References and Notes Supporting Online Material Materials and Methods Som Text Figs. S1 to S6 Tables S1 to S4 Gender Disparity in Liver Cancer Due to Sex Differences in Myd88-dependent Il-6 Production-猫眼课题宝

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C. B. D. Lemos;D. L. Meiklejohn;Nat Hartl;B Lemos;B. R. Bettencourt;C. Meiklejohn;D. L. Hartl

加拿大研究理事会、魁北克自然与技术研究基金会和哈佛大学弗兰克·诺克斯纪念基金会。原始微阵列数据登录号为GSE 7537（GEO数据库）。肝细胞癌（HCC）是最常见的肝癌，主要发生在男性身上。在给予化学致癌物二乙基亚硝胺（DEN）的小鼠中也观察到类似的性别差异。DEN管理引起更大的血清白细胞介素-6（IL-6）浓度的增加，男性比女性。此外，IL-6的消融消除了小鼠肝癌发生的性别差异。DEN暴露以依赖于Toll样受体衔接蛋白MyD 88的方式促进Kupffer细胞（KCs）中IL-6的产生，其消融也保护雄性小鼠免受DEN诱导的肝癌发生。雌激素可抑制暴露于坏死肝细胞的KC分泌IL-6，并降低DEN处理的雄性小鼠中IL-6的循环浓度。我们认为雌激素介导的KC抑制IL-6的产生可以降低女性患肝癌的风险，这些发现可以用于预防男性的HCC。肝细胞癌（HCC）是最常见的原发性肝癌，是慢性肝病的一种可怕并发症，发生在B型肝炎（HBV）和丙型肝炎（HCV）病毒感染、酒精性肝病、血色素沉着症和非酒精性脂肪性肝炎等风险因素的背景下（1）。大多数HCC出现在经过多年慢性炎症后的硬化肝脏中。HCC患者的5年生存率仅为7%，其发病率的增加可能是由于HCV的传播（2）。值得注意的是，男性患肝癌的可能性是女性的三到五倍（3）。在啮齿动物HCC模型中观察到类似或甚至更明显的性别差异（4，5）。此外，给予雄性小鼠雌激素可抑制化学（DEN）诱导的HCC的发展（6）。尽管如此，解释这种性别差异的机制和雌激素的抗癌活性尚不清楚。炎症是致癌的主要因素（7）。HCC代表炎症相关癌症的典型病例（8），化学或遗传诱导的HCC取决于炎症信号传导（5，9，10）。为了了解HCC中性别差异的潜在机制，我们使用了化学致癌物二乙基亚硝胺（DEN），该物质在100%的雄性小鼠中引起HCC，但仅在10%至30%的雌性同窝小鼠中引起HCC（5，6）。这种小鼠模型中HCC的发病机制与人类不同，因此可能无法与人类直接比较。

Research Council of Canada, the Fonds québécois de la recherche sur la nature et les technologies, and the Frank Knox Memorial Foundation at Harvard University. Raw microarray data accession number is GSE7537 (GEO database). Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases in serum interleukin-6 (IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice. We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings may be used to prevent HCC in males. H epatocellular carcinoma (HCC), the most common primary liver cancer, is a dreaded complication of chronic liver disease that occurs in the setting of risk factors such as hepatitis B (HBV) and hepatitis C (HCV) viral infections, alcoholic liver disease, hemo-chromatosis, and nonalcoholic steatohepatitis (1). Most HCC appears in cirrhotic livers after years of chronic inflammation. The 5-year survival rate for patients with HCC, the increasing incidence of which is likely due to the spread of HCV (2), is only about 7%. Notably, men are about three to five times more likely to develop HCC than women (3). A similar or even more pronounced gender disparity is seen in rodent HCC models (4, 5). Furthermore, administration of estrogens to male mice inhibits development of chemically (DEN)–induced HCC (6). Nonetheless, the mechanisms that account for this gender disparity and the anticarcinogenic activity of estrogens are unknown. Inflammation is a major contributing factor to carcinogenesis (7). HCC represents a classic case of inflammation-linked cancer (8), and chemically or genetically induced HCC depends on inflammatory signaling (5, 9, 10). To understand the mechanisms underlying gender disparity in HCC, we used the chemical carcinogen diethyl-nitrosamine (DEN), which causes HCC in 100% of male mice but only in 10 to 30% of female littermates (5, 6). The pathogenesis of HCC in this mouse model differs from that in humans and thus may not be directly comparable to human …

References and Notes Supporting Online Material Materials and Methods Som Text Figs. S1 to S6 Tables S1 to S4 Gender Disparity in Liver Cancer Due to Sex Differences in Myd88-dependent Il-6 Production

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