OCT4-NANOG Promotes Lung Cancer Oncogenesis through Induction of Epithelial-Mesenchymal Transdifferentiations.

陳啟仁(Chi-Jen Chen)

指導教授 ： 吳成文 ； 劉銀樟

國立清華大學/生命科學院/分子醫學研究所/碩士(2009年)

https://doi.org/10.6843/NTHU.2009.00257

摘要

OCT4 and NANOG are overexpressed in several cancers and involved in self-renewal signaling of stem cells, and downstream targets of OCT4 and NANOG are more frequently overexpressed in poorly differentiated tumors than in well-differentiated ones. However, little is known about the role of OCT4-NANOG signaling in lung cancer development. We discovered that both OCT4 and NANOG were co-overexpressed in adenocarcinoma. Overexpression of OCT4 and NANOG enhanced anchorage-independent cell growth in lung cancer, and promoted Xenograft lung tumor growth with poorly differentiated phenotype. Interestingly, overexpression of OCT4 and NANOG in lung cancer induced CD133+ cells and sphere formation, suggesting a regulatory role of OCT4-NANOG signaling in cancer stem cell formation. We identified that OCT4-NANOG promoted cell migration and induced epithelial-mesenchymal transition (EMT) through upregulation of SLUG, SNAIL, TWIST and TGF-β RI. As our knowledge, this is the first report demonstrating that OCT4-NANOG signaling promotes oncogenesis through induction of EMT.

關鍵字

OCT4 ； NANOG ； EMT ； Cancer stem cell

並列摘要

前人研究指出，主要調控幹細胞自我更新 (self-renewal)的兩個重要基因
OCT4及NANOG高量表現在多種癌症中。與分化較完全的腫瘤 (well-differentiated tumor)相較之下，OCT4及NANOG所調控的下游(downstream)訊息分子，高量表現在分化不完全的腫瘤組織(poor differentiated tumor)。然而，OCT4及NANOG所調控的訊息路徑，對於肺癌發展所產生的影響則尚未十分清楚。我們發現OCT4及NANOG在肺腺癌組織中 (primary lung adenocarcinoma)呈現共同超量表現的現象。 OCT4及NANOG在肺腺癌細胞中的超量表現，會增加細胞不貼附生長 (anchorage-independent growth)的特性、促進異體移植(Xenograft)的細胞生長、並產生分化未完全的細胞型態 (poor differentiated phenotype)。 研究結果顯示，OCT4及NANOG具有誘發肺癌中CD133+ 細胞及增強腫瘤球體 (tumor sphere)形成的作用。換言之，OCT4及NANOG可能經由誘發訊息路徑，共同調節癌幹細胞(cancer stem cells)的產生及增生。此外，我們也發現，藉由活化SLUG、 SNAIL、TWIST及TGF-β RI等因子，OCT4-NANOG具有誘導肺癌細胞由上皮細胞轉化為間質細胞 (Epithelial Mesenchymal transition, EMT) 的效果，進而促進肺癌細胞移動能力(migration ability)。上述實驗結果顯示，OCT4及NANOG經由幹細胞路徑，誘導EMT的發生而提高細胞的癌化能力（Oncogenesis）。

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