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基因编码能够同型和异型结合的跨膜细胞粘附分子（CAM），该基因被证明与一般认知活动和一些神经系统疾病（即精神分裂症）有关。我们发现CALL在大脑以外的正常组织中表达，并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，根据阶段的不同，它可能充当肿瘤抑制基因或癌基因。在最初的肿瘤生长过程中，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，并进一步允许肿瘤细胞进入和离开血流、定植远处组织并建立转移性肿瘤。 Bert Vogelstein 领导的团队最近发现 CALL/CHL1 在结直肠癌中是一种 CAN 基因，但在乳腺癌中却没有。他们发现了 CALL 细胞外部分的突变，这为选择性治疗患者提供了治疗抗体。我们将对主要癌症中过度表达的 CALL 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，以及对过度表达突变 CALL 的癌症进行免疫干预的新靶标。对 VHL 基因 (3p25.3) 的研究：我们鉴定了 VHL 表观遗传密码并在转基因中重建了其模式 老鼠；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 启动子岛中具有结合位点，并且可能与其他因子一起在防止肾癌基因异常沉默方面发挥重要作用。我们最近证明转录因子 CTCF 控制参与 TLR（Toll 样免疫受体）下游信号传导的 IRAK2 表达。我们发现 CA 9 /CA12 基因在许多肿瘤类型中被特异性诱导和过度表达。这些酶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。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（临床用于青光眼治疗）芳香族磺酰胺抑制剂。我们在其中鉴定出几种对每种酶表现出纳摩尔特异性抑制的化合物。我们已经证明，VHL 在至少 50% 的常见人类肿瘤中失活/沉默。对 3p21.3 致癌基因的研究：我们鉴定出 RASSF1A 基因是参与许多肿瘤的多 TSG，包括肺癌、乳腺癌、前列腺、肾、头颈、子宫颈等。我们假设 RASSF1 基因及其旁系同源物在大约 70% 的人类癌症中失活。HYAL2 蛋白被鉴定为绵羊肺癌逆转录病毒 JSRV 的 GPI 锚定受体，并且证明了使 HYAL2 蛋白失活的隔离机制。 JSRV 的 env 基因被证明可以在体外转化人支气管上皮细胞并隔离 HYAL2 蛋白。 HYAL2 的缺失（由假定的病毒或突变失活介导）会导致 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。结果表明，假定的人类 JSRV 样病毒与吸烟无关的某些类型肺癌（细支气管肺泡癌，目前占人类肺癌的 20%）的致癌作用有关。我们还一直在研究 RON 在 SCLC 中的作用。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。