
Chapter 5. Tables and Figures 29
Chapter 6. Reference 40

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