Abstract
Our previous proteomics study on human hepatocellular carcinoma (HCC) cell strains revealed that cytokeratin 19 (CK19) was expressed in cells with high metastasis potential; we further studied serum CK19 fragment CYFRA 21-1 level in HCC patients and nude mice model of HCC metastasis. HCC cell line HCCLM3 was injected subcutaneously into 30 nude mice which were then randomized into 6 groups of 5 mice each. The murine serum CYFRA 21-1 and pulmonary metastases were determined 2, 3, 4, 5, 6, and 7 weeks after injection. Serum CYFRA 21-1 levels of 101 normal controls and 108 HCC patients were also determined. In nude mice model, CYFRA 21-1 level increased significantly when pulmonary metastases occurred. Among 108 HCC patients, 24 (22.2%) had increased serum CYFRA 21-1 level. The presence of portal vein tumor emboli was significantly higher in CYFRA 21-1 increased cases (33.3%, 6/24) than in CYFRA 21-1 normal cases (6.0%, 5/84) (x 2 = 7.403, P < 0.01). In addition, the percentage of TNM stage III/IV tumor was significantly higher in CYFRA 21-1 increased patients (54.2%, 13/24) than in CYFRA 21-1 normal cases (21.4%, 18/84) (x 2 = 9.776, P < 0.005). These results suggest that CK19 may play an important role in HCC metastasis.
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References
Cooper D, Schermer A, Sun TT (1985) Classification of human epithelia and their neoplasms using monoclonal antibodies to keratins: strategies, applications, and limitations. Lab Invest 52:243–256
Ding SJ, Li Y, Tan YX, Jiang MR, Tian B, Liu YK, Shao XX, Ye SL, Wu JR, Zeng R, Wang HY, Tang ZY, Xia QC (2004a) From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics 3:73–81
Ding SJ, Li Y, Shao XX, Zhou H, Zeng R, Tang ZY, Xia QC (2004b) Proteome analysis of hepatocellular carcinoma cell strains, MHCC97-H and MHCC97-L, with different metastasis potentials. Proteomics 4:982–994
El Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745–745
Hanash S (2003) Disease proteomics. Nature 422:226–232
Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM, Bao WH (2001) Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 7:630–636
Li Y, Tang ZY, Ye SL, Liu BB, Liu YK, Chen J, Xue Q (2003) Establishment of a hepatocellular carcinoma cell line with unique metastatic characteristics through in vivo selection and screen for metastasis-related genes through cDNA microarray. J Cancer Res Clin Oncol 129:43–51
Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, Liu YK, Tang ZY (2004) Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol 130:460–468
Liu YF, Su Q, Gong MZ (1996) Expression of cytokeratins in hepatocellular and cholangiocellular carcinomas and their cell lines of human and rat. Cell Vis 3:119–125
Moll R, Franke WW, Schiller DL, Gerger B, Krepler R (1982) The catalog of human cytokeratins: pattern of expression in normal epithelia tumors and cultured cells. Cell 31:11–24
Omary MB, Ku NO, Toivola DM (2002) Keratins. Guardians of the liver. Hepatology 35:251–257
Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: globocan 2000. Int J Cancer 94:153–156
Ray MB, Mendenhell CL, French SW, Gartside PS (1993) Bile duct changes in alcoholic liver diseases. Liver 13:36–45
Stosiek P, Kasper M, Karsten U (1990) Expression of cytokeratin 19 during human liver organogenesis. Liver 10:59–63
Su Q, Fu Y, Liu YF, Zhang W, Liu J, Wang CM (2003) Laminin induces the expression of cytokeratin 19 in hepatocellular carcinoma cells growing in culture. World J Gastroenterol 9:921–929
Tabor E (2001) Hepatocellular carcinoma: global epidemiology. Dig Liver Dis 33:115–117
Tang ZY (2000) Surgery of hepatocellular carcinoma with special reference to studies on metastasis and recurrence. Gastroenterol Today 4:191–195
Tang ZY, Ye SL, Liu YK, Qin LX, Sun HC, Ye QH, Wang L, Zhou J, Qiu SJ, Li Y, Ji XN, Liu H, Xia JL, Wu ZQ, Fan J, Ma ZC, Zhou XD, Lin ZY, Liu KD (2004) A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol 130:187–196
Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC (1997) Increase in primary liver cancer in the UK, 1979–1994. Lancet 350:1142–1143
Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, Tanaka S, Kaneda K, Hirohashi K (2003) Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci 94:851–857
UKCCCR (1998) United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Guidelines for the welfare of animals in experimental neoplasia (Second Edition). Br J Cancer 77:1–10
Van Eyken P, Sciot R, Paterson A, Callea F, Kew MC, Desmet VJ (1988) Cytokeratin expression in hepatocellular carcinoma: an immunohistochemical study. Hum Pathol 19:562–568
Van Eyken P, Sciot R, Desmet VJ (1989) A cytokeratin immunohistochemical study of cholestatic liver disease: evidence that hepatocytes can express ‘bile-duct type’ cytokeratins. Histopathology 15:125–135
Wu PC, Fang JW, Lau VK, Lai CL, Lo CK, Lau JY (1996) Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol 149:1167–1175
Wu F, Nishioka M, Fujita J, Murota M, Ohtsuki Y, Ishida T, Kuriyama S (2002a) Expression of cytokeratin 19 in human hepatocellular carcinoma cell lines. Int J Oncol 20:31–37
Wu F, Fujita J, Murota M, Li JQ, Ishida T, Nishioka M, Imaida Y, Kuriyama S (2002b) CYFRA 21-1 is released in TNF alpha induced apoptosis in the hepatocellular carcinoma cell line HuH7. Int J Oncol 21:441–445
Zhang SW, Li LD, Lu FZ, Mu R, Sun XD, Huangfu XM, Sun J, Zhou YS, Dai XD (1999) Mortality of primary liver cancer in China from 1990 through 1992. Zhonghua Zhongliu Zazhi 21:245–249 (in Chinese with English abstract)
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This work was supported by New-Century Excellent Talents Supporting Program of the Ministry of Education (NCET-04-0669), and A Foundation for the Author of National Excellent Doctoral Dissertation of PR China (FANEDD) (200464).
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Li, Y., Tang, ZY., Tian, B. et al. Serum CYFRA 21-1 level reflects hepatocellular carcinoma metastasis: study in nude mice model and clinical patients. J Cancer Res Clin Oncol 132, 515–520 (2006). https://doi.org/10.1007/s00432-006-0098-4
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DOI: https://doi.org/10.1007/s00432-006-0098-4