Rogers Arlin B, Theve Elizabeth J, Feng Yan, Fry Rebecca C, Taghizadeh Koli, Clapp Kristen M, Boussahmain Chakib, Cormier Kathleen S, Fox James G
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Cancer Res. 2007 Dec 15;67(24):11536-46. doi: 10.1158/0008-5472.CAN-07-1479.
Hepatocellular carcinoma (HCC) is a male-predominant cancer associated with chronic hepatitis. Like human viral hepatitis, murine Helicobacter hepaticus infection produces inflammation and HCC with a masculine bias. We used this model to identify potential mechanisms of male HCC predisposition. Male weanling A/JCr mice (n = 67) were gavaged with H. hepaticus or vehicle. At 1 year, mice were distributed into four groups: surgical castration, chemical castration, castration followed by dihydrotestosterone supplementation, or sexually intact controls. Responses to infection were compared with IFN-gamma challenge alone. At 21 months, there was no significant difference in hepatitis between groups. Neither castration nor androgen receptor agonism altered tumor incidence. Infected mice with severe, but not mild, disease exhibited a mosaic of alterations to sexually dimorphic genes and microsomal long-chain fatty acids. By microarray, tumorigenic hepatitis was strongly associated with liver-gender disruption, defined as the loss of a gender-identifying hepatic molecular signature. IFN-gamma alone produced similar changes, demonstrating a role for proinflammatory cytokines in this process. In conclusion, hepatocarcinogenesis in male mice with chronic hepatitis is maturationally imprinted and androgen-independent. Proinflammatory cytokines may promote HCC in a male-predominant fashion due to high sensitivity of the masculinized liver to loss of sex-specific transcriptional balance. Liver-gender disruption has pleiotropic implications for hepatic enzyme activity, lipid processing, nuclear receptor activation, apoptosis, and proliferation. We propose a multistep model linking chronic hepatitis to liver cancer through cytokine-mediated derangement of gender-specific cellular metabolism. This model introduces a novel mechanism of inflammation-associated carcinogenesis consistent with male-predominant HCC risk.
肝细胞癌（HCC）是一种男性为主的与慢性肝炎相关的癌症。与人类病毒性肝炎一样，小鼠肝螺杆菌感染会引发炎症和HCC，且存在男性偏向性。我们利用该模型来确定男性HCC易感性的潜在机制。将雄性断奶A/JCr小鼠（n = 67）用肝螺杆菌或赋形剂灌胃。1年后，将小鼠分为四组：手术去势、化学去势、去势后补充二氢睾酮或性成熟对照。将感染反应与单独的干扰素-γ激发进行比较。21个月时，各组之间肝炎无显著差异。去势和雄激素受体激动均未改变肿瘤发生率。患有严重而非轻度疾病的感染小鼠表现出性二态性基因和微粒体长链脂肪酸的一系列改变。通过微阵列分析，致瘤性肝炎与肝脏性别破坏密切相关，肝脏性别破坏定义为性别识别肝脏分子特征的丧失。单独的干扰素-γ产生了类似的变化，表明促炎细胞因子在此过程中发挥作用。总之，慢性肝炎雄性小鼠的肝癌发生在成熟过程中被印记且不依赖雄激素。由于男性化肝脏对性别特异性转录平衡丧失高度敏感，促炎细胞因子可能以男性为主的方式促进HCC。肝脏性别破坏对肝酶活性、脂质加工、核受体激活、细胞凋亡和增殖具有多效性影响。我们提出了一个多步骤模型，通过细胞因子介导的性别特异性细胞代谢紊乱将慢性肝炎与肝癌联系起来。该模型引入了一种与男性为主的HCC风险一致的炎症相关致癌的新机制。
