Functional Analysis of Cancer Genes from Human Chromosom

人类染色体癌症基因的功能分析

• 批准号: 7337954
• 负责人: MICHAEL LERMAN
• 金额: --
• 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/7337954
• 关键词: Functional; Analysis; Cancer; Genes; Human

Studies on the CALL gene (3p26.3):The gene, CALL encoding a trans-membrane cell adhesion molecule (CAM) capable of both homotypic and heterotypic binding was shown to be involved in general cognitive activities and some neurological diseases (i.e. schizophrenia).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 it may act either as a tumor suppressor or oncogene. During initial tumor growth CALL is not expressed in tumor cells to facilitate in situ tumor growth. Re-expression of CALL on the edge of the tumor mass could promote local invasive growth and furthermore allow tumor cells to enter and leave the blood stream, colonize distant tissues and establish metastatic tumors. CALL/CHL1 was recently discovered as a CAN gene in colorectal cancer but not in breast cancer by a team led by Bert Vogelstein. They discovered mutations in the extra-cellular part of CALL, which affords a therapeutic ab to selectively treat patients. We'll do a comprehensive analysis of CALL in major cancers where it is over-expressed to develop antibodies for personalized treatment.This will validate CALL as a biomarker of invasive tumor growth and metastasis and a novel target for immune intervention in cancers over-expressing mutated CALL.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 DNA binding protein has binding sites in human and mouse VHL CpG promoter islands and may play along with other factors an important role in protecting against aberrant silencing of the gene in kidney cancer. We recently demonstrated that the transcriptional factor CTCF controls expression of IRAK2 involved in downstream signaling from TLR (toll-like immune receptors). We discovered that CA 9 /CA12 genes are specifically induced and over-expressed in many tumor types. These enzymes may control the acidic tumor microenvironment and should be considered molecular targets for development of new treatment modalities. Using purified CAIX/XII enzymes we tested novel and classical (clinically used for glaucoma treatment) aromatic sulfonamide inhibitors that may have potent anti-tumor activity. We identified among them several compounds that showed nanomolar inhibition specific for each enzyme.We have shown that VHL is inactivated/silenced in at least 50% of common human tumors.Studies on 3p21.3 cancer-causing genes: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 hypothesize that RASSF1 genes and their paralogs are inactivated in approximately 70% of human cancers.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. The env gene of JSRV was shown to transform human bronchial epithelial cells in vitro and sequester the HYAL2 protein. The absence of HYAL2 (mediated either by a putative virus or mutational inactivation) 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. The results imply a putative human JSRV-like virus in carcinogenesis of certain types of lung cancer not associated with smoking (bronchioloalveolar carcinomas, now comprising 20% of lung cancer in the human population).We have been also studying the involvement of RON in SCLC. We discovered that in SCLC the promoter of RON is silenced by hypermethylation leading to simultaneous activation of a putative internal promoter.

CALL基因（3p26.3）的研究：CALL基因编码一种跨膜细胞粘附分子（CAM），具有同型和异型结合的能力，与一般的认知活动和某些神经系统疾病（如精神分裂症）有关，我们发现CALL在脑旁正常组织中表达，在多种人类肿瘤中过表达。我们的表达研究表明，CALL可能有助于癌症的浸润性生长和转移，这取决于阶段，它可能作为肿瘤抑制基因或癌基因。在初始肿瘤生长期间，CALL不在肿瘤细胞中表达以促进原位肿瘤生长。CALL在肿瘤块边缘的重新表达可以促进局部侵袭性生长，并且进一步允许肿瘤细胞进入和离开血流，定殖远处组织并建立转移性肿瘤。CALL/CHL 1最近被Bert Vogelstein领导的一个研究小组发现是结直肠癌中的CAN基因，但不是乳腺癌中的CAN基因。他们在CALL的细胞外部分发现了突变，这提供了一种选择性治疗患者的治疗方法。我们将对CALL过表达的主要癌症进行全面分析，以开发用于个性化治疗的抗体。这将验证CALL作为侵袭性肿瘤生长和转移的生物标志物，以及过表达突变CALL的癌症免疫干预的新靶点。（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DNA结合蛋白，在人和小鼠VHL CpG启动子岛上具有结合位点，并可能与其他因子一起沿着在保护VHL中发挥重要作用。针对肾癌中基因的异常沉默。我们最近证明了转录因子CTCF控制IRAK 2的表达，IRAK 2参与TLR（toll样免疫受体）的下游信号传导。我们发现CA 9 /CA 12基因在许多肿瘤类型中被特异性诱导和过表达。这些酶可以控制酸性肿瘤微环境，应该被认为是开发新治疗模式的分子靶点。使用纯化的CAIX/XII酶，我们测试了可能具有有效抗肿瘤活性的新型和经典（临床上用于青光眼治疗）芳族磺酰胺抑制剂。我们在其中鉴定了几种化合物，它们对每种酶都表现出纳摩尔级的特异性抑制作用。我们已经证明，VHL在至少50%的常见人类肿瘤中是失活/沉默的。3p21.3致癌基因的研究：我们鉴定了RASSF 1A基因作为一种多TSG，涉及许多肿瘤，包括肺、乳腺、前列腺、肾、头颈部、子宫颈等。我们假设RASSF 1基因及其旁系同源基因在大约70%的人类癌症中失活。HYAL 2蛋白被鉴定为绵羊肺癌逆转录病毒JSRV的GPI锚定受体，并且证实了使HYAL 2蛋白失活的螯合机制。JSRV的env基因显示在体外转化人支气管上皮细胞并隔离HYAL 2蛋白。HYAL 2的缺失（由推定的病毒或突变失活介导）导致罗恩受体酪氨酸激酶及其下游信号通路（Akt和MAPK）的配体非依赖性激活。我们还鉴定了绵羊/人Hyal 2受体中决定JSRV特异性有效结合和进入的必需氨基酸残基。这些结果表明，在某些类型的肺癌（细支气管肺泡癌，目前占人类肺癌的20%）的致癌作用中存在一种假定的人类JSRV样病毒。我们还研究了罗恩在SCLC中的作用。我们发现，在SCLC中，罗恩的启动子被高甲基化沉默，导致同时激活一个假定的内部启动子。