探討第二型拓樸異構酶β亞型在腸道發炎相關癌症的微環境調控中的參與角色

Abstract

發炎屬於形成腫瘤的標誌之一，慢性的發炎會提高癌症發生的可能性。直腸結腸癌是造成全球癌症死亡的主要原因之一，而像是發炎性腸道疾病（IBD）在全世界的發生率及盛行率逐年攀升，長期且復發性的發炎與腫瘤的形成高度相關。因此，我們對於發炎所導致的腫瘤發展相當感興趣。 先前實驗室發現，第二型拓樸異構酶β亞型(Top2β)參與了發炎過程中一氧化氮(NO)誘導的DNA損傷，並驗證了降低Top2β或抑制Top2β的表達可以減少基因組的不穩定性和腫瘤的發生。但是，我們也注意到VillinCre-Top2β小鼠的腫瘤大小受到影響。我們認為這可能是由於發炎細胞因子或腸道菌群的表現改變了微環境，因為Top2β已知在調節DNA轉錄中扮演重要的作用。我們的動物實驗結果顯示與WT小鼠相比，VillinCre-Top2β小鼠的發炎現象增加。然而在細胞實驗中，敲除Top2β會限制β-defensin在上皮細胞中的表達以及發炎細胞因子在免疫細胞及上皮細胞的表達。這種矛盾的結果可能是因為VillinCre-Top2β小鼠只剔除上皮細胞中的Top2β基因，導致上皮細胞在防禦感染性刺激方面的功能缺失。與動物實驗結果相似，VillinCre-Top2β小鼠的菌相似乎與大腸發炎和大腸癌更為相關。 根據上述結果，發炎反應調控腸道菌群和宿主之間的相互作用，並且在影響腫瘤的發展中有著重要的作用。我們的發現暗示了Top2β在發炎反應的調節作用，進一步探討其相關機制能為了解發炎相關的癌症疾病提供新的方向。

Inflammation is one of the hallmark of tumor formation. Chronic inflammation raises the possibility of developing cancer. Colorectal cancer is one of the top leading causes of cancer death worldwide. Moreover, colon inflammatory disease s such as IBD keep s high prevalence and incidence and is increased yearly. Long term and relapse inflammation is highly associated with tumor. Thus, we are interested in elucidating the mechanisms of the inflammation-related tumor development. Top2β is already known to have a crucial role in the regulation of DNA transcription. Our lab previously found that Top2β was involved in the nitric oxide-induced DNA damage during inflammation and validated that decrease Top2β or inhibit the expression of Top2β could reduce the genome instability and tumor initiation. However, we also noticed the tumor volume affected in VillinCre Top2β mice. This may due to the microenvironment changed by the expression of inflammatory cytokine or gut microbiota Our animal experiment s showed the increased inflammation in VillinCre-Top2β mice compared to WT mice. However in cell experiments, Top2β knockdown restricted the expression of β defensin in epithelial cell line and pro-inflammatory cytokine in both immune cell line and epithelial cell line. We speculate that VillinCre Top2β mice may only deplete Top2β in epithelial, lead to the defect of the epithelial function to defense infectious agents. Consistent with the animal results, the fecal microbiota of VillinCre-Top2β mice seems to more co-related to colon inflammation and colon cancer. From the above results, the inflammatory response is co-related to the interaction between gut microbiota and host and is important in tumor development. Our finding implied the regulatory role of Top2β, and the associated mechanism might give a new direction to treat the inflammation-related cancer disease.