Effects of Superfund Toxicants on Liver Cancer Progenitor Cells

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.

Publication

PubMed Central ID: 

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. 2016 Feb 25;164(5):896-910. doi: 10.1016/j.cell.2015.12.057

PubMedID: 26919428
PubMed Central ID: 

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.

PubMedID: 26502405
PubMed Central ID: 

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.

PubMedID: 26512112
PubMed Central ID: 

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.

PubMedID: 26276631
PubMed Central ID: 

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.

PubMedID: 25457612
PubMed Central ID: 

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.

PubMedID: 25404284
PubMed Central ID: 

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.

PubMedID: 25132496
PubMed Central ID: 

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.

PubMedID: 24983318
PubMed Central ID: 

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.

PubMedID: 24910242
PubMed Central ID: 

Dhar, D., Seki, E., Karin, M. (2014) NCOA5, IL-6, type 2 diabetes, and HCC: The deadly quartet. Cell Metab. 19(1), 6-7.

PubMedID: 24411937
PubMed Central ID: 

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.

PubMedID: 24333183
PubMed Central ID: 

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. 

PubMedID: 24191041
PubMed Central ID: 

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.

PubMedID: 24120137
PubMed Central ID: 

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.

PubMedID: 23341606
PubMed Central ID: 

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.

PubMedID: 23271722
PubMed Central ID: 

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.

PubMedID: 22959272
PubMed Central ID: 

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.

PubMedID: 22958918
PubMed Central ID: 

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.

PubMedID: 22705006

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.

PubMedID: 22698394
PubMed Central ID: 

Sun, B., Karin, M. (2012) Obesity, inflammation, and liver cancer. J Hepatol. 56(3), 704-13.

PubMedID: 22120206
PubMed Central ID: 

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.

PubMedID: 21983082
PubMed Central ID: 

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

PubMedID: 21962514
PubMed Central ID: 

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.

PubMedID: 21173249
PubMed Central ID: 

Budanov, A. V., Lee, J. H., Karin, M. (2010) Stressin' sestrins take an aging fight. EMBO Mol Med. 2(10), 388-400.

PubMedID: 20878915
PubMed Central ID: 

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.

PubMedID: 20606249
PubMed Central ID: 

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.

PubMedID: 20227042
PubMed Central ID: 

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.

PubMedID: 20203043
PubMed Central ID: 

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.

PubMedID: 20141834
PubMed Central ID: 

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.

PubMedID: 20129250
PubMed Central ID: 

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. 

PubMedID: 19171122
PubMed Central ID: 

Budanov, A. V., Karin, M. (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 134(3), 451-60.

PubMedID: 18692468
PubMed Central ID: 

Naugler, W. E., Karin, M. (2008) NF-KappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 18(1), 19-26.

PubMedID: 18440219
PubMed Central ID: 

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.

PubMedID: 16807293

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.

PubMedID: 15989949

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.

PubMedID: 15766528
PubMed Central ID: 

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.

PubMedID: 15601766

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.

PubMedID: 15294155

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.

PubMedID: 15145317

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.

PubMedID: 15037607

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.

PubMedID: 14614859

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.

PubMedID: 12707341

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.

PubMedID: 12637498

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.

PubMedID: 12202685

Main Contact Information

Project Leader

  • Dr. Micheal Karin

Superfund Related Project Members

  • Ju Youn Kim, Post-Doctoral Scholar
  • Anne Chang, Lab Manager
  • Esther Hsueh, Lab Assistant

Other UCSD Superfund Projects:

Administrative Core

Resources

UCSD Pharmacology Department

UCSD Health Sciences, Center for Immunity, Infection, & Inflammation

UCSD Biomedical Sciences Gradaute Program

UCSD Molecular Pathology, PhD Program

References From PubMed (NCBI)

                                                                                                                                                                                                     

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