Functional Analysis of Cancer Genes from Human Chromosome 3p

人类 3p 染色体癌症基因的功能分析

• 批准号: 7592578
• 负责人: MICHAEL LERMAN
• 金额: $ 35.42万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592578
• 关键词: 3p21.3; 3p25.3; Antibodies; Binding; Binding Sites; Bioinformatics; Biological Markers; Brain; Breast; Cancer Etiology; Cell Adhesion; Cell Adhesion Molecules; Cell Proliferation; Cell surface; Cervix Uteri; Chromatin; Cisplatin; Code; Common Carcinoma; Coupled; DNA-Binding Proteins; Databases; Development; Disease; Drug Delivery Systems; Elements; Endoplasmic Reticulum; Enzymes; Epigenetic Process; Essential Amino Acids; Evolution; Gene Cluster; Gene Silencing; Gene Targeting; Genes; Growth; Head and neck structure; Human; Human Chromosomes; Hypermethylation; Hypoxia; Immune; Immune system; International; Intervention; Invasive; Island; Kidney; Laboratory Research; Legal patent; Ligands; Localized; Lung; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Membrane; Methods; Mismatch Repair; Modality; Molecular Target; Mutate; Mutation; Natural Immunity; Natural Killer Cells; Neoplasm Metastasis; Normal tissue morphology; Numbers; Oncogenes; Ovine pulmonary adenocarcinoma virus; PDAP2 Gene; Pathway interactions; Patients; Pattern; Play; Progesterone Receptors; Prostate; Protein Binding; Proteins; Publications; Rate; Reagent; Receptor Protein-Tyrosine Kinases; Research; Retroviridae; Role; STAT1 gene; STAT3 gene; Serum; Sheep; Signal Pathway; Signal Transduction; Specimen; Staging; Tissues; Transcript; Transgenic Mice; Tumor Suppressor Proteins; VHL gene; Validation; cancer stem cell; cancer type; gene therapy; human TGFB1 protein; malignant breast neoplasm; mutant; nephrogenesis; novel; promoter; receptor; transcription factor; tumor; tumor growth; tumor progression

Studies on the CALL gene (3p26.3): The gene CALL (cell adhesion L1 like) encodes a trans-membrane cell adhesion molecule (CAM) capable of both homotypic and heterotypic binding. We showed CALL is expressed in normal tissues beside the brain and is over-expressed in a variety of human tumors. Our expression studies suggest that CALL may contribute to cancer invasive growth and metastasis, depending on stage and tissue it may act either as a tumor suppressor or oncogene. This validates CALL as a biomarker of invasive tumor growth and metastasis and a novel target for personalized immune intervention. Studies on the VHL gene (3p25.3): We identified the VHL epigenetic code and recreated its patterns in transgenic mice; we found that CTCF a ubiquitous chromatin insulator/DNA binding protein has a binding site in VHL CpG promoter island and may play along with other transcription factors an important role in protecting against aberrant silencing of the gene. In cancer we propose VHL is universally mutated/silenced to promote tumor progression, spread and facilitate the creation of cancer stem cells. We discovered that VHL targets, CA 9 /CA12 genes, are specifically induced and over-expressed in many tumor types. They may control the acidic tumor microenvironment and should be considered molecular targets for development of new treatment modalities. We identified several compounds that showed nanomolar inhibition specific for each CAIX and CAXII enzyme. We discovered that STRA13 modulates the activity of STAT1 and STAT3. We outlined a set of targets common for pVHL and TGF-beta1 pathways. These results emphasize a new mechanism that employs relay genes to amplify and diversify the original primary hypoxia signal. We suggest VHL may be involved in the creation of cancer stem cells (CSC) harboring cancer-causing mutations. Studies on 3p21.3 cancer-causing genes: The PL6 protein binds to and modulates the function of two similar progesterone receptors (MAPRs) localized in the endoplasmic reticulum. We showed that PL6 is a hypoxia independent target of VHL; its expression is absent in VHL disease tumors and sporadic CCRCC. PL6 is a biomarker of CCRCC and controls Acy1. We validated the tumor suppressor function of the NPRL2 gene; bioinformatics analysis suggests it may be a potential novel mismatch repair gene and a target of cisplatin. We identified the RASSF1A gene as a multiple TSG involved in many tumors, including lung, breast, prostate, kidney, head & neck, uterine cervix and others. We discovered that RASSF1A is a target of somatic hyper mutability in several human cancers. We created Fus1 null mutants that showed consistent changes in NK cells and serum antibody profiles coupled with changes in the expression of important genes regulating the innate immune system suggesting involvement of Fus1 in the development and activation of the mammalian innate immune system. FUS1 may be used to boost innate immunity in cancer and other immunodeficient diseases. The HYAL2 protein was identified as a GPI-anchored receptor for the sheep lung cancer retrovirus, JSRV, and a sequestration mechanism inactivating HYAL2 protein was demonstrated. This leads to ligand-independent activation of the RON receptor tyrosine kinase and its downstream signaling pathways (Akt and MAPK). We also identified the essential amino acid residues in the sheep/human Hyal2 receptor that determine specific efficient binding and entry of the JSRV. We discovered that in SCLC the promoter of RON is silenced by hypermethylation leading to simultaneous activation of a putative internal promoter. The novel transcript originating from this internal promoter encodes mostly the cytoplasmic portion of the receptor that is constitutively activated and drives cell proliferation Studies on the 3p12.3 gene: Our hunt for the TSG in 3p12.3 resulted in the discovery of two novel ncRNA genes that may function as TSG in lung and breast cancers. These ncRNA genes may harbor HAR elements (human accelerated regions) uniquely involved in the evolution of the human brain. . Current plans are focused: On experimental validation of combined gene therapy of cancer with cancer-causing TSG directed at cancer stem cells (CSC) and patients HSC using cell surface pH regulators as immune, drug, and delivery targets to cure cancer. Contributions (patents, public databases, reagents): In July 2006 NCI filled for a patent entitled: Methods and Compositions for Treating Fus1 Related Disorders Publication number: WO/2007/008671. International Publication Date January 18, 2007. Numerous reagents resulting from our research were freely and promptly distributed to a large number of US and EU research laboratories

Call基因(3p26.3)的研究：Call(细胞黏附L1样蛋白)编码一种跨膜细胞黏附分子(CAM)，既能同型结合又能异型结合。我们发现，Call在大脑旁的正常组织中表达，在各种人类肿瘤中过表达。我们的表达研究表明，Call可能有助于癌症的侵袭性生长和转移，这取决于它可能作为肿瘤抑制因子或癌基因的阶段和组织。这证实了CALL是侵袭性肿瘤生长和转移的生物标志物，也是个性化免疫干预的新靶点。VHL基因(3p25.3)的研究：我们在转基因小鼠中鉴定了VHL的表观遗传密码子并重建了其模式；我们发现CTCF是一种普遍存在的染色质绝缘体/DNA结合蛋白，在VHL CpG启动子岛上有一个结合部位，可能与其他转录因子一起在保护该基因的异常沉默中发挥重要作用。在癌症中，我们认为VHL被普遍突变/沉默，以促进肿瘤的进展、扩散和促进癌症干细胞的产生。我们发现，VHL靶点CA9/CA12基因在许多肿瘤类型中被特异性诱导和过度表达。它们可以控制酸性的肿瘤微环境，应该被认为是开发新的治疗方式的分子靶点。我们鉴定了几个化合物，它们对每个CAIX和CAXII酶都有纳摩尔抑制作用。我们发现STRA13调控STAT1和STAT3的活性。我们概述了pVHL和转化生长因子-β1通路的共同靶点。这些结果强调了一种新的机制，即利用继电基因来放大和多样化原始的初级缺氧信号。我们认为VHL可能参与了携带致癌突变的癌症干细胞(CSC)的产生。3p21.3致癌基因的研究：PL6蛋白结合并调节位于内质网的两个类似的孕激素受体(MAPRs)的功能。我们发现PL6是VHL的一个缺氧非依赖性靶点；它在VHL病、肿瘤和散发性肾细胞癌中不表达。PL6是ccRCC的生物标志物，并控制Acy1。我们验证了NPRL2基因的肿瘤抑制功能；生物信息学分析表明，它可能是一个潜在的新的错配修复基因和顺铂的靶点。我们鉴定了RASSF1A基因是一个多TSG基因，参与了许多肿瘤，包括肺、乳腺、前列腺、肾脏、头颈、子宫颈等。我们发现，在几种人类癌症中，RASSF1A是体细胞高度突变的靶点。我们创造了FUS1缺失突变体，显示出NK细胞和血清抗体谱的一致变化，并伴随着调节天然免疫系统的重要基因表达的变化，表明FUS1参与了哺乳动物天然免疫系统的发育和激活。FUS1可用于提高癌症和其他免疫缺陷疾病的先天免疫力。Hyal2蛋白被鉴定为绵羊肺癌逆转录病毒JSRV的GPI锚定受体，并证明了其灭活Hyal2蛋白的隔离机制。这导致RON受体酪氨酸激酶及其下游信号通路(Akt和MAPK)的配体无关激活。我们还鉴定了绵羊/人的Hyal2受体中决定JSRV特异性有效结合和进入的必需氨基酸残基。我们发现，在小细胞肺癌中，RON的启动子被高甲基化沉默，导致一个可能的内部启动子同时激活。来自这个内部启动子的新转录本主要编码受体的细胞质部分，该部分被结构性激活并驱动细胞增殖。对3p12.3基因的研究：我们在3p12.3中寻找TSG的结果是发现了两个新的ncRNA基因，它们可能在肺癌和乳腺癌中发挥TSG的功能。这些ncRNA基因可能含有与人脑进化有关的独特的HAR元件(人类加速区)。。目前的计划集中在：针对癌症干细胞(CSC)和患者HSC的致癌TSG联合癌症基因治疗的实验验证，使用细胞表面pH调节器作为免疫、药物和传递靶点来治愈癌症。投稿(专利、公共数据库、试剂)：2006年7月，NCI申请了一项名为：治疗FUS1相关疾病的方法和组合物的专利，发表编号：WO/2007/008671。国际出版日期：2007年1月18日。由我们的研究产生的大量试剂被免费和迅速地分发到美国和欧盟的大量研究实验室