Diethylnitrosamine (DEN) induces irreversible hepatocellular carcinogenesis through overexpression of G(1)/S-phase regulatory proteins in rat

Hepatocellular carcinoma (HCC) is the fifth most frequent cause of cancer deaths in males and was the third most frequent cause of cancer deaths in 2007 throughout the world. The incidence rate is 2-3 times higher in developing countries than in developed countries. Animal models have enabled study of the mechanism of HCC and the development of possible strategies for treatment. Diethylnitrosamine (DEN) is a representative chemical carcinogen with the potential to cause tumors in various organs, including the liver, skin, gastrointestinal tract, and respiratory system Specifically in HCC, DEN is a complete carcinogen. Many lines of evidence have demonstrated a relationship between carcinogenesis and cell cycle regulation. In this study we found that cell cycle regulatory proteins were critically involved in cancer initiation and promotion by DEN. Cyclin D1. cyclin E, cdk4. and p21(CIP1/WAF1) I are factors whose expression levels may be useful as criteria for the classification of hepatic disease. In particular, cdk4 had a pivotal role in the transition to the neoplastic stage. In conclusion. we suggest that changes in the level of cdk4 may be useful as a biomarker for detection of HCC. (C) 2009 Elsevier Ireland Ltd. All rights reservedChang JJ, 2008, MOL CELL TOXICOL, V4, P278Sell S, 2008, TUMOR BIOL, V29, P161, DOI 10.1159/000143402*AM CANC SOC, 2007, GLOB CAN FACTS FIG 2Kim MR, 2005, EXP MOL MED, V37, P335LI X, 2005, HEPATOB PANCREAT DIS, V4, P427Masaki T, 2003, HEPATOLOGY, V37, P534, DOI 10.1053/jhep.2003.50112Pascale RM, 2002, HEPATOLOGY, V35, P1341, DOI 10.1053/jhep.2002.33682Masaki T, 2000, HEPATOLOGY, V32, P711, DOI 10.1053/jhep.2000.17705Perez-Roger I, 1999, EMBO J, V18, P5310Johnson PJ, 1999, J GASTROEN HEPATOL, V14, pS32Verna L, 1996, PHARMACOL THERAPEUT, V71, P57SHERR CJ, 1994, CELL, V79, P551HUNTER T, 1994, CELL, V79, P573HUNTER T, 1991, CELL, V66, P1071PITOT HC, 1991, ENVIRON HEALTH PERSP, V93, P181DRAGAN YP, 1991, PREV MED, V20, P15XU YH, 1990, CANCER RES, V50, P472BEER DG, 1987, ARCH TOXICOL S, V10, P68RAO MS, 1986, CANCER RES, V46, P5287FARBER E, 1984, CANCER RES, V44, P4217WARD JM, 1981, VIRCHOWS ARCH A, V390, P339COHEN AH, 1976, J CLIN PATHOL, V65, P631ANDERSEN P, 1976, CLIN EXP IMMUNOL, V26, P57