Effects of Excretory/Secretory Products from Clonorchis sinensis and the Carcinogen Dimethylnitrosamine on the Proliferation and Cell Cycle Modulation of Human Epithelial HEK293T Cells
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Clonorchis sinensis is one of the most prevalent parasitic helminths in Korea. Although cholangiocarcinoma can be induced by C. sinensis infection, the underlying mechanism is not clearly understood. To assess the role of C. sinensis infection in carcinogenesis, an in vitro system was established using the human epithelial cell line HEK293T. In cells exposed to the excretory/secretory products (ESP) of C. sinensis and the carcinogen dimethylnitrosamine (DMN), cellular proliferation and the proportion of cells in the G2/M phase increased. Moreover, the expression of the cell cycle proteins E2F1, p-pRb, and cyclin B was dramatically increased when ESP and DMN were added together. Similarly, the transcription factor E2F1 showed its highest level of activity when ESP and DMN were added simultaneously. These findings indicate that DMN and ESP synergistically affect the regulation of cell cycle-related proteins. Our results suggest that exposure to C. sinensis and a small amount of a carcinogen such as DMN can promote carcinogenesis in the bile duct epithelium via uncontrolled cellular proliferation and the upregulation of cell cycle-related proteins.
Abstract
Clonorchis sinensis is one of the most prevalent parasitic helminths in Korea. Although cholangiocarcinoma can be induced by C. sinensis infection, the underlying mechanism is not clearly understood. To assess the role of C. sinensis infection in carcinogenesis, an in vitro system was established using the human epithelial cell line HEK293T. In cells exposed to the excretory/secretory products (ESP) of C. sinensis and the carcinogen dimethylnitrosamine (DMN), cellular proliferation and the proportion of cells in the G2/M phase increased. Moreover, the expression of the cell cycle proteins E2F1, p-pRb, and cyclin B was dramatically increased when ESP and DMN were added together. Similarly, the transcription factor E2F1 showed its highest level of activity when ESP and DMN were added simultaneously. These findings indicate that DMN and ESP synergistically affect the regulation of cell cycle-related proteins. Our results suggest that exposure to C. sinensis and a small amount of a carcinogen such as DMN can promote carcinogenesis in the bile duct epithelium via uncontrolled cellular proliferation and the upregulation of cell cycle-related proteins.
참고문헌 (30)
- Hong S. T., "International handbook of foodborn pathogens in : Clonorchis sinensis", pp.581~592 (2003), Marcel Dekker
- Choi M. S., "Correlation between sonographics findings and infection intensity in clonorchiasis", AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73, pp.1139~1144 (2005)
- Watanapa P., "Liver fluke-associated cholangiocarcinoma", British Journal of Surgery, 89, pp.962~970 (2002)
- Schwartz D. A., "Helminths in the induction of cancer: Opisthorchis viverrini, Clonorchis sinensis and cholangiocarcinoma", Tropical and Geographical Medicine, 32, pp.95~100 (1980)
- Prempracha N., "Identification and potential use of a soluble tumor antigen for the detection of liverfluke- associated cholangiocarcinoma induced in a hamster model", INTERNATIONAL JOURNAL OF CANCER, 57, pp.691~695 (1994)
- Lee J. H., "Effect of Clonorchis sinensis infection and dimethylnitrosamine administration on the induction of cholangiocarcinoma in Syrian golden hamsters", The Korean Journal of Parasitology, 31, pp.21~30 (1993), 대한기생충학회
- Pinlaor S., "Mechanism of NO-mediated oxidative and nitrative DNA damage in hamsters infected with Opisthorchis viverrini: a model of inflammationmediated carcinogenesis", Nitric Oxide, 11, pp.175~183 (2004)
- Kato M., "Relationship between hepatocyte necrosis, proliferation, and initiation induced by diethylnitrosamine in the male F344 rat", Fundamental and Applied Toxicology, 20, pp.155~162 (1993)
- Pinlaor S., "iNOS-dependent DNA damage via NF-kappaB expression in hamsters infected with Opisthorchis viverrini and its suppression by the antihelminthic drug praziquantel", INTERNATIONAL JOURNAL OF CANCER, 119, pp.1067~1072 (2006)
- King K. L., "Cell cycle regulation and apoptosis", ANNUAL REVIEW OF PHYSIOLOGY, 60, pp.601~617 (1998)
- Nevins J. R., "E2F: a link between the Rb tumor suppressor protein and viral oncoproteins", Science, 258, pp.424~429 (1992)
- Davis J. N., "Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer", CANCER RESEARCH, 66, pp.11897~11906 (2006)
- Dimova D. K., "Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F", RB pathway, 2003, pp.17, 2308~2320
- Ahmad N., "Involvement of retinoblastoma (Rb) and E2F transcription factors during photodynamic therapy of human epidermoid carcinoma cells A431", Oncogene, 18, pp.1891~1896 (1999)
- Ishida S., "Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis", MOLECULAR AND CELLULAR BIOLOGY, 21, pp.4684~4699 (2001)
- Zhu W., "E2Fs link the control of G1", S and G2, EMBO JOURNAL, pp.2004, 23[DOI]
- Blake M. C., "Transcription factor E2F1 is required for efficient expression of the hamster dihydrofolate reductase gene in vitro and in vivo", MOLECULAR AND CELLULAR BIOLOGY, 9, pp.4994~5002 (1989)
- Fry C. J., "Activation of the murine dihydrofolate reductase promoter by E2F1", JOURNAL OF BIOLOGICAL CHEMISTRY, 274, pp.15883~15891 (1999)
- Sowers R., "mRNA expression levels of E2F transcription factors correlated with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma", MOLECULAR CANCER THERAPEUTICS, 2, pp.535~541 (2003)
- Johnson D. G., "Role of E2F in cell cycle control and cancer", FRONTIERS IN BIOSCIENCE, 3, pp.d447~d448 (1998)
- Mundle S. D., "Evolving intricacies and implications of E2F1 regulation", FASEB JOURNAL, 17, pp.569~574 (2003)
- Kim Y. J., "Proliferative effects of excretory", secretory products from Clonorchis sinensis on the human epithelial cell line HEK293 via regulation of the transcription factor E2F1, 2008, pp.102, 411~417
- Slansky J. E., "Transcriptional regulation of the dihydrofolate reductase gene", Bioessays, 18, pp.55~62 (1996)
- Huang C. L., "E2F1 overexpression correlates with thymidylate synthase and survivin gene expressions and tumor proliferation in non small-cell lung cancer", CLINICAL CANCER RESEARCH, 13, pp.6938~6946 (2007)
- Li Z., "Spliceosomal protein E regulates neoplastic cell growth by modulating expression of Cyclin E", CDK2 and G2, JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, pp.2008[DOI]
- Satarug S., "Relationships between the synthesis of N-nitrosodimethylamine and immune responses to chronic infection with the carcinogenic parasite, Opisthorchis viverrini in men", Carcinogenesis, 19, pp.485~491 (1998)
- Rodriguez J. L., "Transcription of the MAT2A gene, coding for methionine adenosyltransferase, is up-regulated by E2F and Sp1 at a chromatin level during proliferation of liver cells", International Journal of Biochemistry and Cell Biology, 39, pp.842~850 (2007)
- Hou P. C., "Chorionepithelioma: an analytical study of 28 necropsied cases, with special reference to the possibility of spontaneous retrogression.", Journal of pathology and bacteriology, 72, pp.95~104 (1956)
- Sripa B., "Liver fluke induces cholangiocarcinoma", PLOS MEDICINE, 4, pp.e201~ (2007)
- Hu X. T., "TGFbeta-mediated formation of pRb-E2F complexes in human myeloid leukemia cells", Biochemical and Biophysical Research Communications, 369, pp.277~280 (2008)