生物谷報道：據(jù)美國麻省理工學(xué)院（MIT）的一項新研究顯示,，男性和女性在基因水平上對慢性肝病反應(yīng)的一個基本的差異能夠解釋為什么男人更容易得肝癌。
這項研究是首次在基因組范圍研究性別對非生殖器官癌的影響,。這項研究的結(jié)果刊登在2007年12月15日的《癌癥研究》（Cancer Research）雜志上,。
肝癌是世界第五大常見癌癥,，并且是第三大殺手。在美國,，男性肝癌發(fā)生率是女性發(fā)病率的兩倍,。在其他國家，尤其是亞洲國家,，男性發(fā)病率則是女性的8到10倍,！
MIT的研究組對小鼠進行了研究，雄性小鼠的肝癌發(fā)病率也較高,。研究人員用肝螺桿菌（Helicobacter hepaticus）感染小鼠,，這樣會使小鼠表現(xiàn)出與人類乙肝和丙肝類似的肝炎癥狀。
在人類和小鼠中,，健康的雄性和雌性都能夠?qū)毙远舅睾蜌怏w壓力作出應(yīng)答,。但是雄性的肝臟對付由特定感染物質(zhì)引起的慢性炎癥的能力則并不是太強。
當(dāng)雄性小鼠發(fā)生慢性肝炎時,，一些雄性肝臟基因被上調(diào),，而另外一些則被關(guān)閉。與此同時,，一些雌性基因則被再次激活,。這導(dǎo)致一種意外的肝臟性別基因表的特征。
當(dāng)研究人員確定性別特異性基因時,，他們發(fā)現(xiàn)與炎癥途徑相關(guān)的基因,。在患有慢性肝炎的雄性中，一些性別特異性基因發(fā)生了過表達,，而另外一些則被抑制,，從而使肝臟不能維持正常的代謝功能，并且一些動物體內(nèi)發(fā)生了癌癥,。
另外，研究人員還發(fā)現(xiàn)這些基因還與男性胃癌和結(jié)腸癌等有慢性炎癥的器官癌癥有關(guān),，并且這些癌癥在男性中也更常見,。
肝癌是我國常見的惡性腫瘤之一，是我國位居第二的癌癥“殺手”,，常見于中年男性,。因其惡性度高,、病情進展快，病人早期一般沒有什么不適,，一旦出現(xiàn)癥狀就診,，往往已屬中晚期。故治療難度大,、療效差,，一般發(fā)病后生存時間僅為6個月，人稱“癌中之王”,。
在我國,，每年有11萬人死于肝癌，其中男性8萬,，女性3萬,，占全世界肝癌死亡人數(shù)的45%。作為最常見的一種惡性腫瘤,，肝癌死亡率僅次于胃癌,，全國每年至少有12萬人被肝癌奪去生命。中國肝癌死亡人數(shù)已占全球肝癌死亡總?cè)藬?shù)的44%,。
生物谷推薦原始出處：
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: [email protected] .
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]
