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Chronic viral hepatitis is one of the major causes of liver disease, and represents a critical risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). An important theme of our research is to identify molecular changes that occur with HCC development, and thus might serve as biomarkers for the early detection of disease. One candidate biomarker for HCC is the normal golgi resident protein GP73 (green in figure). We have found that pro-inflammatory cytokines IL-6 and oncostatin M can increase GP73 expression in cells of human liver cancer origin; levels of both cytokines are positively correlated with GP73 levels in people with liver disease. We also have been investigating the causes and consequences of hyperfucosylation of many liver-derived glycoproteins that appear in the circulation of individuals with HCC. A second HCC-related change in glycosylation is an increase in the production of highly branched structures in tumor but not nearby non-tumor tissue. The roles of these altered glycoforms are as yet poorly understood, but they represent potentially important biomarkers for early detection of disease. We have been investigating the relationship between these disease-related changes and hepatocyte dedifferentiation.

The devastating consequences of chronic HBV infection compel efforts to develop novel antiviral drugs. The drugs that are currently available target the viral polymerase or the host immune system (interferon). We have been characterizing members of a novel class of antiviral agents based on modifications of the prototype imino sugar deoxynojirimycin. The imino sugars inhibit host glucosidases in the endoplasmic reticulum by interfering with correct N-glycan processing. Certain viral glycoproteins such as the HBV MHBs and LHBs proteins have a strong requirement for correct N-glycosylation for secretion, and imino sugars can selectively reduce virus secretion. In addition, blocking secretion results in increased intracellular degradation of viral protein by the protoeasome, leading to enhanced presentation of antigenic peptides by MHC-I in a cell culture based assay. One imino sugar was tested in vivo against the related woodchuck hepatitis virus in conjunction with therapeutic vaccination to test the hypothesis that increased antigen presentation will enhance vaccination efficacy. An exciting outcome of this study was the finding that drug treatment enhanced the cellular immune response to viral antigens. This drug-induced response was associated with reactivity to novel epitopes generated by de-N-glycosylation prior to proteasomal processing and presentation. The ability of certain imino sugars to augment epitope presentation by MHC class I in cultured cells suggests a possible role for these compounds in stimulating the production of virus-specific cytolytic CD8+ T cells.

Selected Research Publications

Norton, PA and Mehta, AS
World J. Gastroenterol. 25:2947-2960. doi: 10.3748/wjg.v25.i23.2947 (2019)

Jacobs, NR and Norton, PA
World J. Hepatol. 13:662-672. doi: 10.4254/wjh.v13.i6.662 (2021)

Norton PA, Comunale MA, Herrera H, Wang MJ, Houser J,  Wimmerova M, Romano PR, and Mehta A
Proteomics 16:3126, 2016

Mehta A, Comunale MA, Rawat, S, Casciano, JC, Lamontagne, J, Herrera H, Ramanathan A, Betesh L, Wang M, Norton P, Steel L and M Bouchard
Scientific Rep. 6:27965, 2016. (doi: 10.1038/srep27965)

Liang H, Block TM, Wang M, Nefsky B, Long R, Hafner J, Mehta AS, Marrero J, Gish R, and PA Norton
Cancer Biomarkers, 11:161-71, 2012

Mehta A, Norton P, Liang H, Comunale MA, Wang M, Rodemich-Betesh L, Koszycki A, Noda K, Miyoshi E, and T Block
Cancer Epidemiol. Biomarkers Prev., 21: 925-933, 2012

Comunale MA, Rodemich-Betesh L, Hafner J, Wang M, Norton P, Di Bisceglie AM, Block T and A Mehta
PLoS One 5, e12419, 2010

Norton PA, Menne S, Sinnathamby G, Betesh L, Cote PJ, Philip R, Mehta AS, Tennant BC and TM Block
Hepatology, 52: 1242-1250, 2010

Simsek E, Sinnathamby G, Block TM, Liu Y, Philip R, Mehta AS, and PA Norton
Virology, 384:12-15, 2009

Liu Y, Simsek E, Norton P, Sinnathamby G, Philip R, Block TM, Zhou T, and AS Mehta
Virology, 365: 10-19, 2007

Norton PA, Comunale MA, Krakover J, Rodemich L, Pirog N, D'Amelio A, Philip R, Mehta AS, and TM Block
J. Cell. Biochem., 104:136-149, 2007

Dougherty AM., Guo H, Westby G, Liu Y, Simsek E, Guo J-T, Mehta A, Norton P, Gu B, Block TM, and A Cuconati
Antimicrob. Agents Chemother., 51:4427-4437, 2007

Norton PA, Conyers B, Gong Q, Steel LF, Block TM, and AS Mehta
J. Virol. Methods, 124: 167-172, 2005

Norton PA, Reis HMGPV, Prince S, Larkin J, Pan J, Liu J, Gong Q, Zhu M, and MA Feitelson
J. Viral. Hep., 11: 332-341, 2004.

Norton PA, Gong Q, Mehta AS, Lu X, and TM Block
J. Virol., 77: 5503-5506, 2003

Wu J, Liu S-L, Zhu JL, Norton PA, Nojiri S, Hoek JB, and MA Zern
J. Biol. Chem., 275: 22213-22219, 2000