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United States Department of Agriculture

Agricultural Research Service

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Location: Jean Mayer Human Nutrition Research Center On Aging

2011 Annual Report

1a. Objectives (from AD-416)
LAB: VITAMINS & CARCINOGENESIS 1. To define the role that availability of each of the one-carbon nutrients plays in determining the risk of common cancers and to determine the nature of the interactions between these nutrients in this regard. 2. Determine how genetic differences interact with dietary antagonists of one-carbon nutrients in determining cancer risk. (PDRAM NAA09). LAB: NUTRITION & CANCER 1. Determine whether high fat diet induced non-alcoholic steatohepatitis is a promoting factor in hepatic carcinogenesis. 2. Determine whether dietary lycopene will protect against high fat diet promoted liver cancer development.

1b. Approach (from AD-416)
LAB: VITAMINS & CARCINOGENESIS Appropriate alterations in dietary and nutritional habits have an important role to play in cancer prevention. The nutrients involved in one-carbon metabolism (methionine, choline and the B-vitamins, folate, B12, B6, and B2) have drawn considerable attention in this regard and are the focus of this laboratory. Our mission is to examine the complex roles that these nutrients play in modifying metabolic and genetic pathways that lead to human carcinogenesis and thereby define the means by which cancers can be nutritionally prevented. The program of research emphasizes how these dietary compounds interact with genetic background to modify molecular and signaling pathways which alter the development of cancers and to examine how other exogenous factors, such as alcohol consumption also play a role. The laboratory focuses on colorectal cancer and breast cancer and utilizes animal studies, cell culture studies, and human studies to accomplish our research goals. LAB: NUTRITION & CANCER We will use both high fat diet-induced nonalcoholic steatohepatitis (NASH) rats and genetically-induced obese mice with injections of liver-specific carcinogen, diethylnitrosamine, followed by treatment with tomato extract or lycopene for both short and long durations. We will focus on the role of the stress-activated protein c-Jun-NH2-kinase (JNK) signaling, a key component mediating the high fat-induced oxidative stress and inflammatory processes, in response to tomato extract and lycopene supplementation on both cell proliferation/apoptosis, inflammation and premalignant and malignant lesions in obesity related hepatic tumorigenesis. We will complement animal study with cell culture studies (e.g., use siRNA silencing of JNK) using human hepatocyte lines and liver cancer cells to facilitate mechanistic studies to determine the contribution of the JNK signaling pathway to lycopene action. Since adiposity contributes to the increased incidence and/or death from liver cancer, we will examine metabolic alteration, including insulin resistance, and pro-inflammatory signaling in intra-abdominal fat tissue and its potential contribution to hepatic carcinogenesis. Once we establish that there is an association between metabolic alteration and hepatic carcinogenesis, we will examine insulin and insulin growth factors (IGF-I/IGF-II) signaling cascades and address their differential activation in NASH and its related hepatic carcinogenesis, as well as potential actions of tomato extract and lycopene prevention against the onset of high fat diet/obesity-related liver disease.

3. Progress Report
This progress report includes the work of two subordinate projects at the HNRCA funded through a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information and progress report, see 1950-51000-074-01S (One-Carbon Nutritients in the Prevention of Cancer) and 1950-51000-074-02S (Nutritional Determinants of Non-Alcholoic Steatohepatitis in Hepatic Carcinogenesis).

4. Accomplishments

Review Publications
Flood, A., Mason, J., Liu, Z., Cash, B., Schatzkin, A., Schoenfeld, P., Cross, A. 2011. Concentration of folate in colorectal tissue biopsies predicts prevalence of adenomatous polyps. Gut. 60(1):66-72.

Choi, S.W., Friso, S. 2010. Epigenetics: a new bridge between nutrition and health. Advances in Nutrition. 1:8-16.

Chung, J., Sudipta, V., Chun, L., Russell, R.M., Wang, X., Heather, H. 2010. Vitamin E supplementation does not prevent ethanol-reduced hepatic retinoic acid levels in rats. Nutrition Research. 29(9):664-670.

Marian, C., Tao, M., Mason, J., Goerlitz, D., Nie, J., Chanson, A., Freudenheim, J., Shields, P. 2011. Single nucleotide polymorphisms in uracil-processing genes, intake of one-carbon nutrients and breast cancer risk. European Journal of Clinical Nutrition. 65(6):638-639.

Kim, K., Jang, H., Zimmerly, E., Liu, Z., Chason, A., Smith, D., Frisco, S., Choi, S. 2011. Folate supplementation differently affects uracil content in DNA in the mouse colon and liver. British Journal of Nutrition. 105(5):688-693.

Sauer, J.A., Hyeran, J., Zimmerly, E., Kim, K., Liu, Z., Chason, A., Smith, D., Mason, J., Friso, S., Choi, S.W. 2010. Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon. British Journal of Nutrition. 104(1):24-30.

Zhang, Y., Lian, F., Zhu, Y., Xia, M., Wang, Q., Ling, W., Wang, X. 2010. Cyanidin-3-O-beta-glucoside inhibits LPS-induced expression of inflammatory mediators through decreasing IkBa Phosphorylation in THP-1 Cells. Inflammation Research. 59(9):723-730.

Mein, J., Dolnikowski, G., Hansgeorg, E., Russel, R., Wang, X. 2011. Enzymatic formation of apo-carotenoids from the xanthophyll carotenoids lutein, zeaxanthin and b-cryptoxanthin by ferret carotene-9, 10-monooxygenase. Archives Of Biochemistry and Biophysics. 506:109-121 PMID 21081106.

Luvizotto, R., Nascimento, A., Veeramachnei, S., Liu, C., Wang, X. 2010. Chronic alcohol intake up-regulates hepatic expressions of carotenoid cleavage enzymes and peroxisomal proliferator-activated receptors in rats. Journal of Nutrition. 140(10):1808-1814. PMID 20702748.

Chavez, P., Chung, J., Liu, C., Paiva, S., Seitz, H., Wang, X., Lian, F. 2011. Long term ethanol consumption promotes hepatic tumorigenesis but impairs normal hepatocyte proliferation in rats. Journal of Nutrition. 141(6):1049-1055 PMID 21490289.

Last Modified: 10/18/2017
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