生物谷报道：最近，研究人员报告，男性比女性产生更多的与肝癌相关的蛋白，这可以解释为什么男性的肝癌发病风险高于女性。身体产生一种称为IL-6的蛋白，她可以对肝脏造成损害，IL-6可以增加能够引起肝癌的肝脏慢性炎症。
加州大学圣迭戈分校研究小组发现女性不仅产生较少的蛋白质，雌激素可以制衡蛋白的产生量。慢性肝病，过量饮酒，乙型或丙型肝炎病毒感染或癌症家族史都可以引起肝癌，男性患肝癌的风险是女性的3到5倍。
在他们的研究中，他们首先给小鼠致癌剂，与五分之一的雌性小鼠产生肝癌相比，所有的雄性小鼠都产生了肝癌。他们发现雄性IL-6水平要比雌性高，当给不能产生IL-6的小鼠致癌剂时，仅仅十分之一的雄性鼠患傻上癌症。他们给第三组雄性小鼠雌激素，然后给予致癌剂，在这种情况下，肝癌的发生率与正常雌性小鼠相同。仔细分析干细胞发现，雌激素有助于降低IL-6的产生。加州大学圣迭戈分校临床医学系的Willscott Naugle在准备好的发言中说“有些器官，如乳房，就明显受到性别的影响，而别的器官，如肝，就不会。因此肝的炎症可以被雌激素明显抑制是非常有趣的，它产生了这样一种可能性，通常不受性别影响的器官可能由同一种机制控制。比如膀胱癌，男性比女性多发，这种差异可能源于高的IL-6水平和男性膀胱的炎症。”
刊登在七月号科学杂志上的文章建议，减少男性IL-6水平或者让其使用类似雌激素的化合物，可能会有助于降低肝癌的发病率。
Fig. 2. Lower incidence of HCC tumors and longer survival of IL-6–/– mice. (A)Livers of 8-month-old DEN-treated mice. Multiple HCCs are seen only in WT male liver. (B) Incidence of HCC (> 0.5 mm) in WT male (n = 14), WT female (n = 13), IL-6–/– male (n = 14), and IL-6–/– female (n = 15) mice 8 months after DEN (25 mg/kg) injection. Asterisks indicate significant (P < 0.05; Student's t test) differences relative to WT male mice. (C) Survival curves of WT and IL-6–/– mice injected with DEN (25 mg/kg) at 15 days of age (P = 0.0006; log-rank test for significance). [View Larger Version of this Image (139K JPEG file)]
原文出处：
Science 6 July 2007: Vol. 317. no. 5834, pp. 121 - 124
DOI: 10.1126/science.1140485
Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production
Willscott E. Naugler, Toshiharu Sakurai, Sunhwa Kim, Shin Maeda, KyoungHyun Kim, Ahmed M. Elsharkawy, and Michael Karin
The greater production of an inflammatory cytokine in male mice explains their higher susceptibility to liver cancer.
Abstract »| Full Text »| PDF »| Supporting Online Material »|
作者简介：
Michael Karin
Affiliation: UCSD SOM
Professor, Department of Pharmacology, School of Medicine
Biography
B.Sc. Biology, 1975, Tel Aviv University, Tel Aviv, Israel
Ph.D. Molecular Biology, 1979, University of California, Los Angeles
Dr. Michael Karin is currently a Professor of Pharmacology at the School of Medicine, University of California, San Diego, where has been on the faculty since 1987. He has served as a member of the Signal Research Division of Celgene since 1992. Dr. Karin also serves as a member of the National Advisory Council for Environmental Health Sciences and has been an American Cancer Society Research Professor since 1999. He is a leading world authority on signal transduction pathways that regulate gene expression in response to extracellular stimuli. Key achievements include definition of cis elements that mediate gene induction by hormones, cytokines and stress, identification and characterization of the transcription factors that recognize these elements and the protein kinase cascades that regulate their activities. Dr. Karin received his Ph.D. in Molecular Biology from UCLA and completed his postdoctoral training at the Fox Chase Institute for Cancer Research (Dr. Beatrice Mintz) and the Departments of Medicine and Biochemistry at the University of California, San Francisco (Dr. John Baxter). He has published over 200 scientific articles and is an inventor on over 14 different patents or pending patent applications. Recently Dr. Karin was ranked first worldwide by the Institute of Scientific Information (ISI) in a recent listing of most-cited molecular biology and genetic research papers published in prestigious journals.
Research Summary
Dr. Karin's research interests focus on five areas of study. 1) Regulation of transcription in mammalian cells by steroid hormones, growth factors, and adverse environmental conditions and during cellular differentiation. Biochemical and genetic approaches are utilized to isolate transacting regulatory proteins, which mediate responses to developmental, hormonal and environmental signals, by binding to specific DNA sequences. Current efforts are to understand the regulation of gene transcription by growth factors, cytokines and polypeptide hormones and cell type specific gene expression. 2) Response of the human genome to stress. The molecular basis for the UV response, the mammalian counterpart of the bacterial SOS response is being studied by various molecular genetics techniques. 3) Protein kinase cascades and their role in growth control, cell differentiation and programmed cell death. These studies focus on the JNK and p38 MAP kinase cascades and their roles in cellular regulation and specific gene induction. 4) The IKK/NF-kB signaling pathway and its physiological and pathophysiological functions. We are most interested in studying IKK and NF-kB as important links between chronic inflammation and cancer. These studies utilize biochemical as well as whole animal approaches. 5) The regulation of mRNA turnover. In addition to gene transcription, an important control point, is mRNA turnover. We are studying both the general mechanisms responsible for rapid mRNA degradation in mammals and the control of protooncogene and cytokine mRNA turnover by extracellular signals.
Dr. Karin made seminal contributions to the discipline of signal transduction describing how extracellular stimuli, including growth factors, cytokines, tumor promoters and UV radiation, regulate gene expression in eukaryotic cells. Starting with cloning of the human metallothionein IIA gene and analysis of its promoter, Karin and coworkers were the first to identify cis elements that mediate induction of cellular genes by stress signals, glucocorticoids and tumor promoters. This resulted in identification of several transcription factors, including AP-1, that recognize these cis elements. AP-1 was subsequently shown by Karin and coworkers to be composed of Jun and Fos proteins. This provided one of the first demonstrations that nuclear protooncoproteins function as transcription factors. Analysis of the mechanisms by which growth factors and UV radiation induce AP-1 activity led to identification of a major signaling pathway (the JNK MAP kinase cascade), elucidation of the mechanisms by which protein phosphorylation controls transcription factor activity and an explanation for the ability of membrane associated oncoproteins, such as Ras, to modulate gene transcription. Karin and coworkers have also described how proinflammatory stimuli regulate the activity of transcription factor NF-kB and identified the IkB kinase (IKK) complex, which they have shown to be a major regulator of innate immunity and inflammation. Genetic analysis of IKK function resulted in identification of a novel signaling pathway that controls development of the mammalian epidermis. Karin and coworkers were also the first to biochemically identify a cell type specific transcription factor (GHF-1/Pit1), demonstrate its kinship to homeodomain proteins and provide important insights to the mechanism of tissue specific gene expression.
References
References From PubMed (NCBI)
相关基因：
IL6
Official Symbol IL6 and Name: interleukin 6 (interferon, beta 2) [Homo sapiens]
Other Aliases: BSF2, HGF, HSF, IFNB2, IL-6
Chromosome: 7; Location: 7p21
Annotation: Chromosome 7, NC_000007.12 (22733344..22738140)
MIM: 147620
GeneID: 3569
