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標題: 外遺傳分析肌動素調節蛋白在TGF-beta 1誘導分化人乳癌幹細胞與鼻咽癌幹細胞的表現
Epigenetic analysis of gelsolin in TGF-beta 1 induced differentiation of human breast cancer stem cells and nasopharyngeal cancer stem cells.
作者: 陳智源
Chen, Zhi-Yuan
關鍵字: 乳癌幹細胞;breast cancer stem cell;鼻咽癌幹細胞;肌動素調節蛋白;轉化生長因子beta 1;外遺傳分析;nasopharyngeal cancer stem cell;gelsolin;TGF-beta 1;epigenetic
出版社: 生命科學系所
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乳癌是世界上常見的癌症死亡原因之一,約有5%的乳癌患者會有轉移的情形,同時約有30-40%的病人在初步的檢測中未發現轉移,但之後卻出現了癌轉移的情形。因此,腫瘤細胞可能從原發處被釋出到末梢循環中,是透過循環腫瘤細胞,遷移到骨髓等微環境。透過將細胞維持在非增生—類似於幹細胞的形態下,或是被誘導成腫瘤啟動細胞來啟動癌細胞的轉移。肌動素調節蛋白是一種可結合肌動蛋白並進行調控的蛋白質,基因位於人類的第九對染色體。目前已知藉由肌動蛋白的調節,可調控細胞型態、細胞移動、細胞分化及細胞凋亡,許多人類癌症中,肌動素調節蛋白的表現下降,然而肌動素調節蛋白在癌症幹細胞所扮演的角色還不是很清楚。在本研究中我們發現,在CD44+/CD24-乳癌細胞與鼻咽癌細胞亞群中,肌動素調節蛋白的表現會有明顯減少的情形,但透過TGF-beta 1處理後,CD44+/CD24-癌細胞亞群中,肌動素調節蛋白則呈現明顯上升的情形,這個情形發生在乳癌細胞與鼻咽癌細胞中。我們也發現透過TGF-beta 1處理後,肌動素調節蛋白表現增加,會增強乳癌細胞與鼻咽癌細胞,這兩種癌細胞遷移與入侵的能力。此外,在肌動素調節蛋白的表關遺傳學分析方面,我們將經由TGF-beta 1處理後的細胞亞群分別進行分析,結果發現,透過TGF-beta 1處理後,CD44+/CD24-乳癌與鼻咽癌細胞亞群中,肌動素調節蛋白基因的啟動子區域,甲基化的情形會下降,同時去甲基化的情形會增加,說明了肌動素調節蛋白會透過外遺傳調控影響,進而去改變染色質的結構。綜合以上的結果我們發現,TGF-beta 1影響癌細胞中基因啟動子區域甲基化減少,與促進去甲基化的增加,進而去改變肌動素調節蛋白的表現。

Breast cancer is one of most common cause of cancer death in the world. Approximately 5% of patients with breast cancer have clinically detectable metastases at the time of initial diagnosis and 30-40% of patients who appear clinically free of metastases accumulate hidden metastases. Presumably, tumor cells shed from the primary lesions are released into the peripheral circulation as circulating tumor cells (CTCs), and then CTCs migrate to the bone marrow microenvironment where there is a selection to maintain a non-proliferative stem cell like phenotype or to be induced to become cancer-initiating stem cells (CSCs) for metastases. Gelsolin (GSN) is an actin-binding protein encoded by the gene, which is located at human chromosome 9q33. GSN is known to regulate cell morphology, motility, differentiation, and apoptosis. Down-regulation of GSN was found in many types of human malignant cancers. However, the role of GSN in cancer stem cell has not been well evaluated. In this study, we demonstrated that GSN expression was decreased in CD44+/CD24- subpopulation of MDA-MB-231 breast cancer cells and HONE-1 nasopharyngeal carcinoma cells without TGF-beta 1 treatment, while GSN expression was increased with TGF-beta 1 treatment. The increased GSN expression was accompanied by increased cell migration and invasion for TGF-beta 1 treated cells. Epigenetic analysis showed that TGF-beta 1 caused to modify GSN expression in both MDA-MB-231 cells and HONE-1 cells through epigenetic alteration in chromatin structure. In summary, the results found in this study suggest that TGF-beta 1 induction attenuated the methylation but facilitated the unmethylation on GSN DNA promoter region such as that increased GSN expression in cancer cells.
其他識別: U0005-0508201314085100
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