流行病學和臨床研究指出慢性發炎增加某些癌症的風險，可能是藉由影響染色體不穩定。然而，伴隨發炎而引發的染色體不穩定與癌症發生的機轉還沒有被完全地釐清。轉錄因子CCAAT/enhancer binding protein delta (C/EBP, CEBPD) 可被腫瘤壞死因子a(TNF a) 誘導，並且表現在慢性發炎的組織中。在此我們利用HeLa細胞模式，顯示CEBPD參與，至少一部分，TNF a所誘導的基因體不穩定。在本篇研究中發現，降低CEBPD可減少TNF a誘導的非整數倍體細胞。此外，TNF a誘導的CEBPD表現可促使非貼附性生長 (anchorage-independent growth) 增加。我們發現TNF a藉由CEBPD誘導AURKC的表現，而那AURKC也可促使非整數倍體細胞的生成。詳細的機制經由染色質免疫沈澱技術 (chromatin immunoprecipitation assay, ChIP) 和電泳遷移率實驗 (Electrophoretic mobility shift assay, EMSA) 分析證實，結果顯示當處理TNF a時，CEBPD可以直接接合上AURKC的啟動子上，結合的位置在-78~-87和-424~-433區域。而且，CEBPD的高表現與AURKC的表現在發炎的子宮頸組織具有一致性。進一步以酵母菌雜交法 (yeast two-hybrid analysis) 鑑定出一個AURKC的交互作用蛋白，Fanconi anemia zinc finger，FAZF。FAZF具有誘導G1期停滯和凋亡的功能。觀察到AURKC誘使FAZF經由不依賴泛素的降解路徑 (ubiquitin-independent degradation pathway) 降解。這些結果對CEBPD在發炎反應中藉由活化AURKC誘導染色體不穩定的功能提供創新的見解。

Epidemiologic and clinical research indicates that chronic inflammation increases the risk of certain cancers, possibly through chromosomal instability. However, the mechanism of inflammation-dependent chromosomal instability associated with tumorigenesis is not well characterized. The transcription factor CCAAT/enhancer binding protein delta (C/EBP , CEBPD) is induced by tumor necrosis factor  (TNF  and is expressed in chronically inflamed tissue. Using HeLa cells as a model system, we show here that CEBPD mediates, at least in part, TNF induced genomic instability. In this study, loss of CEBPD attenuated TNF -induced aneuploidy. Additionally, TNF -induced CEBPD expression augmented anchorage-independent growth. We found that TNF  induced expression of aurora kinase C (AURKC) through CEBPD, and that AURKC also causes aneuploidy. The detailed mechanism was confirmed by ChIP (chromatin immunoprecipitation assay) and EMSA (Electrophoretic mobility shift assay), and these results indicated that CEBPD can directly bind to AURKC promoter via-78~-87 and -424~-433 regions when treated with TNF. Furthermore, a high CEBPD expression level was correlated with AURKC expression in inflamed cervical tissue specimens. An AURKC-interacting protein, Fanconi anemia zinc finger, FAZF, was identified using yeast two-hybrid analysis. FAZF induces G1 arrest and apoptosis. It is observed that AURKC induced the degradation of FAZF through a ubiquitin-independent degradation pathway. These data provide insight into a novel function for CEBPD in inducing genomic instability through the activation of AURKC expression in response to inflammatory signals.

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