小孢子靈芝免疫調節蛋白質GMI抑制口腔癌幹性之功效及其機制探討

Elucidation of the effects and molecular mechanisms of immunomodulatory protein from Ganoderma microsporum (GMI) on targeting oral cancer stemness

王棟源(Tung-Yuan Wang)

指導教授 ： 余承佳

中山醫學大學/口腔醫學院/牙醫學系博士班/博士(2018年)

摘要

癌症幹細胞已被證實能導致口腔鱗狀上皮細胞癌的腫瘤起始、復發及轉移，並對化療產生阻抗性。於本研究中，我們發現小孢子靈芝免疫調節蛋白可明顯抑制口腔癌症幹細胞的增生能力，具有細胞毒性。小孢子靈芝免疫調節蛋白還能有效減少口腔癌症幹細胞標記ALDH1的活性表現、降低CD44表現量，並呈現濃度依賴趨勢。此外，小孢子靈芝免疫調節蛋白亦可以有效降低口腔癌症幹細胞之幹細胞球體自我更新能力、軟瓊脂細胞群落生成力、細胞侵襲力及化療抗藥性。機制探討上也發現小孢子靈芝免疫調節蛋白透過調控IL6/Stat3訊息傳遞路徑達到腫瘤抑制效果。動物實驗也證實小鼠餵食小孢子靈芝免疫調節蛋白後能有效抑制腫瘤生成。基於上述實驗結果，我們證實孢子靈芝免疫調節蛋白能標靶口腔癌症幹細胞，並可作為化療藥物順鉑的天然佐劑，預防癌症復發。

關鍵字

口腔鱗狀上皮細胞癌 ； 小孢子靈芝免疫調節蛋白 ； 癌症幹細胞 ； 化療抗藥性 ； IL-6/Stat3訊息傳遞路徑

並列摘要

Cancer stem cells (CSCs) have been identified to exert tumor-initiating ability, resulting in the recurrence, metastasis and chemoresistance of oral squamous cell carcinomas. In the present study, we showed that GMI, an immunomodulatory protein from Ganoderma microsporum, induced a cytotoxic effect in oral carcinomas stem cells (OCSCs). Treatment of GMI dose-dependently inhibited the expression of CSC markers, including ALDH1 activity and CD44 positivity. Moreover, GMI suppressed the self-renewal property, colony formation, migration, and invasion abilities as well as potentiated chemo-sensitivity in OCSCs. Our results suggested that the tumor suppressive effect of GMI was mediated through inhibition of IL-6/Stat3 signaling pathway. Furthermore, tumor growth was reduced in mice bearing xenograft tumors after oral administration of GMI. Taken together, we demonstrated the anti-CSC effect of GMI in oral cancer and GMI may serve as a natural cisplatin adjuvant to prevent cancer recurrence.

並列關鍵字

oral squamous cell carcinomas ； immunomodulatory protein GMI ； cancer stem cells ； chemoresistance ； IL-6/Stat3 signaling

參考文獻

參考文獻

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