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: 7732922
• 负责人: MICHAEL LERMAN
• 金额: $ 44.96万
• 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/7732922
• 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 基因（细胞粘附 L1 样）编码能够同型和异型结合的跨膜细胞粘附分子 (CAM)。 我们发现 CALL 在大脑以外的正常组织中表达，并且在多种人类肿瘤中过度表达。我们的表达研究表明，CALL 可能有助于癌症侵袭性生长和转移，具体取决于阶段和组织，它可能充当肿瘤抑制基因或癌基因。这验证了 CALL 作为侵袭性肿瘤生长和转移的生物标志物以及个性化免疫干预的新靶标。 VHL 基因研究 (3p25.3)：我们鉴定了 VHL 表观遗传密码并在转基因小鼠中重建了其模式； 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 启动子岛中具有结合位点，并且可能与其他转录因子一起在防止基因异常沉默中发挥重要作用。在癌症中，我们认为 VHL 普遍突变/沉默，以促进肿瘤进展、扩散并促进癌症干细胞的产生。我们发现 VHL 靶标 CA 9 /CA12 基因在许多肿瘤类型中被特异性诱导和过度表达。它们可以控制酸性肿瘤微环境，应被视为开发新治疗方式的分子靶标。我们鉴定了几种对每种 CAIX 和 CAXII 酶表现出纳摩尔抑制作用的化合物。我们发现 STRA13 调节 STAT1 和 STAT3 的活性。我们概述了 pVHL 和 TGF-β1 途径的一组常见靶点。这些结果强调了一种利用中继基因来放大原始初级缺氧信号并使之多样化的新机制。我们认为 VHL 可能参与了含有致癌突变的癌症干细胞 (CSC) 的产生。对 3p21.3 致癌基因的研究：PL6 蛋白与位于内质网的两个相似的孕酮受体 (MAPR) 结合并调节其功能。我们证明 PL6 是 VHL 的缺氧独立靶点；它在 VHL 疾病肿瘤和散发性 CCRCC 中不表达。 PL6 是 CCRCC 的生物标志物并控制 Acy1。我们验证了NPRL2基因的抑癌功能；生物信息学分析表明它可能是一个潜在的新型错配修复基因和顺铂的靶标。 我们发现 RASSF1A 基因是一个涉及多种肿瘤的多 TSG，包括肺癌、乳腺癌、前列腺癌、肾癌、头颈癌、宫颈癌等。我们发现 RASSF1A 是多种人类癌症中体细胞高度突变的靶标。我们创建了 Fus1 无效突变体，其显示 NK 细胞和血清抗体谱的一致变化，以及调节先天免疫系统的重要基因表达的变化，表明 Fus1 参与哺乳动物先天免疫系统的发育和激活。 FUS1 可用于增强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，并且证明了 HYAL2 蛋白失活的隔离机制。这导致 RON 受体酪氨酸激酶及其下游信号通路（Akt 和 MAPK）的配体独立激活。我们还鉴定了绵羊/人 Hyal2 受体中的必需氨基酸残基，这些残基决定了 JSRV 的特异性有效结合和进入。我们发现，在 SCLC 中，RON 的启动子因超甲基化而沉默，导致假定的内部启动子同时激活。源自该内部启动子的新转录物主要编码受体的细胞质部分，该部分被组成性激活并驱动细胞增殖。 对 3p12.3 基因的研究：我们对 3p12.3 中 TSG 的寻找导致发现了两个新的 ncRNA 基因，它们可能在肺癌和乳腺癌中充当 TSG。这些 ncRNA 基因可能含有独特参与人类大脑进化的 HAR 元件（人类加速区）。 。目前的计划重点是：使用细胞表面 pH 调节剂作为免疫、药物和递送靶标来治疗癌症，对癌症联合基因疗法与针对癌症干细胞 (CSC) 和患者 HSC 的致癌 TSG 进行实验验证。贡献（专利、公共数据库、试剂）：2006 年 7 月，NCI 申请了一项专利，名称为：“治疗 Fus1 相关疾病的方法和组合物”，公开号：WO/2007/008671。国际出版日期 2007 年 1 月 18 日。我们研究所得的大量试剂被免费、及时地分发给大量的美国和欧盟研究实验室。

项目成果

An integrated physical and gene map of the 3.5-Mb chromosome 3p21.3 (AP20) region implicated in major human epithelial malignancies.

• 发表时间: 2003-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: A. Protopopov;V. Kashuba;V. Zabarovska;O. Muravenko;M. Lerman;G. Klein;E. Zabarovsky

Third International Meeting on von Hippel-Lindau disease.

第三届冯·希佩尔-林道病国际会议。

• 发表时间: 1999
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Zbar,B;Kaelin,W;Maher,E;Richard,S
• 通讯作者: Richard,S