生物谷报道:据美国麻省理工学院(MIT)的一项新研究显示,男性和女性在基因水平上对慢性肝病反应的一个基本的差异能够解释为什么男人更容易得肝癌。
这项研究是首次在基因组范围研究性别对非生殖器官癌的影响。这项研究的结果刊登在2007年12月15日的《癌症研究》(Cancer Research)杂志上。
肝癌是世界第五大常见癌症,并且是第三大杀手。在美国,男性肝癌发生率是女性发病率的两倍。在其他国家,尤其是亚洲国家,男性发病率则是女性的8到10倍!
MIT的研究组对小鼠进行了研究,雄性小鼠的肝癌发病率也较高。研究人员用肝螺杆菌(Helicobacter hepaticus)感染小鼠,这样会使小鼠表现出与人类乙肝和丙肝类似的肝炎症状。
在人类和小鼠中,健康的雄性和雌性都能够对急性毒素和气体压力作出应答。但是雄性的肝脏对付由特定感染物质引起的慢性炎症的能力则并不是太强。
当雄性小鼠发生慢性肝炎时,一些雄性肝脏基因被上调,而另外一些则被关闭。与此同时,一些雌性基因则被再次激活。这导致一种意外的肝脏性别基因表的特征。
当研究人员确定性别特异性基因时,他们发现与炎症途径相关的基因。在患有慢性肝炎的雄性中,一些性别特异性基因发生了过表达,而另外一些则被抑制,从而使肝脏不能维持正常的代谢功能,并且一些动物体内发生了癌症。
另外,研究人员还发现这些基因还与男性胃癌和结肠癌等有慢性炎症的器官癌症有关,并且这些癌症在男性中也更常见。
肝癌是我国常见的恶性肿瘤之一,是我国位居第二的癌症“杀手”,常见于中年男性。因其恶性度高、病情进展快,病人早期一般没有什么不适,一旦出现症状就诊,往往已属中晚期。故治疗难度大、疗效差,一般发病后生存时间仅为6个月,人称“癌中之王”。
在我国,每年有11万人死于肝癌,其中男性8万,女性3万,占全世界肝癌死亡人数的45%。作为最常见的一种恶性肿瘤,肝癌死亡率仅次于胃癌,全国每年至少有12万人被肝癌夺去生命。中国肝癌死亡人数已占全球肝癌死亡总人数的44%。
生物谷推荐原始出处:
Cancer Research 67, 11536-11546, December 15, 2007. doi: 10.1158/0008-5472.CAN-07-1479
Molecular Biology, Pathobiology, and Genetics
Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice
Arlin B. Rogers1,2, Elizabeth J. Theve1, Yan Feng1, Rebecca C. Fry2, Koli Taghizadeh2, Kristen M. Clapp1, Chakib Boussahmain1, Kathleen S. Cormier1 and James G. Fox1,2
1 Division of Comparative Medicine and 2 Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts
Requests for reprints: Arlin Rogers, Division of Comparative Medicine 16-849, Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: 617-253-9442; Fax: 617-252-1882; E-mail: abr@mit.edu .
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- 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- 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. [Cancer Res 2007;67(24):11536–46]