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標題: | LOXL2通過IFIT1和IFIT3促進頭頸癌癌幹細胞特性並增強吉非替尼的抗腫瘤作用 LOXL2 promotes stemness and enhances anti-tumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3 |
作者: | 呂怡潔 Yi-Jie Lu |
指導教授: | 郭彥彬 Mark Yen-Ping Kuo |
關鍵字: | 口腔鱗狀細胞癌,離胺基氧化酶樣蛋白2,上皮細胞間質轉化,癌幹細胞,表皮生長因子受體,IFIT1,IFIT3,Gefitinib, Lysyl oxidase-like 2,cancer stem cells,interferon-induced protein with tetratricopeptide repeats 1,interferon-induced protein with tetratricopeptide repeats 3,gefitinib., |
出版年 : | 2023 |
學位: | 博士 |
摘要: | 根據衛生福利部110年統計,口腔癌居臺灣男性十大癌症中發生年齡最年輕的。也是死亡年增率最高的癌症。儘管不斷有新的治療方法,由於癌細胞發展出轉移能力及治療抗性。口腔癌病人的五年存活率只有45-50 %。離胺基氧化酶樣蛋白2 (lysyl oxidase-like 2; LOXL2)是LOX家族的一種胺基氧化酶。最近研究發現細胞內LOXL2可誘導上皮細胞間質轉化(EMT)及幹細胞特性,可使癌細胞具侵襲與轉移作用。其作用機轉隨不同細胞而不同。但LOXL2蛋白表現與口腔癌癌化過程,機轉及癌幹細胞的關係, 先前尚未有學者發表。本研究先將LOXL2 cDNA的質體送入內生性LOXL2蛋白表現量低的人類口腔癌細胞株TW2.6 和下咽FaDu細胞株。結果顯示,TW2.6及FaDu高表現LOXL2蛋白(TW2.6/LOXL2,FaDu/LOXL2)時,會造成癌細胞生長速度加快,移動及侵襲的能力增強。並可誘導上皮-間葉細胞轉化轉錄因子Snail1,Slug,Twist1 及間質型標記蛋白 N-cadherin 和 Vimentin增加,上皮型標記蛋白E-cadherin減少。亦可誘導誘導TW2.6及 FaDu細胞產生癌幹細胞的特性,例如增加形成癌症聚球體(sphere)的能力,增加幹細胞特性蛋白CD133, CD44,Klf4 ,OCT4, SOX2 和 Nanog 的表現。以siLOXL2 RNA剔除SAS癌症細胞聚球體中LOXL2表現,可以抑制形成癌症聚球體的能力,使聚球體細胞減少。並抑制SAS聚球體幹細胞特性蛋白的表現。免疫缺陷SCID鼠異種移植(xenograft)研究發現,TW2.6/LOXL2比TW2.6及較易形成腫瘤,形成的腫瘤也比較大。使用基因表現微陣列晶片比較高表現LOXL2 的TW2.6及FaDu細胞株與對照組細胞株的基因表現差異,找到下游分子為IFIT1 (Interferon-induced protein with tetratricopeptide repeats 1) 及IFIT3。以IFIT1 及IFIT3 shRNA 分別刪除TW2.6-LOXL2的IFIT1 及IFIT3表現,可抑制 LOXL2誘導的EMT 標記蛋白和幹細胞標記蛋白表現。 口腔鱗狀細胞癌檢體中LOXL2蛋白的表現量與IFIT1 及IFIT3蛋白的表現量呈正相關。值得注意的是,當LOXL2過度表現增加了TW2.6 和FaDu細胞中p-EGFR Y1068 的表現。以EGPR抑制劑Gefitinib藥物,處理TW2.6/LOXL2 和FaDu/LOXL2細胞,相較於TW2.6/Vector 和FaDu/Vector細胞,對於藥物有較敏感的反應。在動物實驗中,也發現Gefitinib對TW2.6/LOXL2的抗腫瘤作用比TW2.6/Vector高 4 倍。LOXL2過度表現增加增強了吉非替尼的腫瘤抑制作用。 LOXL2過度表現可作辨識患者對於EGFR標靶治療的效用。 Despite substantial progress in the detecting and treating head and neck squamous cell carcinoma (HNSCC), the ongoing challenges in overcoming recurrence or metastasis warrant new strategies to improve overall patient survival. Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. However, the mechanisms by which LOXL2 affects head and neck cancer are not thoroughly understood. This study found LOXL2-overexpressing buccal SCC TW2.6 cells exhibited enhanced proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC)-phenotypes and significantly increased tumor initiating frequency in SCID mice. LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), IFIT3 and phospho-EGFR-Y1086 in LOXL2-overexpressing TW2.6 and hypopharyngeal SCC FaDu cells. IFIT1 and IFIT3 are key downstream components of LOXL2 action in migration, invasion, EMT, and CSC-phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human oral SCC tissues was observed. In addition, LOXL2-overexpressing TW2.6 and FaDu cells were 3.3- to 3.6-fold more susceptible to the EGFR inhibitor gefitinib than were their respective controls. The anti-tumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was 4-fold higher than that on controls. Our results indicate that LOXL2 may be used as a marker to identify patients most likely to respond to EGFR-targeted therapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91652 |
DOI: | 10.6342/NTU202304389 |
全文授權: | 未授權 |
顯示於系所單位: | 口腔生物科學研究所 |
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