生物體內長期慢性發炎與癌症的產生有著密不可分的關係，但其中詳細的分子機制尚未被清楚釐清。CEBPD (C/EBPδ, NF-IL6β) 為CCAAT/enhancer binding protein (C/EBP) 家族成員之一，可結合至啟動子上的C/EBP binding site，調控下游基因表現，影響細胞生理功能。近年來的一些文獻以及實驗室先前的研究顯示在細胞中誘導CEBPD表現，可以誘發細胞生長停滯、細胞凋亡以及促進細胞分化。另一方面，我們在子宮頸癌及肝癌病人的腫瘤組織中觀察到CEBPD基因表現有靜默的情形，主要是因為SUZ12和EZH2在其中大量表現，並促使DNMTs將CEBPD啟動子上的CpG islands高度甲基化，進而導致CEBPD基因的靜默，此現象可能參與細胞癌化過程。因此，探討如何使癌細胞中CEBPD重新大量表現，並了解其中分子機轉，期望可以對於癌症治療提供更好的策略方針。在本研究中，我們證實目前許多臨床上使用的抗癌藥可誘導CEBPD的表現。其中，針對甘草萃取成分的衍生物－hydroxymethyldibenzoylmethane (HMDB)，發現其能夠透過活化p38MAPK/CREB pathway促進CEBPD基因的轉錄活化作用，並活化下游兩個促細胞凋亡基因－PPARG2和GADD153的表現，致使細胞走向凋亡。進一步地，我們透過同時活化訊息傳遞路徑以及調控外顯遺傳修飾作用的兩種機制，將HMDB合併另一甲基轉移酶抑制劑－5-aza-2’-deoxycitidine (5azadC) 處理癌細胞株，證實對於誘導CEBPD和下游促凋亡基因的表現以及誘發癌細胞凋亡的程度可產生加成性的效果。除此之外，我們建構了皮下異植癌細胞的腫瘤動物模式，實際給予動物體單獨或合併兩種藥物處理，發現合併給予HMDB和5azadC的給藥方式，能更有效地抑制腫瘤生長，同時觀察到此合併用藥方式，對動物體並不會產生嚴重毒性的副作用。未來誘導CEBPD抑癌基因在癌細胞中重新表現的方式，將可成為癌症治療的新標的。另一方面，亦可進一步評估HMDB使用於抗癌的臨床應用可能，甚至也可利用合併用藥的方法，期待在其他現行許多抗癌藥物所引發之對正常細胞具毒性副作用的基礎下，來達到加成性抑制癌細胞生長的治療效果。

Chronic inflammation can result in the formation of cancer. However, the details remain unclear. In our previous study, we demonstrated that CCAAT/enhancer binding protein delta (CEBPD, C/EBPδ, NF-IL6β), a potential tumor suppressor, can respond to the inflammatory factors treatment, and induce apoptosis to inhibit tumor progression. The E2F1-mediated activation of SUZ12/EZH2 can specifically result in inactivation of CEBPD gene through the hypermethylation of promoter to benefit the further process of tumorigenesis. Single compound of anticancer drug easily results in drug-resistant effects. Therefore, a combination treatment could provide an efficient methodology for cancer therapy. Herein, we demonstrated that CEBPD is a common anticancer drug-responsive protein. A structurally related β-diketone compound, hydroxymethyldibenzoylmethane (HMDB), could act through the activation of p38 kinase pathway to activate CEBPD transcription, followed by activation of PPARG2 and GADD153 transcription. Moreover, combination of HMDB and 5-aza-2’-deoxycytidine (5azadC), a DNA methyltransferase inhibitor, showed a synergistic effect on inducing CEBPD expression and cell apoptosis. In addition, in vivo study showed that combination treatment with HMDB and 5azadC can efficiently attenuate the growth of A431 and Huh7 xenografts in SCID mice. Taken together, these results not only provide new insight for the importance of reversing CEBPD induction to serve as therapeutic anticancer targets but also suggest that HMDB combined with 5azadC may provide a better therapeutic way in treatment of cancer patients with lower toxicity.

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