Tom K. Hei, Ph.D.

      Center for Radiological Research
      630 West 168th Street, VC 11-205/218
      New York, N.Y. 10032

      Email: tkh1@columbia.edu
      Tel: 212-305-8462 / Fax: 212-305-3229 

   Current Academic and Professional Appointments  

• Vice-Chairman, Department of Radiation Oncology, College of Physicians & Surgeons of Columbia University

• Associate Director, Center for Radiological Research, College of Physicians & Surgeons of Columbia University

• Professor of Radiation Oncology & Professor of Environmental Health Sciences, Columbia University

• Adjunct Professor of Radiological Health Sciences, Colorado State University

• Adjunct Professor and Ph.D. Mentor, Chinese Academy of Sciences, China

• Adjunct Professor, School of Radiation Medicine and Public Health, Soochow University

• Ad Hoc Member, Cancer Etiology Study Section, NIH

• Editor, Advances in Space Research (Radiation Biology Section)

• Associate Editor, Journal of Radiation Research

   Current Research  

Dr. Hei's research program focuses on environmental carcinogenesis, specifically mechanisms of chemical and radiation carcinogenesis/mutagenesis at the cellular and molecular levels. In risk assessment studies, in vitro neoplastic transformation assays based on rodent fibroblasts are used to obtain quantitative dose response data for environmental carcinogens such as tobacco smoke, radon, asbestos fibers, and heavy metals. Immortalized human bronchial and breast epithelial cell models are used to examine the molecular mechanisms involved in the multistage nature of human carcinogenesis. Activation of oncogenes, loss of tumor suppressor genes, altered signal transduction pathways in radon and asbestos induced bronchial carcinogenesis are currently funded research programs.

A second area of research centers around fiber toxicology, particularly, the how and why of mineral fibers, including asbestos and other man-made fibers, in causing lung fibrosis and cancers of the lung and peritoneum. Emphases are on mechanisms of fiber mutagenesis, effects of reactive oxygen species in fiber toxicology, and the synergistic interaction of asbestos with other environmental carcinogenesis such as radon and cigarette smoke.

A third but related area of research focuses on the molecular mechanisms of mutagenesis by various environmental carcinogens. Since exposure of human to environmental agents frequently involve more than one agent, the emphasis is on the identification of "molecular signature" among mutant induced by a combination of these agents.

   Research Highlights  

I.  Radiation-Induced Bystander Effects: 

Exposure to environmental radon is the second leading cause of human lung cancer. Previously studies from our laboratory have shown that targeted nuclear irradiation of 10% of cells in a population of confluent monolayer with a single alpha particle resulted in a mutant fraction similar to that observed when all of the cells in the population are irradiated Zhou et al., Proc. National Academy Science U.S.A. 98:14410, 2001). This effect was significantly eliminated in cells pretreated with a 1mM dose of octanol, which inhibits gap junction-mediated intercellular communication, or in cells carrying a dominant negative connexin 43 vector. These data suggest the presence of a transmissible signaling molecule is involved in the bystander process.

Nature of the Signaling Molecule(s):

In our quest to identify the signaling pathways involved in radiation induced bystander effect, we first focused on the genes that are differentially expressed among the bystander versus control cells. Using a signal transduction pathway specific SuperArray, we compared the differentially expressed genes among the non-irradiated control NHLF cells and the bystander cells. Among the 96 genes represented on the platform, transcription level of one gene, cyclooxygenase-2 (COX-2), was found to be consistently up-regulated by more than three-fold, while the RNA level of insulin growth factor binding protein-3 (IGFBP3) was found to be consistently lower by more than seven-fold in multiple analyses of multiple bystander samples. Semi-quantitative reverse transcription (RT) PCR was used to confirm the expression levels of these two genes using expression level of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene as internal control.  The expression of the COX-2 protein in the non-irradiated bystander cells was further confirmed by Western blotting.  Addition of the COX-2 inhibitor NS-398 (50 mM) suppressed COX-2 activity in NHLF cells and finally, after 24 hours, reduced the COX-2 protein level in bystander cells to a non-detectable level. Furthermore, treatment of bystander cells with NS-398 significantly reduced the bystander effect. Since the critical event of the COX-2 signaling is the activation of the mitogen-activated protein kinase (MAPK) pathways, our finding that inhibition of the extracellular signal-related kinase (ERK) phosphorylation suppressed bystander response further confirmed the important role of MAPK signaling cascade in the bystander process. These results provide the first evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory response, is the critical signaling link for the bystander phenomenon (Zhou et al., Proc. National Academy Science U.S.A. 102:14641, 2005).

Since inflammatory response usually involved reactive oxygen species and oxyradicals are intimately linked to mitochondrial function, we next examined the role of mitochondria in bystander effects. We found that mitochondrial DNA depleted human skin fibroblasts (ρ⁰) showed a higher bystander mutagenic response in confluent monolayers when a fraction of the same population were irradiated with lethal doses, compared with their parental, mitochondria functional cells (ρ⁺). However, using mixed cultures of ρ⁰ and ρ⁺ cells and targeted only one population of cells with a lethal dose of alpha particles, a decreased bystander mutagenesis was uniformly found in non-irradiated bystander cells of both cell types, indicating that signals from one cell type can modulate expression of bystander response in another cell type (Zhou et al., Cancer Research, 2008 in press). In addition, we found that Bay 11-7082, a pharmacological inhibitor of nuclear factor-κB (NF-κB) activation, and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), a scavenger of nitric oxide (NO), significantly decreased the mutation frequency in both bystander ρ⁰ and ρ⁺ cells. Furthermore, we found that NF-κB activity and its dependent proteins, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), were lower in bystander ρ⁰ cells when compared with their ρ⁺ counterparts. Our results indicated that mitochondria play an important role in the regulation of radiation-induced bystander effects, and that mitochondria-dependent NF-κB/iNOS/NO and NF-κB/COX-2/prostaglandin-E2 (PGE2) signaling pathways are important to the process.

Radiation induced bystander effects imply that the relevant target for radiation mutagenesis is larger than an individual cell and suggest a need to reconsider the validity of the linear extrapolation in making risk estimate for low dose radiation exposure (for review: Hei et al., Mutation Research 568:111, 2004; Mol. Carcinog 45:455-60, 2006)

II. Genotoxic Mechanism of Arsenic:

As a naturally occurring metalloid, arsenic is ubiquitously present in the environment. Epidemiological data gathered for more than a century have shown that arsenic is a potent human carcinogen. However, mechanisms by which arsenic induces cancer are not known. Using confocal scanning microscopy with a fluorescent probe, we show recently that arsenite induces, within 5 min after treatment, a dose-dependent increase of up to 3-fold in intracellular oxyradical production. Electron spin resonance (ESR) spectroscopy using TEMPOL-H as a probe indicates that arsenite increases the levels of superoxide-driven hydroxyl radicals in these cells (Liu et al., Proc. National Academy Science U.S.A. 98:1643, 2001). Concurrent treatment of cells with either superoxide dismutase or catalase reduced both the cytotoxicity and mutagenicity of arsenite by an average of 2-3 fold, respectively. Using immunoperoxidase staining with a monoclonal antibody specific for 8-hydroxy-2'-deoxyguanosine (8-OHdG), we demonstrated that arsenic induced oxidative DNA damage in A_L cells. This induction was significantly reduced in the presence of the antioxidant enzymes. Furthermore, reducing the intracellular levels of non-protein sulfhydryls (mainly glutathione) using buthionine S-R-Sulfoximine increased the total mutant yield by more than 3-fold as well as the proportion of mutants with multilocus deletions (Kessel et al., Mol. Cell Biochem. 234:301, 2002). Taken together, our data provide clear evidence that reactive oxygen species play an important causal role in the genotoxicity of arsenic in mammalian cells. For an updated review, please refer to Hei and Filipic, Free Radical Biology & Medicine 37:574, 2004.

Origin of the Free Radicals:

Recent studies have focused on the elucidation of the origin of these radicals and the pathways involved in their production. Since mitochondria are the energy metabolic center of cells and mitochondrial membrane damage has been shown to increase intracellular oxidative stress, we examined if mitochondria contribute to the genotoxicity of the trivalent sodium arsenite using two complementary approaches. Treatment of enucleated cells with arsenic followed by rescue fusion with karyoplasts from controls resulted in significant mutant induction. An important corollary of this finding is that nucleus is not necessarily the only and sufficient target for arsenic carcinogenesis. Treatment of cytoplasts with arsenic, in the absence of nucleus, initiated similar oxyradical production, as detected by using the fluorescent probe, 5',6'-chloromethyl-2',7'dichlorodihydro-fluorescein diacetate (CM-H2DCFDA).

In contrast, treatment of mitochondrial DNA depleted cells followed by rescue fusion with cytoplasts produced very few mutations.

Mitochondrial damage can lead to the release of superoxide anions which then react enzymatically with nitric oxide to produce the highly reactive peroxynitrites. The mutagenic damage was dampened by the nitric oxide synthase inhibitor, NG-methyl-L-arginine. Thus, the genotoxicity of arsenic is mediated by a combination of both reactive oxygen and nitrogen species. These data illustrate that mitochondria are a primary target in arsenic-induced genotoxic response and that a better understanding of the mutagenic/carcinogenic mechanism of arsenic should provide a basis for better interventional approach in both treatment and prevention of arsenic induced cancer (Liu et al., Cancer Research 65:3236, 2005).

Arsenic treatment has a profound effect on mitochondria morphology and function. Arsenite-treated cultures (1 µg /ml for 60 days) exhibited a dramatically elongated or filamentous morphology (Partridge et al., Cancer Research 67:5239, 2007). This extended mitochondrial morphology was also evident in cells stained histochemically for cytochrome c oxidase (COX) after only 15 days of arsenic exposure. This change in mitochondrial morphology correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions.

Using quantitative RT-PCR and primers for the hamster 12S and 18S rRNA genes, we found that arsenic treatment (1 µg/ml for 60 days) reduced the mtDNA copy number to <65% of control levels. The effect was dose dependent and could be detected at a lower dose of 0.25µg/ml. Furthermore, using nested PCR analyses, we showed that arsenic treatment induced large heteroplasmic mutations in mtDNA of hamster cells. Similarly, we detected an increase in mtDNA deletions after arsenic exposure in two normal human cell lines: small airway epithelial cells and normal lung fibroblasts, both derived from tissues that are known to have high incidences of cancer in arsenic exposed humans (Partridge et al., Cancer Research 67:5239, 2007)

III. Arsenic as a Two-sided Sword - Therapeutic Function:

Melanoma is often a deadly disease due to the lack of effective treatment options. Studies conducted in the laboratory of Dr. Tom K. Hei have shown that short term treatment with low concentrations of sodium arsenite (2-10 mM) which has little or no effects on normal melanocytes induces apoptosis of human melanoma including highly metastatic ones in a process independent of Fas ligand binding. The apoptotic response depends on low nuclear NFkB activity and an endogenous expression of TNF_a. Simultaneous inhibition of PI3K-AKT and MEK-ERK pathways induces TRAIL-mediated apoptosis of human melanoma cells that can be substantially enhanced by low dose of arsenite treatment. Taken together, these data suggest that arsenite may be a powerful therapeutic agent in the treatment of disseminated melanoma (Ivanov and Hei, J. Biol. Chem. 276:22747-22758, 2004; Oncogene 24:616, 2005).

Most human melanomas express Fas receptor on the cell surface, and treatment with exogenous Fas Ligand (FasL) efficiently induces apoptosis of these cells. In contrast, endogenous surface expression of FasL is suppressed in Fas-positive melanomas. Using a combination of sodium arsenite, an inhibitor of NF-kappaB activation, and NS398, a cyclooxygenase-2 (COX-2) inhibitor, we show that the surface FasL expression can readily be restored. We observed a large increase of Fas-mediated apoptosis in Fas-positive melanomas. This was due to induction of FasL surface expression and increased susceptibility to Fas death signaling after arsenite and NS398 treatment. Furthermore, silencing COX-2 expression by specific RNAi also effectively increased surface FasL expression following arsenite treatment. Upregulation of the surface FasL levels was based on an increase in the efficiency of translocation to the cell surface and stabilization of FasL protein on the cell surface, rather than on acceleration of the FasL gene transcription. Data obtained demonstrate that the combination of arsenite with inhibitors of COX-2 may affect the target cancer cells via induction of FasL-mediated death signaling (Ivanov and Hei, Exp Cell Res. 312:1401, 2006, J Biol Chem. 281:1840, 2006).

Many melanomas exhibit high levels of radioresistance. The direct consequence of gamma-irradiation for most melanoma cells is growth arrest at the G2-M phase of cell cycle. However, radiation-induced signaling pathways may ffect numerous additional targets in cancer cells. Recently, we have shown that gamma-irradiation, as well as alpha-particles, dramatically increases the susceptibility of melanoma cells to recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via up-regulation of surface TRAIL-receptor 1/receptor 2 (DR4/ DR5) levels and to Fas ligand-mediated apoptosis. Additionally, increased dynamin-2 expression after irradiation is critically important in the translocation of death receptor to the cell surface. These data highlight the efficacy of combined modality treatment involving radiation and arsenite in clinical management of this often fatal form of skin cancer (Ivanov et al., Cancer Res 67: 5397, 2007).

Recently, we have also shown that resveratrol (a polyphenolic phytoalexin) down-regulates STAT3 activation, while activating JNK that suppressed expression of the anti-apoptotic cFLIP (an inhibitor of caspase-8) and Bcl-xL proteins and increases the sensitivity of DR5-positive melanomas to exogenous TRAIL. Interestingly, sodium arsenite treatment or -irradiation substantially up-regulates surface expression of DR5 in human melanomas. This approach and the subsequent down regulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient way to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. Taken together, these results suggest that resveratrol in combination with TRAIL may have a significant efficacy in the treatment of human melanomas (Ivanov et al. Exp. Cell Res. In press 2008).

IV. The bigH3 is a Tumor Suppressor Gene:  

Using a human lung cell model, we have previously identified that the gene, bigH3, which encodes a secreted adhesion molecule induced by transforming growth factor-b (TGF-b), has pronounced tumor suppressor function. The findings identified a potential target for interventional therapy in lung cancer treatment. Led by Dr. Tom K. Hei, professor of radiation oncology and public health, the study found the bigH3 gene is markedly decreased in many human cancer cell lines as well as in a high percentage of human lung cancer samples (Zhao et al., Brit. J. Cancer, 86:1923, 2002, Oncogene 21:7471, 2002). Reintroduction of this gene into tumor cells resulted in a significant reduction in tumor growth. While integrin receptor a5b1 was overexpressed in tumor cells, its expression was corrected to the level found in normal lung cells after betaig-H3 transfection. These data suggest that the bigH3 gene is involved in tumor progression by regulating integrin receptor a5b1.

Recently, we examined the expression of bigH3 in 130 primary human lung carcinomas by immunohistochemistry. bigH3 protein was absent or reduced by more than two-fold in 45 of 130 primary lung carcinomas relative to normal lung tissues examined. Recovery of bigH3 expression in H522 lung cancer cells lacking endogenous bigH3 protein significantly suppressed their in vitro cellular growth and in vivo tumorigenicity. In addition, parental H522 cancer cells are resistant to the etoposide induced apoptosis compared with normal human bronchial epithelial cells. However, recovery of bigH3 expression in H522 cancer cells results in significantly higher sensitivity to apoptotic induction than parental tumor cells. These observations demonstrate that downregulation of bigH3 gene is a frequent event and related to the tumor progression in human lung cancer (Zhao et al., Mol. Carcinogenesis 45:84, 2006). 

To determine the mechanism of how the bigH3 was inactivated, we found no mutations either in the gene sequence or the promoter region of the gene. Gene silencing by CpG island methylation in the promoter region is one of the mechanisms by which tumor suppressor genes are inactivated in human cancers. To unravel the underlying molecular mechanism(s) for this phenomenon, DNA methylation patterns of bigH3 CpG islands were examined in normal, immortalized, and cancer cell lines derived from lung, prostate, mammary, and kidney. A good correlation was observed between promoter hypermethylation and lost expression of bigH3 gene, which was supported by the data that demethylation of promoter by 5-aza-2'-deoxycytidine reactivated bigH3 and restored its expression in bigH3-silenced tumor cell lines. This result was further substantiated by a luciferase reporter assay, showing the restoration of promoter activities and increased response to transforming growth factor-beta treatment in bigH3-negative 293T cells when transfected with unmethylated bigH3 promoter. In contrast, activity of bigH3 promoter was completely inactivated by in vitro methylation. Furthermore, CpG methylation of bigH3 promoter was also shown in primary lung tumors that expressed decreased level of bigH3 protein. These results suggest that promoter methylation plays a critical role in promoter silencing of the bigH3gene in human tumor cells (Shao et al., Cancer Research 66: 4566, 2006).

V.  Establishment of an h-TERT Immortalized Human Small Airway Epithelial Cells:

To better understand the cellular and molecular mechanisms involved in human bronchial carcinogenesis by respiratory carcinogens such as tobacco smoke, asbestos fibers and radon, it will be ideal to use a genomically stable human bronchial cell line to assess the various transformation stages leading to malignancies. Until recently, no human cell model is available for this area of research because primary human cells senescent and are refractory to malignant transformation in vitro. The signal for senescence has been attributed to what is now widely known as the chromosomal end replication problem due to telomere shortening with each cell division. The senescent signal can be circumvented by the addition of telomeres at the chromosomal ends that consist of tandem repeats of guanine-rich sequence, TTAGGG to prevent degradation by nucleases and end fusion of chromosomes. Our laboratory has recently succeeded in generating a number of immortalized human small airway epithelial (SAE) cells using ectopically expressed catalytic subunit of telomerase (hTERT). These cells are characterized by over-expression of hTERT mRNA, elongated telomere length and higher telomerase activity. Early passage of these cells (<20 population doublings) expressed the p16 protein at a level comparable to their parental cells. In later passages (>150 population doublings), p16 protein was decreased but recovered to the early passage level upon treatment with a methylation inhibitor, 5-Aza-CdR. Chromosome analysis showed a near diploid karyotype albeit with a gain or loss of certain chromosomes and a few stable translocations. No p53 gene alterations were found in these cell lines. The immortalized clones remained anchorage dependent in growth and were non tumorigenic in nude mice. These cell lines are the first reported immortalized human airway epithelial cell lines by hTERT expression without virus incorporation, which may serve as a useful model system for studies on bronchial carcinogenesis (Piao et al., Carcinogenesis 26:725, 2005).

VI. Mechanism of radiation induced breast carcinogenesis:

Breast cancer is a complex disease involving numerous genetic aberrations. Immunochemical analysis of protein expression is presented in a human breast epithelial cell line neoplastically transformed by high linear energy transfer (LET) alpha particle radiation in the presence of 17beta estradiol (E) and in the parental human breast epithelial cell line (MCF-10F) which served as a non-tumorigenic control. The levels of mRNA and protein expression of PCNA, c-fos, JNK2 and Fra-1 were increased in the transformed cell line compared to the levels in non-tumorigenic control cells. The transforming factor Rho A was significantly increased only in the tumor cell line. Furthermore, the levels of mRNA and protein expression of ErbB2 were significantly increased in the transformed cell line and in tumor cells derived from the transformed cells after injecting them into nude mice. A decrease in RbA/p48 protein expression and mRNA levels was observed in cells treated with double doses of alpha particle radiation in the presence of estrogen, regardless of tumorigenicity. Such expression was lower than that in the control untreated MCF-10F cells. These studies show that estrogen and high LET-radiation induce changes in oncoprotein expression and mRNA levels of human breast cell lines. These changes are indicative of a cascade of events that characterize the process of cell transformation in breast cancer. These results provide evidence that multiple steps with consecutive changes are involved when normal cells become tumorigenic cells as a result of alpha particle irradiation and estrogen treatments (Calaf et al., Histochem Cell Biol.124:261, 2005).

Allelic alterations in a refined position on the long arm of chromosome 11 were studied to identify the spectrum of induced damage at different stages of malignant transformation of MCF-10F cell lines after exposure to high-LET radiation using alpha-particles and exposure to estradiol by using PCR-single strand conformation polymorphism (SSCP) and fluorescence in situ hybridization (FISH) analysis. Microsatellite markers were selected from chromosome 11 (11q23-q24 loci) and it was found that frequency of allelic imbalance occurs at different stages of tumor progression with a range of 15-45% depending on the marker studied. These results strongly suggested the presence of several tumor suppressor genes in this critical region of chromosome 11 (11q23-q24). It also represents the first indication of allele loss at these loci in human breast epithelial cells induced by radiation and estrogen treatment suggesting a potential interventional target in breast carcinogenesis (Roy et al., Int. J. Oncol. 28:667, 2006).

   Select Publications Online  

If you do not find what you are looking for below, try searching for Tom Hei on PubMed.

• Hei TK, Ballas LK, Brenner DJ and Geard CR. Advances in radiobiological studies using a microbeam. J Radiat Res (Tokyo) 50 Suppl A:A7-A12, 2009. [abstract]

• Zhou H, Hong M, Chai Y and Hei TK. Consequences of cytoplasmic irradiation: studies from microbeam. J Radiat Res (Tokyo) 50 Suppl A:A59-65, 2009. [abstract]

• Ivanov VN, Zhou H, Partridge MA and Hei TK. Inhibition of ataxia telangiectasia mutated kinase activity enhances TRAIL-mediated apoptosis in human melanoma cells. Cancer Res 69:3510-9, 2009. [abstract]

• Partridge MA, Huang SX, Kibriya MG, Ahsan H, Davidson MM and Hei TK. Environmental mutagens induced transversions but not transitions in regulatory region of mitochondrial DNA. J Toxicol Environ Health A 72:301-4, 2009. [abstract]

• Xu A, Chai Y, Nohmi T and Hei TK. Genotoxic responses to titanium dioxide nanoparticles and fullerene in gpt delta transgenic MEF cells. Part Fibre Toxicol 6:3, 2009. [abstract]

• Zhang Y, Wen G, Shao G, Wang C, Lin C, Fang H, Balajee AS, Bhagat G, Hei TK and Zhao Y. TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res 69:37-44, 2009. [abstract]

• Wen G, Partridge MA, Calaf GM, Meador JA, Hu B, Echiburu-Chau C, Hong M and Hei TK. Increased susceptibility of human small airway epithelial cells to apoptosis after long term arsenate treatment. Sci Total Environ 407:1174-81, 2009. [abstract]

• Hei TK, Zhou H, Ivanov VN, Hong M, Lieberman HB, Brenner DJ, Amundson SA and Geard CR. Mechanism of radiation-induced bystander effects: a unifying model. J Pharm Pharmacol. 60:943-50, 2008. [abstract]

• Mense SM, Remotti F, Bhan A, Singh B, El-Tamer M, Hei TK and Bhat HK. Estrogen-induced breast cancer: alterations in breast morphology and oxidative stress as a function of estrogen exposure. Toxicol Appl Pharmacol 232:78-85, 2008. [abstract]

• Chen S, Zhao Y, Han W, Zhao G, Zhu L, Wang J, Bao L, Jiang E, Xu A, Hei TK, et al. Mitochondria-dependent signalling pathway are involved in the early process of radiation-induced bystander effects. Br J Cancer 98:1839-44, 2008. [abstract]

• Johnson GE, Ivanov VN and Hei TK. Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival. Apoptosis 13:790-802, 2008. [abstract]

• Calaf GM, Echiburu-Chau C, Zhao YL and Hei TK. BigH3 protein expression as a marker for breast cancer. Int J Mol Med 21:561-8, 2008. [abstract]

• Mense SM, Hei TK, Ganju RK and Bhat HK. Phytoestrogens and breast cancer prevention: possible mechanisms of action. Environ Health Perspect 116:426-33, 2008. [abstract]

• Shao G, Balajee AS, Hei TK and Zhao Y. p16INK4a downregulation is involved in immortalization of primary human prostate epithelial cells induced by telomerase. Mol Carcinog 47:775-83, 2008. [abstract]

• Zhou H, Ivanov VN, Lien YC, Davidson M and Hei TK. Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects. Cancer Res 68:2233-40, 2008. [abstract]

• Ivanov VN, Partridge MA, Johnson GE, Huang SX, Zhou H and Hei TK. Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. Exp Cell Res 314:1163-76, 2008. [abstract]

• Wen G, Calaf GM, Partridge MA, Echiburu-Chau C, Zhao Y, Huang S, Chai Y, Li B, Hu B and Hei TK. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med 14:2-10, 2008. [abstract]

• Persaud R, Zhou H, Hei TK and Hall EJ. Demonstration of a radiation-induced bystander effect for low dose low LET beta-particles. Radiat Environ Biophys 46:395-400, 2007. [abstract]

• Ivanov VN, Zhou H and Hei TK. Sequential treatment by ionizing radiation and sodium arsenite dramatically accelerates TRAIL-mediated apoptosis of human melanoma cells. Cancer Res 67:5397-407, 2007. [abstract]

• Partridge MA, Huang SX, Hernandez-Rosa E, Davidson MM and Hei TK. Arsenic induced mitochondrial DNA damage and altered mitochondrial oxidative function: implications for genotoxic mechanisms in mammalian cells. Cancer Res 67:5239-47, 2007. [abstract]

• Xu A, Huang X, Lien YC, Bao L, Yu Z and Hei TK. Genotoxic mechanisms of asbestos fibers: role of extranuclear targets. Chem Res Toxicol 20:724-33, 2007. [abstract]

• Xu A, Smilenov LB, He P, Masumura K, Nohmi T, Yu Z and Hei TK. New insight into intrachromosomal deletions induced by chrysotile in the gpt delta transgenic mutation assay. Environ Health Perspect 115:87-92, 2007. [abstract]

• Zhou H, Xu A, Gillispie JA, Waldren CA and Hei TK. Quantification of CD59- mutants in human-hamster hybrid (AL) cells by flow cytometry. Mutat Res 594:113-9, 2006. [abstract]

• Ivanov VN and Hei TK. Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression. Exp Cell Res 312:4120-38, 2006. [abstract]

• Jin YJ, Wang J, Qiao C, Hei TK, Brandt-Rauf PW and Yin Y. A novel mechanism for p53 to regulate its target gene ECK in signaling apoptosis. Mol Cancer Res 4:769-78, 2006. [abstract]

• Zhao Y, El-Gabry M and Hei TK. Loss of Betaig-h3 protein is frequent in primary lung carcinoma and related to tumorigenic phenotype in lung cancer cells. Mol Carcinog 45:84-92, 2006. [abstract]

• Hei TK, Xu A, Huang SX and Zhao Y. Mechanism of fiber carcinogenesis: from reactive radical species to silencing of the beta igH3 gene. Inhal Toxicol 18:985-90, 2006. [abstract]

• Hei TK. Cyclooxygenase-2 as a signaling molecule in radiation-induced bystander effect. Mol Carcinog 45:455-60, 2006. [abstract]

• Roy D, Calaf GM, Hande MP and Hei TK. Allelic imbalance at 11q23-q24 chromosome associated with estrogen and radiation-induced breast cancer progression. Int J Oncol 28:667-74, 2006.[abstract]

• Shao G, Berenguer J, Borczuk AC, Powell CA, Hei TK and Zhao Y. Epigenetic inactivation of Betaig-h3 gene in human cancer cells. Cancer Res. 66:4566-73, 2006. [abstract]

• Ivanov VN and Hei TK. Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells. Exp. Cell Res. 312:1401-17, 2006. [abstract]

• Ivanov VN, Ronai Z and Hei TK. Opposite roles of FAP-1 and dynamin in the regulation of Fas (CD95) translocation to the cell surface and susceptibility to Fas ligand-mediated apoptosis. J. Biol. Chem. 281:1840-52, 2006. [abstract]

• Calaf GM, Roy D and Hei TK. Growth factor biomarkers associated with estrogen- and radiation-induced breast cancer progression. Int J Oncol 28:87-93, 2006. [abstract]

• Persaud R, Zhou H, Baker SE, Hei TK and Hall EJ. Assessment of low linear energy transfer radiation-induced bystander mutagenesis in a three-dimensional culture model. Cancer Res. 65:9876-82, 2005. [abstract]

• Zhou H, Ivanov VN, Gillespie J, Geard CR, Amundson SA, Brenner DJ, Yu Z, Lieberman HB and Hei TK. Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway. Proc. Natl. Acad. Sci. USA 102:14641-6, 2005. [abstract]

• Liu SX, Davidson MM, Tang X, Walker WF, Athar M, Ivanov V, and Hei TK. Mitochondrial damage mediates genotoxicity of arsenic in mammalian cells. Cancer Research 65:3236-42, 2005. [abstract]

• Ivanov VN and Hei TK. Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene 24:616-26, 2005. [abstract]

• Piao CQ, Liu L, Zhao YL, Balajee AS, Suzuki M, and Hei TK. Immortalization of human small airway epithelial cells by ectopic expression of telomerase. Carcinogenesis 26:725-31, 2005. [abstract]

• Hei TK and Filipic M. Role of oxidative damage in the genotoxicity of arsenic. Free Radic Biol Med 37:574-81, 2004. Review. [abstract]

• Ivanov V and Hei TK. Arsenic sensitizes human melanomas to apoptosis via tumor necrosis factor alpha-mediated pathways. Journal of Biological Chemistry 279:22747-22758, 2004. [abstract]

• Bhar HK, Calaf G, Hei TK, Loya T, and Vadgama JV. Critical role of oxidative stress in estrogen induced carcinogenesis. Proc. National Academy Science U.S.A. 100:3913-3918 (2003). [abstract]

• Zhou H, Suzuki M, Randers-Pehrson G, Vannais D, Chen G, Trosko JE, Waldren CA, Hei TK. Radiation risk to low fluences of alpha particles may be greater than we thought. Proc Natl Acad Sci USA. 98(25):14410-14415 (2001). [abstract]

• Liu SX, Athar M, Lippai I, Waldren C, Hei TK. Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity. Proc Natl Acad Sci USA. 98(4):1643-1648 (2001). [abstract]

• Zhou H, Randers-Pehrson G, Waldren CA, Vannais D, Hall EJ, Hei TK. Induction of a bystander mutagenic effect of alpha particles in mammalian cells. Proc Natl Acad Sci USA. 97(5):2099-21104 (2000). [abstract]

• Wu LJ, Randers-Pehrson G, Xu A, Waldren CA, Geard CR, Yu Z, Hei TK. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci USA. 96(9):4959-4964 (1999). [abstract]

• Hei TK, Liu SX, Waldren C. Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species. Proc Natl Acad Sci USA. 95(14):8103-8107 (1998). [abstract]

• Hei TK, Wu LJ, Liu SX, Vannais D, Waldren CA, Randers-Pehrson G. Mutagenic effects of a single and an exact number of alpha particles in mammalian cells. Proc Natl Acad Sci USA. 94(8):3765-3770 (1997). [abstract]

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