Summary
Dr. Michael Karin's project studies how Superfund toxicants and mixtures thereof increase liver cancer risk. Project efforts will focus on specific progenitor cells responsible for generation of hepatocellular carcinoma (HCC), the most common form of liver cancer, in mice administered diethylnitrosamine (DEN), an hepatocarcinogen that represents the nitrosamine class of Superfund substances. DEN and its relative DMN undergo metabolic activation in the liver and give rise to HCC through induction of genetic alterations and compensatory proliferation that is triggered by hepatocyte cell death. We will characterize HCC initiating cells (HIC) isolated from livers of DEN-treated mice before tumors are detectable and use them to identify marker genes and genetic and epigenetic alterations that distinguish HIC from normal, non-tumorigenic, hepatocytes and fully transformed HCC cells. We will determine whether the same gene set is activated in HIC from mutant mice that spontaneously develop HCC and investigate whether signaling pathways, whose ablation augments HCC development, affect the appearance, growth and progression of HIC. We will also examine whether obesity, which increases HCC risk in humans and acts as a tumor promoter in mice, accelerates the appearance and growth of HIC and affects expression of HIC signature genes. Similar experiments will be conducted with Superfund substances that act as liver tumor promoters, such as carbon tetrachloride, polychlorinated biphenyls (PCBs) and the nuclear receptor CAR, which mediates their biological effects. We will examine whether such chemicals, alone or in combination with DEN, affect HIC formation and growth. These studies will result in identification of genetic, epigenetic and cellular programs responsible for induction and development of HCC.
This knowledge and information will serve as the foundation for a new approach to rapid assessment of the hepatocarcinogenicity of diverse substances and mixtures found at Superfund sites.Also, we will work with the Research Translation Core and Community Engagement Core to share our findings pertinent to tumor promotion and obesity. High levels of obesity are a problem in Tribal and low-income border communities (the vulnerable populations targeted by our SRP). These vulnerable communities may face greater risks to their health when obesity is coupled with exposure to Superfund toxicants, a point we can help the RTC and CEC communicate to broader audiences.
Publications
Chen, S., Lu, W., Yueh, M.-F., Rettenmeier, E., Liu, M., Auwerx, J., Yu, R.T., Evans, R.M., Wang, K., Karin, M., Tukey, R.H. (2017) Intestinal NCoR1, a newly discovered regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia. Proc. Nat. Acad. Sci. USA.114:E1432-E1440. doi: 10.1073/pnas.1700232114.
Moscat, J., Karin, M., Diaz-Meco, M.T. (2016) p62 in Cancer: Signaling Adaptor Beyond Autophagy. Cell. 167:606-609. doi:10.1016/j.cell.2016.09.030.
Duran, A., Hernandez, E.H, Reina-Campos, M, Castilla, E.A., Subramaniam, S., Raghunandan, S., Roberts, L.R., Kisseleva, T., Karin, M., Diaz-Meco, M.T., Moscat, J. (2016) p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis and liver cancer. Cancer Cell. 30:595-609. doi: 10.1016/j.ccell.2016.09.004.
Taniguchi, K., Yamachika, S., He, F., Karin, M. (2016) p62/SQSTM1- Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Lett. 590:2375-97.doi: 10.1002/1873-3468.12301.
Lee, J.H., Cho, U.S., Karin, M. (2016) Sestrin regulation of TORC1: Is Sestrin a leucine sensor? Sci Signal. 9:re5. doi: 10.1126/scisignal.aaf2885.
Umemura, A., He, F., Nakagawa, H., Yamachika, S., Taniguchi, K., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., Linares, J.F., Reina-Campos, M., Valasek, M.A., Seki, E., Yamaguchi, K., Koike, K., Itoh, Y., Diaz-Meco, M.T., Moscat, J., Karin, M. (2016) p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell. 29:935-48. doi: 10.1016/j.ccell.2016.04.006.
Karin, M., Dhar, D. (2016) Liver Carcinogenesis: From Naughty Chemicals to Soothing Fat- and the Suprising Role of NRF2. Carcinogenesis. 37:541-6. doi: 10.1093/carcin/bgw060.
Zhong, Z., Umemura, A., Sanchez-Lopez, E., Liang, S., Shalapour, S., Wong, J., He, F., Boassa, D., Perkins, G., Ali, S. R., McGeough, M. D., Ellisman, M. H., Seki, E., Gustafsson, A. B., Hoffman, H. M., Diaz-Meco, M. T., Moscat, J., Karin, M. (2016) NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell. 164(5):896-910. doi: 10.1016/j.cell.2015.12.057.
Clevers H., Karin M. (2016) Reparative Inflammation Takes Charge of Tissue Regeneration. Nature. 529:307-15. doi: 10.1038/nature17039.
Finkin, S., Yuan, D., Stein, I., Taniguchi, K., Weber, A., Unger, K., Browning, J. L., Goossens, N., Nakagawa, S., Gunasekaran, G., Schwartz, M. E., Kobayashi, M., Kumada, H., Berger, M., Pappo, O., Rajewsky, K., Hoshida, Y., Karin, M., Heikenwalder, M., Ben-Neriah, Y., Pikarsky, E. (2015) Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 16(12):1235-44. doi: 10.1038/ni.3290.
Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. (2015) Antonucci, L., Fagman, J. B., Kim, J. Y., Todoric, J., Gukovsky, I., Mackey, M., Ellisman, M. H., Karin, M. Proc Natl Acad Sci U S A. 112(45), E6166-74. doi: 10.1073/pnas.1519384112.
Font-Burgada, J., Shalapour, S., Ramaswamy, S., Hsueh, B., Rossell, D., Umemura, A., Taniguchi, K., Nakagawa, H., Valasek, M. A., Ye, L, Kopp, J. L., Sander, M., Carter, H., Deisseroth, K., Verma, I. M., Karin, M. (2015) Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell. 162(4), 766-79. doi: 10.1016/j.cell.2015.07.026.
Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y. C., Akopiants, K., Guan, K. L., Karin, M., Budanov, A. V. (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 9(4), 1281-91. doi: 10.1016/j.celrep.2014.10.019
Yueh, M. F., Taniguchi, K., Chen, S., Evans, R. M., Hammock, B. D., Karin, M., Tukey, R. H. (2014) The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci USA. 111(48):17200-5. doi: 10.1073/pnas.1419119111.
Nakagawa, H., Umemura, A., Taniguchi, K., Font-Burgada, J., Dhar, D., Ogata, H., Zhong, Z., Valasek, M. A., Seki, E., Hidalgo, J., Koike, K., Kaufman, R. J., Karin, M. (2014) ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 26(3), 331-43. doi: 10.1016/j.ccr.2014.07.001.
Inokuchi-Shimizu, S., Park, E. J., Roh, Y. S., Yang, L., Zhang, B., Song, J., Liang, S., Pimienta, M., Taniguchi, K., Wu, X., Asahina, K., Lagakos, W., Mackey, M. R., Akira, S., Ellisman, M. H., Sears, D. D., Olefsky, J. M., Karin, M., Brenner, D. A., Seki, E. (2014) ETAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest. 124(8), 3566-78. doi: 10.1172/JCI74068.
Umemura, A., Park, E. J., Taniguchi, K., Lee, J. H., Shalapour, S., Valasek, M. A., Aghajan, M., Nakagawa, H., Seki, E., Hall, M. N., Karin, M. (2014) Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. doi: 10.1016/j.cmet.2014.05.001.
Dhar, D., Seki, E., Karin, M. (2014) NCOA5, IL-6, type 2 diabetes, and HCC: The deadly quartet. Cell Metab. 19(1), 6-7. doi: 10.1016/j.cmet.2013.12.010.
Moles, A., Murphy, L., Wilson, C. L., Chakraborty, J. B., Fox, C., Park, E. J., Mann, J., Oakley, F., Howarth, R., Brain, J., Masson, S., Karin, M., Seki, E., Mann, D. A. (2014) A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. J Hepatol. 60(4), 782-91.
Chen, S., Yueh, M. F., Bigo, C., Barbier, O., Wang, K., Karin, M., Nguyen, N., Tukey, R. H. (2013) Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc Natl Acad Sci USA. 110,19143-19148. doi: 10.1073/pnas.1319123110.
He, G., Dhar, D., Nakagawa, H., Font-Burgada, J., Ogata, H., Jiang, Y., Shalapour, S., Seki, E., Yost, S. E., Jepsen, K., Frazer, K. A., Harismendy, O., Hatziapostolou, M., Iliopoulos, D., Suetsugu, A., Hoffman, R. M., Tateishi, R., Koike, K., Karin, M. (2013) Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 155(2), 384-96. doi: 10.1016/j.cell.2013.09.031.
Du, H., Sun, X., Guma, M., Luo, J., Ouyang, H., Zhang, X., Zeng, J., Quach, J., Nguyen, D. H., Shaw, P. X., Karin, M., Zhang, K. (2013) JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Natl Acad Sci USA. 110(6), 2377-82. doi: 10.1073/pnas.1221729110.
Sakurai, T., Kudo, M., Umemura, A., He, G., Elsharkawy, A. M., Seki, E., Karin, M. (2013) p38α inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res. 73(1), 215-24. doi: 10.1158/0008-5472.CAN-12-1602.
Yu, G. Y., He, G., Li, C. Y., Tang, M., Grivennikov, S., Tsai, W. T., Wu, M. S., Hsu, C. W., Tsai, Y., Wang, L. H., Karin, M. (2012) Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production. Mol Cell. 48(2), 313-21. doi: 10.1016/j.molcel.2012.07.032.
Lee, J. H., Budanov, A. V., Talukdar, S., Park, E. J., Park, H. L., Park, H. W., Bandyopadhyay, G., Li, N., Aghajan, M., Jang, I., Wolfe, A. M., Perkins, G. A., Ellisman, M. H., Bier, E., Scadeng, M., Foretz, M., Viollet, B., Olefsky, J., Karin, M. (2012) Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab. 16(3), 311-21. doi: 10.1016/j.cmet.2012.08.004.
Seki, E., Brenner, D. A., Karin, M. (2012) A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 143(2), 307-20. doi: 10.1053/j.gastro.2012.06.004.
Font-Burgada, J., Seki, E., Karin, M. (2012) CYLD and HCC: when being too sensitive to your dirty neighbors results in self-destruction. Cancer Cell. 21(6), 711-2.
Sun, B., Karin, M. (2012) Obesity, inflammation, and liver cancer. J Hepatol. 56(3), 704-13. doi: 10.1016/j.jhep.2011.09.020.
Fujiwara, R., Chen, S., Karin, M., Tukey, R. H. (2012) Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia. Gastroenterology. 142(1), 109-118.
Holzer, R. G., Park, E. J., Li, N., Tran, H., Chen, M., Choi, C., Solinas, G., Karin, M. (2011) Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell. 147(1), 173-84. doi: 10.1016/j.cell.2011.08.034.
Österreicher, C.H., Penz-Österreicher, M., Grivennikov, S. I., Guma, M., Koltsova, E. K., Datz, C., Sasik, R., Hardiman, G., Karin, M., Brenner, D. A., (2011) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc Natl Acad Sci USA. 108(1), 308-13. doi: 10.1073/pnas.1017547108.
Budanov, A. V., Lee, J. H., Karin, M. (2010) Stressin' sestrins take an aging fight. EMBO Mol Med. 2(10), 388-400. doi: 10.1002/emmm.201000097.
Lee, J. H., Bodmer, R., Bier, E., Karin, M. (2010) Sestrins at the crossroad between stress and aging. Aging (Albany NY). 2(6), 369-74. doi: 10.18632/aging.100157
He, G., Yu, G. Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., Sieghart, W., Peck-Radosavlijevic, M., Leffert, H. L., Karin, M. (2010) Hepatocyte IKKB/NF-KB inhibits tumor promotion and progression by preventing oxidative stress driven STAT3 activation. Cancer Cell. 17(3), 286-297. doi: 10.1016/j.ccr.2009.12.048.
Lee, J. H., Budanov, A. V., Park, E. J., Birse, R., Kim, T. E., Perkins, G. A., Ocorr, K., Ellisman, M. H., Bodmer, R., Bier, E., Karin, M. (2010) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science. 327(5970),1223-8. doi: 10.1126/science.1182228.
Park, E., Lee, J., Yu, G. Y., He, G., Ali, S., Holzer, R., Osterreicher, C., Takahashi, H., Karin, M. (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 140, 197-208. doi: 10.1016/j.cell.2009.12.052.
Takahashi, H., Ogata, H., Nishigaki, R., Broide, D. H., Karin, M. (2010) Tobacco smoke promotes lung tumorigenesis by triggering IKKb and JNK1 dependent inflammation. Cancer Cell. 17, 89-97. doi: 10.1016/j.ccr.2009.12.008.
Koch, K. S., Maeda, S., He, G., Karin, M., Leffert, H. L. (2009) Targeted deletion of hepatocyte IKKβ; confers growth advantages. Biochem Biophys Res Commun. 380, 349-354. doi: 10.1016/j.bbrc.2009.01.085.
Budanov, A. V., Karin, M. (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 134(3), 451-60. doi: 10.1016/j.cell.2008.06.028.
Naugler, W. E., Karin, M. (2008) NF-KappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 18(1), 19-26. doi: 10.1016/j.gde.2008.01.020.
Sakurai, T., Maeda, S., Chang, L., Karin, M. (2006) Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci USA. 103(28),10544-51. doi: 10.1073/pnas.0603499103
Maeda, S., Kamata, H., Luo, J. L., Leffert, H., Karin, M. (2005) IKKbeta; Couples Hepatocyte Cell Death to Cytokine-driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis. Cell. 121, 977-990. doi: 10.1016/j.cell.2005.04.014
Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., Karin, M. (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 120, 649-61. doi: 10.1016/j.cell.2004.12.041.
Valledor, A. F., Hsu, L. C., Ogawa, S., Sawka-Verhelle, D., Karin, M., Glass, C. K. (2004) Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc Natl Acad Sci USA. 101(51), 17813-8. doi: 10.1073/pnas.0407749101
Greten, F. R., Eckmann, L., Greten, T. F., Park, J. M., Li, Z. W., Egan, L. J., Kagnoff, M. F., Karin, M. (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 118(3), 285-96. doi: 10.1016/j.cell.2004.07.013
Bonizzi, G., Karin, M. (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25(6), 280-8. doi: 10.1016/j.it.2004.03.008
Galijatovic, A., Beaton, D., Nguyen, N., Chen, S., Bonzo, J., Johnson, R., Maeda, S., Karin, M., Guengerich, F. P., Tukey, R. H. (2004) The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice. J Biol Chem. 279(23), 23969-76. doi: 10.1074/jbc.M400973200
Maeda, S., Chang, L., Li, Z. W., Luo, J. L., Leffert, H., Karin, M. (2003) IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity. 19(5), 725-37. doi: 10.1016/S1074-7613(03)00301-7.
Li, Z. W., Omori, S. A., Labuda, T., Karin, M., Rickert, R. C. (2003) IKK beta is required for peripheral B cell survival and proliferation. J Immunol. 170(9), 4630-7. doi: 10.4049/jimmunol.170.9.4630.
Chen, S., Nguyen, N., Tamura, K., Karin, M., Tukey, R. H. (2003) The role of the Ah receptor and p38 in benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis. J Biol Chem. 278(21), 19526-33. doi: 10.1074/jbc.M300780200.
Park, J. M., Greten, F. R., Li, Z. W., Karin, M. (2002) Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science. 297(5589), 2048-51. doi: 10.1126/science.1073163
Main Contact Information
Project Leader
- Dr. Michael Karin
Superfund Related Project Members
- Ju Youn Kim, Post-Doctoral Scholar
- Anne Chang, Lab Manager
Other UCSD Superfund Projects:
Resources
UCSD Health Sciences, Center for Immunity, Infection, & Inflammation
UCSD Biomedical Sciences Gradaute Program
Phone: 858-534-1361
Fax: 858-534-8158
E-mail: karinoffice@ucsd.edu
Contact
UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722
Supporting Partners
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