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

对呼叫基因的研究（3P26.3）：基因呼叫（细胞粘附L1）编码能够具有同型和异型结合的反膜细胞粘附分子（CAM）。我们表明，呼叫在大脑旁边的正常组织中表达，并且在各种人类肿瘤中表达过表达。我们的表达研究表明，呼叫可能有助于癌症的侵入性生长和转移，具体取决于阶段和组织，它可以用作肿瘤抑制剂或癌基因。这证实了呼吁是侵入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目标。对VHL基因的研究（3P25.3）：我们确定了VHL表观遗传密码，并在转基因小鼠中重新创建了其模式。我们发现CTCF无处不在的染色质绝缘子/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发挥作用，在防止异常的基因沉默中起重要作用。在癌症中，我们建议VHL普遍突变/沉默，以促进肿瘤进展，扩散和促进癌症干细胞的产生。我们发现，在许多肿瘤类型中，VHL靶标Ca 9 /Ca12基因被特异性诱导和过表达。他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。我们确定了几种对每种CAIX和CAXII酶特异的纳摩尔抑制作用的化合物。我们发现Stra13调节了STAT1和STAT3的活动。我们概述了PVHL和TGF-BETA1途径常见的一组目标。这些结果强调了一种新机制，该机制采用继电器基因扩大和多样化原始的原发性低氧信号。我们建议VHL可能参与携带引起癌症突变的癌症干细胞（CSC）的创建。 3P21.3引起癌症基因的研究：PL6蛋白与内质网中定位的两个相似的孕酮受体（MAPR）的功能结合并调节。我们表明PL6是VHL的低氧靶标。它的表达在VHL疾病肿瘤和零星CCRC中不存在。 PL6是CCRC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型不匹配修复基因和顺铂的靶标。我们将RASSF1A基因确定为许多参与许多肿瘤的TSG，包括肺，乳腺，前列腺，肾脏，头颈，子宫宫颈等。我们发现RASSF1A是几种人类癌症中躯体超突变性的靶标。我们创建了FUS1 NULL突变体，该突变体显示出NK细胞和血清抗体谱的一致变化，并结合了调节先天免疫系统的重要基因表达的变化，这表明FUS1参与了哺乳动物先天免疫系统的发展和激活。 FUS1可用于增强癌症和其他免疫缺陷疾病的先天免疫。透明蛋白被鉴定为绵羊肺癌逆转录病毒，JSRV的GPI锚定受体，并证明了一种失活透明蛋白的隔离机制。这导致了RON受体酪氨酸激酶及其下游信号通路（AKT和MAPK）的非配体无关激活。我们还确定了确定JSRV的特定有效结合和进入的绵羊/人透明受体中必需的氨基酸残基。我们发现在SCLC中，RON的启动子被过度甲基化沉默，从而导致推定的内部启动子同时激活。起源于该内部启动子的新型转录本主要是由组成型激活的受体的细胞质部分编码，并驱动了3P12.3基因的细胞增殖研究：我们在3P12.3中寻找TSG的人数导致了两个新颖的NCRNA基因，从而发现了两个新颖的NCRNA基因，这些基因可能在Lung and Brespercerscercers and Cancers Cancers Cancersc中起作用。这些NCRNA基因可能具有与人脑进化的独特相关的HAR元素（人类加速区域）。 。目前的计划是集中的：使用针对癌症干细胞（CSC）的癌症的癌症结合基因治疗的实验验证，使用细胞表面调节剂作为免疫，药物和治疗癌症的递送靶标HSC患者。贡献（专利，公共数据库，试剂）：2006年7月，NCI填写了一项有权的专利：用于治疗FUS1相关疾病出版物的方法和组成：WO/2007/008671。国际出版日期2007年1月18日。我们的研究产生的许多试剂自由并迅速分发给了我们的许多人和欧盟研究实验室