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標題: | 探討TIF1β於癌幹細胞之幹性維持上所扮演的角色 Participation of TIF1β in Regulating Stemness of Cancer Stem Cells |
作者: | Ya-Pei Peng 彭雅珮 |
指導教授: | 周涵怡(Han-Yi Chou) |
關鍵字: | 癌症幹細胞,TIF1β,幹性維持,缺氧,HIF1α, cancer stem cells,TIF1β,stemness,hypoxia,HIF1α, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 癌症幹細胞被認為具有類似幹細胞特性,能夠自我更新,促進腫瘤的增生與分化並負責腫瘤轉移。另外,它還具有抗化學治療及放射治療的能力。輔助轉錄因子TIF1β是一個epigenetic的調控者,其重要功能為藉由與HP1蛋白或其他染色質調控因子的結合,影響染色質的重組,進而去調控基因的表現。另外,TIF1β本身也被認為能夠被後轉譯修飾,包含磷酸化及sumo化。TIF1β的Serine473位於其與HP1蛋白結合的序列附近,已被證實能夠藉由磷酸化來調控與HP1蛋白的結合。而TIF1β高度參與在維持胚胎幹細胞多能性的蛋白交互網絡之中,並能夠調控胚胎幹細胞多能性的維持與分化的過程。本文的研究利用肺癌幹細胞探討,發現了當細胞在失去了幹性之後,在S473磷酸化的TIF1β有明顯的受到調控,顯示出TIF1β-S473的磷酸化會參與癌症幹細胞的幹性維持。藉由免疫組織染色我們也發現TIF1β-S473的磷酸化確實與癌細胞侵犯及抗藥性相關。此外,在使細胞暴露於缺氧的系統之下,TIF1β-磷酸化的狀態和HIF1α的誘導有相反的情況,並且會影響到HIF1α的轉錄活性,而且在具有抗化療的病人組織中,TIF1β和HIF1α有高度相似的表現。這些證據暗示了TIF1β-S473的磷酸化可能在癌症幹細胞的幹性維持上扮演了重要角色,且可能經由與HIF1α交互調控,進而導致腫瘤的復發,轉移及抗性的發展。 Cancer stem cells were initially defined by their extensive self-renewal capacity, tumorigenicity, multipotentiality, and drug resistance. Transcription intermediary factor 1 beta (TIF1β) is an epigenetic modulator that can regulate chromatin remodeling and gene expression through the interaction with heterochromatin protein 1 (HP1) among other chromatin factors. The serine 473 residue of TIF1β is located just upstream of the HP1 binding domain of TIF1β, and has been shown to alter its association with HP1. Furthermore, TIF1β was previously identified as a component of the central protein interaction networks for maintenance of pluripotency in mouse embryonic stem cells. TIF1β is highly expressed in cancer; however, the role of TIF1β in tumorigenesis and its contribution to the maintenance of stemness properties in cancer stem cells have never been addressed. Using lung cancer stem cell models, we report that phosphorylation of TIF1β at the S473 residue is suppressed upon loss of stemness properties, and this phosphorylation state could occur in cancer progression events by immunohistochemistry analysis. Interestingly, we found that the phosphorylation status of TIF1β Ser473 inversely correlates with HIF1α induction during hypoxic stress. We also found that this phosphorylation state could influence the transcriptional activity of HIF1α, but we could not identify that HIF1α is associated with TIF1β-containing immunocomplexes. In addition, TIF1β is highly colocalized with HIF1α in chemo-resistant lung cancer patients. Taken together, our results suggest that phosphorylation of TIF1β at the S473 residue may play roles in regulating stemness in cancer stem cells, and may hence contribute to tumor recurrence, metastasis and the development of resistance to therapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30962 |
全文授權: | 有償授權 |
顯示於系所單位: | 口腔生物科學研究所 |
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