Gene Expression Analysis Indicates Divergent Mechanisms in DEN-Induced Carcinogenesis in Wild Type and Bid-Deficient Livers

Bid is a Bcl-2 family protein. In addition to its pro-apoptosis function, Bid can also promote cell proliferation, maintain S phase checkpoint, and facilitate inflammasome activation. Bid plays important roles in tissue injury and regeneration, hematopoietic homeostasis, and tumorigenesis. Bid participates in hepatic carcinogenesis but the mechanism is not fully understood. Deletion of Bid resulted in diminished tumor burden and delayed tumor progression in a liver cancer model. In order to better understand the Bid-regulated events during hepatic carcinogenesis we performed gene expression analysis in wild type and bid-deficient mice treated with a hepatic carcinogen, diethylnitrosamine. We found that deletion of Bid caused significantly fewer alterations in gene expression in terms of the number of genes affected and the number of pathways affected. In addition, the expression profiles were remarkably different. In the wild type mice, there was a significant increase in the expression of growth regulation-related and immune/inflammation response-related genes, and a significant decrease in the expression of metabolism-related genes, both of which were diminished in bid-deficient livers. These data suggest that Bid could promote hepatic carcinogenesis via growth control and inflammation-mediated events.

Bid是Bcl-2家族蛋白（Bcl-2 family protein）。除具备促凋亡功能外，Bid还可促进细胞增殖、维持S期检验点（S phase checkpoint），并促进炎性小体（inflammasome）活化。Bid在组织损伤与再生、造血稳态（hematopoietic homeostasis）以及肿瘤发生（tumorigenesis）中发挥重要调控作用。Bid参与肝癌发生（hepatic carcinogenesis）过程，但其具体分子机制尚未完全阐明。在肝癌模型中，敲除Bid可显著降低肿瘤负荷并延缓肿瘤进展。为更好地解析肝癌发生过程中Bid调控的分子事件，我们对给予肝致癌物二乙基亚硝胺（diethylnitrosamine）的野生型与Bid缺陷型（bid-deficient）小鼠开展了基因表达分析。研究发现，相较于野生型小鼠，Bid缺陷小鼠的基因表达改变显著更少——无论是受影响的基因数量，还是受影响的信号通路数量。此外，二者的基因表达谱存在显著差异：野生型小鼠体内，生长调控相关基因与免疫/炎症应答相关基因的表达显著上调，而代谢相关基因的表达显著下调；上述两类表达变化在Bid缺陷小鼠的肝脏组织中均被显著削弱。上述数据表明，Bid可通过生长调控及炎症介导的分子通路促进肝癌发生。