美国研究人员揭示男性易患肝癌的基因学机制

张医生

　　美国麻省理工学院（MIT）科学家的最新研究表明，男性与女性对于慢性肝炎回应方式的根本差异，有助于在基因水平上解释为何男性更容易罹患肝癌。这是科学家首次在基因水平上研究非繁殖性器官癌症中的男女性别差异，相关论文发表在去年12月的《癌症研究》（Cancer Research）期刊上。

　　男性与女性的肝脏天生不同，大部分差异从青春期开始出现，那时男性肝脏受到周期性的生长激素暴发的冲击，从而使得男性肝脏的基因表达有别于女性。这也解释了为何男性与女性对于某些抗生素与其他药物会出现不同反应。

　　MIT研究团队通过对老鼠的研究发现，雄鼠也有较高的罹患肝癌比率。老鼠受到肝螺杆菌感染后可产生与人类乙型及丙型肝炎相同的症状。

　　无论人类还是老鼠，健康的雄性与雌性都能对剧毒以及其他压力做出反应。但雄性肝脏却缺乏对付由某些传染介质引发的慢性炎症的能力。

　　当雄性老鼠发展出慢性肝炎时，一些雄性肝脏基因上调而另外一些则关闭。同时，某些雌性基因会再次激活。结果出现一种称为“肝性别失调”（liver-gender disruption）的基因表达谱。当研究人员绘制出性别特异性基因的图谱时，他们发现该图谱与炎症路径密切相关。在患有慢性肝炎的雄性中，某些性别特异性基因会表达过度，而其他一些则表达不足，肝脏无法维持正常的新陈代谢功能，这时相当多的动物开始出现癌症。

　　研究人员提出，成年雌性不容易受到“肝性别失调”的影响，她没有必要靠激活指令来维持雄性基因表达图谱。因为雌性肝脏遵循默认的发展路径，需要更大的扰动才能启动致癌程序。

　　研究人员曾预期，如对患上慢性肝炎、但还未发展成为癌症的1岁老鼠进行阉割，将会起到保护作用。他们还给老鼠注入一种强力男性激素，来观察其是否会促进肿瘤发展。结果，这两种方法都没有奏效，这也证明了男性性激素，如睾丸激素，并不会直接促进成鼠患上肝癌。

　　这项发现也许对其他器官癌症（如胃癌与结肠癌）也有重大意义，因为这些疾病也与慢性炎症有所关联，而且在男性中很常见。

Cancer Res. 2007 Dec 15;67(24):11536-46.

Hepatocellular carcinoma associated with liver-gender disruption in male mice.

Rogers AB, Theve EJ, Feng Y, Fry RC, Taghizadeh K, Clapp KM, Boussahmain C, Cormier KS, Fox JG.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

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.