AKT AND TUMOR SUPPRESSOR PATHWAYS IN MESOTHELIOMA

最近的研究表明，石棉和SV40在恶性肿瘤的病因中可以起到共同致癌物的作用 间皮瘤(MM)和AKT，细胞生存信号的关键中介，在这种情况下经常被激活 疾病。人类多发性骨髓瘤常表现为NF2肿瘤抑制基因(TSG)突变。此外， 编码TSG产物p16(INK4a)和p14(ARF)的INK4a/ARF基因座的纯合缺失， 尽管在MM中p16(INK4a)与p14(ARF)的相对贡献是经常观察到的 发病机制尚未阐明。我们的假设是，这三个TSG和 SV40和AKT癌蛋白的表达是间皮细胞生理学中的关键障碍 共同为MM的发展做出贡献。了解MM的分子发病机制和 在这种恶性肿瘤中干扰的信号通路可能阐明有价值的分子靶点 治疗/预防干预，这是本项目的广泛、长期目标。具体目标 1)通过体外和体内实验，我们将确定NF2表达的恢复是否可以抑制 NF2缺陷型多发性骨髓瘤细胞的生长和侵袭力我们还将进行实验，以评估 腺病毒介导表达NF2和选择性PAK抑制剂的治疗潜力 进一步阐明梅林功能的实验。2)使用各种小鼠基因敲除模型，评估 Nf2、p19(Arf)和p16(Lnk4a)失活对石棉诱发多发性骨髓瘤的相对贡献。分子 将对来自这些小鼠的肿瘤进行基因特征分析，以确定这一要求 用于易感TSG的双等位基因失活和/或癌基因或其他TSG的合作。我们会 比较p16(Lnk4a)+/-、p14(Arf)+/-和双重杂合子对石棉诱发多发性骨髓瘤的易感性 Ink4a/Arf+/-小鼠具有相同的遗传背景。此外，确定SV40标签/标签鼠标型号是否 容易自发性地和/或在石棉治疗后患多发性骨髓瘤。3)进一步描述 AKT在多发性骨髓瘤中的参与及药物抑制AKT信号通路的研究 可以抑制MM细胞的生长，如果将AKT途径抑制剂与化疗药物联合使用 拥有不同的行动模式会带来更高的疗效。该项目将提供重要的见解 关于关键癌蛋白和TSG产物在多发性骨髓瘤发病机制中的作用 从项目1、B和C岩芯以及 来自项目2中进行的共同致癌和信号传递工作。

Recent work suggests that asbestos and SV40 can act as co-carcinogens in the etiology of malignant mesothelioma (MM) and that AKT, a critical mediator of cell survival signals, is frequently activated in this disease. Human MMs often exhibit mutation of the NF2 tumor suppressor gene (TSG). Furthermore, homozygous deletion of the INK4a/ARF locus, which encodes the TSG products p16(INK4a) and p14(ARF), is frequently observed, although the relative contribution of p16(INK4a) versus p14(ARF) in MM pathogenesis has not been elucidated. Our hypothesis is that alterations of these three TSGs and expression of SV40 and AKT oncoproteins represent key disturbances in mesothelial cell physiology that collectively contribute to the development of MM. Understanding the molecular pathogenesis of MM and signaling pathways perturbed in this malignancy may elucidate invaluable molecular targets for therapeutic/preventive intervention, which is the broad, long-term objective of this project. The specific aims are: 1) Using in vitro and in vivo assays, we will determine whether restoration of NF2 expression can inhibit the growth and invasiveness of NF2-deficient MM cells. We will also conduct experiments to evaluate the therapeutic potential of adenovirus-mediated expression of NF2 and selective PAK inhibitors, as well as experiments to further elucidate merlin's function. 2) Using various murine knockout models, evaluate the relative contribution of Nf2, p19(Arf), and p16(lnk4a) inactivation to induction of MM by asbestos. Molecular genetic characterization of tumors derived from these mice will be conducted to establish the requirement for biallelic inactivation of the predisposing TSG and/or cooperation of oncogenes or other TSGs. We will compare susceptibility to asbestos-induced MM in p16(lnk4a)+/-, p14(Arf)+/- and doubly heterozygous Ink4a/Arf+/- mice in the same genetic background. In addition, determine if a SV40 Tag/tag mouse model is predisposed to MM spontaneously and/or following treatment with asbestos. 3) Further characterize the involvement of AKT in MM and determine whether pharmacologic inhibition of the AKT signaling pathway can repress MM cell growth and if combining an AKT pathway inhibitor with chemotherapeutic agents having a different mode of action results in increased efficacy. This Project will provide important insights regarding the involvement of key oncoproteins and TSG products in the pathogenesis of MM and will benefit from the availability of human and hamster MM samples through Project 1 and Cores B and C as well as from co-carcinogenesis and signaling work conducted in Project 2.