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.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Ivanov, Sergey V; Ivanova, Alla V; Salnikow, Konstantin et al. (2008) Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors. Biochem Biophys Res Commun 370:536-40
Angeloni, D; Danilkovitch-Miagkova, A; Ivanova, T et al. (2007) Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter. Oncogene 26:4499-512
Ivanova, A V; Ivanov, S V; Pascal, V et al. (2007) Autoimmunity, spontaneous tumourigenesis, and IL-15 insufficiency in mice with a targeted disruption of the tumour suppressor gene Fus1. J Pathol 211:591-601
Yi Lo, Paulisally Hau; Chung Leung, Alfred Chi; Xiong, Wenjun et al. (2006) Expression of candidate chromosome 3p21.3 tumor suppressor genes and down-regulation of BLU in some esophageal squamous cell carcinomas. Cancer Lett 234:184-92
Miller, A D; Vigdorovich, V; Strong, R K et al. (2006) Hyal2, where are you? Osteoarthritis Cartilage 14:1315-7
Angeloni, Debora; ter Elst, Arja; Wei, Ming Hui et al. (2006) Analysis of a new homozygous deletion in the tumor suppressor region at 3p12.3 reveals two novel intronic noncoding RNA genes. Genes Chromosomes Cancer 45:676-91
Yau, Wing Lung; Lung, Hong Lok; Zabarovsky, Eugene R et al. (2006) Functional studies of the chromosome 3p21.3 candidate tumor suppressor gene BLU/ZMYND10 in nasopharyngeal carcinoma. Int J Cancer 119:2821-6
Kuzmin, Igor; Geil, Laura; Gibson, Lauren et al. (2005) Transcriptional regulator CTCF controls human interleukin 1 receptor-associated kinase 2 promoter. J Mol Biol 346:411-22
Li, Jingfeng; Wang, Fuli; Haraldson, Klas et al. (2004) Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.3C. Cancer Res 64:6438-43
Ivanov, Sergey V; Ward, Jerrold M; Tessarollo, Lino et al. (2004) Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene. Am J Pathol 165:1007-18

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