Kay Huebner, PhD
Professor, Dept. of Molecular Virology, Immunology and Medical Genetics
The Ohio State University Comprehensive Cancer Center
455C Wiseman Hall
410 W. 12th Avenue
Columbus, Ohio 43210
Phone (614)292-4850
Fax (614)292-3312
Kay.huebner@osumc.edu

Laboratory Members

Teresa Druck-Commisso, Laboratory Manager and Research Assistant
Dimitrios Iliopoulos, PhD candidate
Kelly McCorkell, PhD Candidate
Haiyan (Rebekah) Qin, PhD  student
Shuho Semba, MD, PhD, Postdoctoral Fellow

Current Research
The Laboratory is focused on understanding the role of fragile genes, that is, genes at common chromosomal fragile sites, in cancer development.  The research currently entails studies of function of several genes, including FHIT and WWOX, definition of the signal pathways engaged by these genes in normal and cancer cells, and the consequences to cells, organs and organisms deficient for these genes, using the gamut of molecular genetic methods: normal and cancer cells, as well as mice deficient for genes of interest are used in comparative studies to define differences in negative and positive cells or animals; expression of the fragile genes or their effector genes are up or down modulated by transfection, and effect on biological or biochemical features assessed; interacting proteins are identified to build pathways; precancer and cancer phenotypes of knockout mice are assessed and viruses carrying the fragile suppressor genes are used in cancer prevention and therapy by infection of knockout mice to restore tumor suppressor expression; cells positive and negative for the genes of interest are compared using massive parallel analysis methods such as microarray expression profiling. The long-term goal is to use our understanding of the fragile tumor suppressor signal pathways to determine how these signals, that have been lost in cancer cells, may be reactivated in tumors to cause prevention or reversal of tumor growth.

Education
PhD, Microbiology, University of Pensylvania, 1974
Postdoctoral Training, Molecular Genetics, The Wistar Institute, Philadelphia, PA

Selected Publications

Kastury K, Baffa R, Druck T, Ohta M, Cotticelli MG, Inoue H, Negrini M, Rugge M, Huang D, Croce CM, Palazzo J, Huebner K.  Potential gastrointestinal tumor suppressor locus at the 3p14.2 FRA3B site identified by homozygous deletions in tumor cell lines.  Cancer Res., 56:978-983, 1996.

Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K.  The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers.  Cell, 84: 587-597, 1996.

Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K.  Fhit, a putative tumor suppressor in humans, is a dinucleoside 5,5’-P1,P3-triphosphate hydrolase.  Biochemistry, 35:11529-11535, 1996.

Sorio C, Melotti P, D’Arcangelo D, Mendrola J, Calabretta B, Croce CM, Huebner K.  Receptor protein tyrosine phosphatase gamma, Ptpg, regulates hematopoietic differentiation.  Blood, 90:49-57, 1997.

Druck T, Hadaczek P, Fu T-B, Ohta M, Siprashvili Z, Baffa R, Negrini M, Kastury K, Veronese ML, Rosen D, Rothstein J, McCue P, Cotticelli MG, Inoue H, Croce CM, Huebner K.  Structure and expression of the human FHIT gene in normal and tumor cells.  Cancer Res., 57:504-512, 1997.

Zimonjic DB, Druck T, Ohta M, Kastury K, Popescu NC, Huebner K.  Positions of chromosome 3p14.2 fragile sites (FRA3B) within the FHIT gene.  Cancer Res., 57:1166-1170, 1997.

Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K.  Replacement of Fhit in cancer cells suppresses tumorigenicity.  Proc. Natl. Acad. Sci. USA, 94:13771-13776, 1997.

Pekarsky Y, Druck T, Cotticelli MG, Ohta M, Shou J, Mendrola J, Montgomery JC, Buchberg AM, Siracusa L, Manenti G, Fong LYY, Croce CM, Dragani T, Huebner K.  The murine Fhit locus: Isolation, characterization and expression in normal and tumor cells.  Cancer Res., 58:3401-3408, 1998.

Ingvarsson S, Agnarsson BA, Sigbjornsdottir BI, Kallioniemi O-P, Barkardottir RB, Kovatich A, Schwarting R, Hauck WW, Huebner K, McCue PA.  Reduced Fhit expression in familial and sporadic breast carcinomas.  Cancer Res., 59:2682-2689, 1999.

Fong LYY, Fidanza V, Zanesi N, Lock L, Siracusa L, Mancini R, Siprashvili Z, Ottey M, Martin SE, Druck T, McCue PA, Croce CM, Huebner K.  Muir-Torre-like syndrome in Fhit deficient mice.  Proc. Natl. Acad. Sci. USA, 97:4742-4747, 2000.

Ishii H, Dumon K, Vecchione A, Trapasso F, Mimori K, Alder H, Mori M, Sozzi G, Baffa R, Huebner K, Croce CM.  Effect of adenoviral transduction of FHIT into esophageal cancer cells.  Cancer Res., 61:1578-1589, 2001.

Dumon KR, Ishii H, Fong LYY, Zanesi N, Fidanza V, Vecchione A, Baffa R, Trapasso F, During MJ, Huebner K, Croce CM.  FHIT gene therapy prevents tumor development in Fhit-deficient mice.  Proc. Natl. Acad. Sci. USA, 98:3346-3351, 2001.

Turner B, Ottey M, Potoczek M, Hauck WW, Pequignot E, Keck-Waggoner C, Zimonjic DB, Sevignani C, Aldaz M, McCue P, Palazzo J, Huebner K, Popescu NC.  The FHIT/FRA3B locus and repair deficient cancers.  Cancer Res., 62:4054-4060, 2002.

Ishii H, Zanesi N, Vecchione A, Trapasso F, Yendamuri S, Sarti M, Baffa R, During MJ, Huebner K, Fong LYY, Croce CM.  Prevention and regression of upper gastric cancer in mice by FHIT gene therapy.  FASEB J., 17:1768-1770, 2003.

Guler G, Uner A, Guler N, Engin H, Han SY, Hauck WW, Iliopoulos D, McCue P, Huebner K.  The fragile genes, FHIT and WWOX, are coordinately inactivated in invasive breast cancer: Correlations with clinical features.  Cancer, 100:1605-1614, 2004.

Ottey M, Han SY, Druck T, Barnoski B, McCorkell KA, Croce CM, Suarez CR, Fairchild C, Wange Y, Huebner K.  Fhit deficient normal and cancer cells are mitomycin C and UVC resistant.  Brit. J. Cancer, 91:1669-1677, 2004

Iliopoulos D, Guler G, Han S-Y, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R, Huebner K.  Fragile genes as biomarkers: Epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.  Oncogene 24:1625-1633, 2005

Guler G, Uner A, Guler N, Han S-Y, McCue P, Huebner K.  Concordant loss of fragile genes, Fhit and Wwox, in breast cancer development.  Path. Internatl. 55: 471-478, 2005

Zanesi N, Mancini R, Sevignani C, Vecchione A, Kaou M, Valtieri M, Calin GA, Pekarsky Y, Gnarra J, Croce   CM, Huebner K. Lung cancer in Fhit deficient mice: synergism with Vhl. Cancer Res. 65: 6576-6582, 2005

Zanesi N, Mancini R, Sevignani C, Vecchione A, Kaou M, Valtieri M, Calin GA, Pekarsky Y, Gnarra JR, Croce CM, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16061637&itool=iconabstr&query_hl=7 Lung cancer susceptibility in Fhit-deficient mice is increased by Vhl haploinsufficiency.
Cancer Res. 2005 Aug 1;65(15):6576-82.
PMID: 16061637 [PubMed - in process]

Guler G, Uner A, Guler N, Han SY, Iliopoulos D, McCue P, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15998374&itool=iconabstr&query_hl=7 Concordant loss of fragile gene expression early in breast cancer development.
Pathol Int. 2005 Aug;55(8):471-8.
PMID: 15998374 [PubMed - in process]

Ishii H, Inageta T, Mimori K, Saito T, Sasaki H, Isobe M, Mori M, Croce CM, Huebner K, Ozawa K, Furukawa Y
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15983387&itool=iconabstr&query_hl=7
Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis.
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9655-60. Epub 2005 Jun 27.
PMID: 15983387 [PubMed - in process]

Guler G, Iliopoulos D, Han SY, Fong LY, Lubet RA, Grubbs CJ, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15937960&itool=iconabstr&query_hl=7  Hypermethylation patterns in the Fhit regulatory region are tissue specific.
Mol Carcinog. 2005 Jul;43(3):175-81.
PMID: 15937960 [PubMed - indexed for MEDLINE]

Iliopoulos D, Guler G, Han SY, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15674328&itool=iconabstr&query_hl=7  Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.
Oncogene. 2005 Feb 24;24(9):1625-33.
PMID: 15674328 [PubMed - indexed for MEDLINE]

Lubet RA, Huebner K, Fong LY, Altieri DC, Steele VE, Kopelovich L, Kavanaugh C, Juliana MM, Soong SJ, Grubbs CJ.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15591090&itool=iconabstr&query_hl=7  4-Hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers in mice: characterization of FHIT and survivin expression and chemopreventive effects of indomethacin.
Carcinogenesis. 2005 Mar;26(3):571-8. Epub 2004 Dec 9.
PMID: 15591090 [PubMed - indexed for MEDLINE]

 Ottey M, Han SY, Druck T, Barnoski BL, McCorkell KA, Croce CM, Raventos-Suarez C, Fairchild CR, Wang Y, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15494723&itool=iconabstr&query_hl=7  Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant.
Br J Cancer. 2004 Nov 1;91(9):1669-77.
PMID: 15494723 [PubMed - indexed for MEDLINE]

 Fujishita T, Doi Y, Sonoshita M, Hiai H, Oshima M, Huebner K, Croce CM, Taketo MM.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15467769&itool=iconabstr&query_hl=7  Development of spontaneous tumours and intestinal lesions in Fhit gene knockout mice.
Br J Cancer. 2004 Oct 18;91(8):1571-4.
PMID: 15467769 [PubMed - indexed for MEDLINE]

Hu B, Han SY, Wang X, Ottey M, Potoczek MB, Dicker A, Huebner K, Wang Y.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15389587&itool=iconabstr&query_hl=7  Involvement of the Fhit gene in the ionizing radiation-activated ATR/CHK1 pathway.
J Cell Physiol. 2005 Feb;202(2):518-23.
PMID: 15389587 [PubMed - indexed for MEDLINE]

Ishii H, Vecchione A, Furukawa Y, Croce CM, Huebner K, Fong LY.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15361827&itool=iconabstr&query_hl=7  Differentially expressed genes execute zinc-induced apoptosis in precancerous esophageal epithelium of zinc-deficient rats.
Oncogene. 2004 Oct 21;23(49):8040-8.
PMID: 15361827 [PubMed - indexed for MEDLINE]

Matsuyama A, Croce CM, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15145773&itool=iconabstr&query_hl=7  Common fragile genes.
Eur J Histochem. 2004;48(1):29-36. Review.
PMID: 15145773 [PubMed - indexed for MEDLINE]

Aqeilan RI, Kuroki T, Pekarsky Y, Albagha O, Trapasso F, Baffa R, Huebner K, Edmonds P, Croce CM.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15131042&itool=iconfft&query_hl=7  Loss of WWOX expression in gastric carcinoma.
Clin Cancer Res. 2004 May 1;10(9):3053-8.
PMID: 15131042 [PubMed - indexed for MEDLINE]

Guler G, Uner A, Guler N, Han SY, Iliopoulos D, Hauck WW, McCue P, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15073846&itool=iconabstr&query_hl=7  The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma.
Cancer. 2004 Apr 15;100(8):1605-14.
PMID: 15073846 [PubMed - indexed for MEDLINE]

Aqeilan RI, Pekarsky Y, Herrero JJ, Palamarchuk A, Letofsky J, Druck T, Trapasso F, Han SY, Melino G, Huebner K, Croce CM.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15070730&itool=iconpmc&query_hl=7  Functional association between Wwox tumor suppressor protein and p73, a p53 homolog.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4401-6.
PMID: 15070730 [PubMed - indexed for MEDLINE]

Ishii H, Vecchione A, Fong LY, Zanesi N, Trapasso F, Furukawa Y, Baffa R, Huebner K, Croce CM.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15032614&itool=iconabstr&query_hl=7  Cancer prevention and therapy in a preclinical mouse model: impact of FHIT viruses.
Curr Gene Ther. 2004 Mar;4(1):53-63. Review.
PMID: 15032614 [PubMed - indexed for MEDLINE]

Han SY, Iliopoulos D, Druck T, Guler G, Grubbs CJ, Pereira M, Zhang Z, You M, Lubet RA, Fong LY, Huebner K.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15007387&itool=iconabstr&query_hl=7  CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors.
Oncogene. 2004 May 13;23(22):3990-8.
PMID: 15007387 [PubMed - indexed for MEDLINE]

Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15007172&itool=iconpmc&query_hl=7  Fhit is a physiological target of the protein kinase Src.
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3775-9. Epub 2004 Mar 8.
PMID: 15007172 [PubMed - indexed for MEDLINE