This project focuses on identification and functional characterization of human 3p recessive oncogenes (tumor suppressor genes, TSGs), with the initial emphasis being on discovery of TSGs in a 630 kb, completely sequenced, 3p21.3 region found to be homozygously deleted in lung and breast cancers. Our overall hypothesis is that biallelic inactivation or haploinsufficiency of one or more of these genes is of fundamental importance in the pathogenesis of many human cancers and that this inactivation occurs early in the multistep process of carcinogenesis. We have just completed the isolation and initial characterization of 25 genes in this area (23 of which are new) and found two, RASSF1A (Ras interacting protein with a DAG binding domain), and SEMA3B (secreted class III semaphorin) to have biallelic expression loss and potent tumor suppressing activity. We also found several others to have some characteristics of TSGs (loss of expression, mutation, suppression of the malignant phenotype) including CACNA2D2, 101F6, NPR21/G21, BLU, FUSI, HYAL1, and FUS2. The current proposal will: Confirm the tumor suppressing function of RASSF1A and SEMA3B and further implicate or dismiss the other candidate 3p21.3 TSGs in multiple human cancer cell lines with different genetic abnormalities by in vitro and in vivo xenograft assays (Aim 1); Confirm that tumor acquired loss of expression of RASSF1A and SEMA3B and some of the other 3p21.3 TSG candidates occurs in human cancers but not in normal tissues, and is explained by tumor acquired methylation of CpG islands in their promoter regions (Aim 2); Study the potential mechanisms for tumor suppression of RASSF1A and SEMA3B using human cancer cell lines and thus determine the pathways involved in RASSF1A and SEMA3B suppression of the tumor phenotype; in the process also determine if acquired and germline amino acid sequence alterations in these genes inactivate their function potentially predisposing to cancer development (Aim 3); Determine whether a Sema3b knockout mouse model challenged with carcinogens confirms SEMA3B as a TSG and also test whether SEMA3B haploinsufficiency is sufficient for aiding carcinogen induced lung cancer in the mouse.
(Aim 4). The characterization of these gene(s) should ultimately have translational benefit for the development of new cancer diagnostics and therapeutics, including use in cancer early detection, prevention, and treatment.
|Gao, Boning; Xie, Xian-Jin; Huang, Chunxian et al. (2008) RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers. Cancer Res 68:22-5|
|Castro-Rivera, Emely; Ran, Sophia; Brekken, Rolf A et al. (2008) Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. Cancer Res 68:8295-303|
|Whitehurst, Angelique W; Ram, Rosalyn; Shivakumar, Latha et al. (2008) The RASSF1A tumor suppressor restrains anaphase-promoting complex/cyclosome activity during the G1/S phase transition to promote cell cycle progression in human epithelial cells. Mol Cell Biol 28:3190-7|
|Ohtani, Shoichiro; Iwamaru, Arifumi; Deng, Wuguo et al. (2007) Tumor suppressor 101F6 and ascorbate synergistically and selectively inhibit non-small cell lung cancer growth by caspase-independent apoptosis and autophagy. Cancer Res 67:6293-303|
|Deng, Wu-Guo; Kawashima, Hiroyaki; Wu, Guanglin et al. (2007) Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells. Cancer Res 67:709-17|
|Jayachandran, Gitanjali; Sazaki, Ji-ichiro; Nishizaki, Masahito et al. (2007) Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch. Cancer Res 67:10379-88|
|Iijima, Hironobu; Tomizawa, Yoshio; Iwasaki, Yasuki et al. (2006) Genetic and epigenetic inactivation of LTF gene at 3p21.3 in lung cancers. Int J Cancer 118:797-801|
|Sato, Mitsuo; Vaughan, Melville B; Girard, Luc et al. (2006) Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells. Cancer Res 66:2116-28|
|Moshnikova, Anna; Frye, Judson; Shay, Jerry W et al. (2006) The growth and tumor suppressor NORE1A is a cytoskeletal protein that suppresses growth by inhibition of the ERK pathway. J Biol Chem 281:8143-52|
|Ueda, Kentaro; Kawashima, Hiroyuki; Ohtani, Shoichiro et al. (2006) The 3p21.3 tumor suppressor NPRL2 plays an important role in cisplatin-induced resistance in human non-small-cell lung cancer cells. Cancer Res 66:9682-90|
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