Clinicopathologic and prognostic values of apolipoprotein D alterations in hepatocellular carcinoma
Tohru Utsunomiya
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorKazuhiko Ogawa
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorKeiji Yoshinaga
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorMitsuhiko Ohta
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorKeishi Yamashita
Department Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA
Search for more papers by this authorKoshi Mimori
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorHiroshi Inoue
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorTakahiro Ezaki
Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
Search for more papers by this authorYasuji Yoshikawa
Department of Pathology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorCorresponding Author
Masaki Mori
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Fax: +81-977-27-1651
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu 874-0838, JapanSearch for more papers by this authorTohru Utsunomiya
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorKazuhiko Ogawa
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorKeiji Yoshinaga
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorMitsuhiko Ohta
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorKeishi Yamashita
Department Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA
Search for more papers by this authorKoshi Mimori
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorHiroshi Inoue
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorTakahiro Ezaki
Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
Search for more papers by this authorYasuji Yoshikawa
Department of Pathology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Search for more papers by this authorCorresponding Author
Masaki Mori
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Fax: +81-977-27-1651
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu 874-0838, JapanSearch for more papers by this authorAbstract
We previously identified apolipoprotein D (Apo D) as a novel tumor suppressor gene based on the pharmacological unmasking of epigenetic silencing. We analyzed Apo D expression using real-time reverse transcription-PCR and evaluated its expression status based on the clinicopathological parameters of 70 patients with hepatocellular carcinoma (HCC). Immunohistochemical staining was also performed. We determined the methylation status of Apo D gene promoter by methylation-specific PCR (MSP). The Apo D gene-expression in tumor tissue was significantly lower than that in nontumor tissue (p = 0.011). A low Apo D expression significantly correlated with less-differentiated HCC (p = 0.019). Immunohistochemical studies confirmed a decreased Apo D expression in poorly differentiated tumors. The prognosis of patients with a lower Apo D gene-expression was significantly worse than that in those with a higher expression (p = 0.028). The Apo D gene-expression was an independent prognostic factor (relative risk: 2.36, p = 0.018). An MSP assay showed a low-level of methylation in well differentiated HCC and a high-level of methylation in less differentiated tumors. Apo D may be a novel tumor suppressor gene of HCC, and its expression status may be a useful biomarker for predicting the patient outcome. © 2005 Wiley-Liss, Inc.
References
- 1 Yamashita K, Upadhyay S, Osada M, Hoque MO, Xiao Y, Mori M, Sato F, Meltxer SJ, Sidransky D. Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2002; 2: 485–95.
- 2 McConathy WJ, Alaupovic P. Isolation and partial characterization of apolipoprotein D: a new protein moiety of the human plasma lipoprotein system. FEBS Lett 1973; 37: 178–82.
- 3 Francone OL, Gurakar A, Fielding C. Distribution and functions of lecithin: cholesterol acyltransferase and cholesterol ester protein in plasma lipoproteins. J Biol Chem 1989; 264: 7066–72.
- 4 Lopez-Boado YS, Tolivia J, Lopez-Otin C. Apolipoprotein D gene induction by retinoic acid is concomitant with growth arrest and cell differentiation in human breast cancer cells. J Biol Chem 1994; 269: 26871–8.
- 5 Diez-Itza I, Vizoso F, Merino AM, Sanchez LM, Tolivia J, Fernandez J, Ruibal A, Lopez-Otin C. Expression and prognostic significance of apolipoprotein D in breast cancer. Am J Pathol 1994; 144: 310–20.
- 6 Vazquez J, Gonzalez L, Merino A, Vizoso F. Expression and clinical significance of apolipoprotein D in epithelial ovarian carcinomas. Gynecol Oncol 2000; 76: 340–7.
- 7 Utsunomiya T, Okamoto M, Hashimoto M, Yoshinaga K, Shiraishi T, Tanaka F, Momori K, Inoue H, Watanabe G, Barnard GF, Mori M. A gene-expression signature can quantify the degree of rat hepatic fibrosis. J Hepatol 2004; 41: 399–406.
- 8 Utsunomiya T, Hara Y, Kataoka A, Morita M, Arakawa H, Mori M, Nishimura S. Cystatin-like metastasis-associated protein mRNA expression in human colorectal cancer is associated with both liver metastasis and patient survival. Clin Cancer Res 2002; 8: 2591–4.
- 9 Utsunomiya T, Inoue H, Taguchi K, Shimada M, Sugimachi K, Mori M. G protein g7 expression as a new clinicopathological marker in patients with intrahepatic cholangiocarcinoma. Arch Surg 2002; 137: 181–5.
- 10 Masuda TA, Inoue H, Nishida K, Sonoda H, Yoshikawa Y, Kakeji Y, Utsunomiya T, Mori M. Cyclin-dependent kinase 1 gene expression is associated with poor prognosis in gastric carcinoma. Clin Cancer Res 2003; 9: 5693–8.
- 11 Ogawa K, Utsunomiya T, Mimori K, Tanaka Y, Tanaka F, Inoue H, Murayama S, Mori M. Clinical significance of elongation factor-1 mRNA expression in esophageal carcinoma. Br J Cancer 2004; 91: 282–6.
- 12 Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baykin SB, Sidransky D. 5′ CpG island methylation is associated with transcriptional silencing of the tumor suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995; 1: 686–92.
- 13
Cox DR.
Regression models and life tables.
J R Stat Soc (B)
1972;
34:
187–220.
10.1111/j.2517-6161.1972.tb00899.x Google Scholar
- 14 Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer, 4th ed. Tokyo: Kanahara Shuppan, 2000. 68p.
- 15 Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415–28.
- 16 Feinberg AP. Cancer epigenetics takes center stage. Proc Natl Acad Sci U S A 2001; 98: 392–4.
- 17 Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. New Engl J Med 2003; 349: 2042–54.
- 18 Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, Willis J, Willson JK, et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 2003; 100: 8412–7.
- 19
Kanai Y,
Ushijima S,
Hui AM,
Ochiai A,
Tsuda H,
Sakamoto M,
Hirohashi S.
The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas.
Int J Cancer
1997;
71:
355–9.
10.1002/(SICI)1097-0215(19970502)71:3<355::AID-IJC8>3.0.CO;2-X CAS PubMed Web of Science® Google Scholar
- 20 Liew CT, Li HM, Lo KW, Leow CK, Chan JY, Hin LY, Lau WY, Lai PBS Lim BK, Huang J, Leung WT, Wu S, et al. High frequency of p16INK4A gene alterations in hepatocellular carcinoma. Oncogene 1999; 18: 789–95.
- 21 Iwata N, Yamamoto H, Sasaki S, Itoh F, Suzuki H, Kikuchi T, Kaneto H, Iku S, Ozeki I, Karino K, Satoh T, Toyota J, et al. Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 sigma gene in human hepatocellular carcinoma. Oncogene 2000; 19: 5298–02.
- 22 Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 2001; 28: 29–35.
- 23 Wong CM, Lee JMF, Ching YP, Jin DY, Ng OL. Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res 2003; 63: 7646–51.
- 24 Schagdarsurengin U, Wilkens L, Steinemann D, Flemming P, Kreipe HH, Pfeifer GP, Schlegelberger B, Dammann R. Frequent epigenetic inactivation of the RASSF1A gene in hepatocellular carcinoma. Oncogene 2003; 22: 1866–71.
- 25 Motiwala T, Ghoshal K, Das A, Majumder S, Weichenhan D, Wu Y-Z, Holman K, James SJ, Jacob ST, Plass C. Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinoma. Oncogene 2003; 22: 6319–31.
- 26 Fukai K, Yokosuka O, Chiba T, Hirasawa Y, Tada M, Imazeki F, Kataoka H, Saisho H. Hepatocyte growth factor activator inhibitor 2/placental bikunin (HAI-2/PB) gene is frequently hypermethylated in human hepatocellular carcinoma. Cancer Res 2003; 63: 8674–9.
- 27 Kubo T, Yamamoto J, Shikauchi Y, Niwa Y, Matsubara K, Yoshikawa H. Apoptotic speck protein-like, a highly homologous protein to apoptotic speck protein in the pyrin domain, is silenced by DNA methylation and induces apoptosis in human hepatocellular carcinoma. Cancer Res 2004; 64: 5172–7.
- 28 Izumi R, Shimizu K, Ii T, Yagi M, Matsui O, Nonomura A, Miyazaki I. Prognostic factors of hepatocellular carcinoma in patients undergoing hepatic resection. Gastroenterology 1994; 106: 720–7.
- 29 Shimada M, Takenaka K, Taguchi K, Fujiwara Y, Gion T, Kajiyama K, Maeda T, Shirabe K, Yanaga K, Sugimachi K. Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Ann Surg 1998; 227: 80–5.
- 30
King KL,
Li AFY,
Chau GY,
Chi CW,
Wu CW,
Huang CL,
Lui YW.
Prognostic significance of heat shock protein-27 expression in hepatocellular carcinoma and its relation to histologic grading and survival.
Cancer
2000;
88:
2464–70.
10.1002/1097-0142(20000601)88:11<2464::AID-CNCR6>3.0.CO;2-W CAS PubMed Web of Science® Google Scholar
- 31 Do Carmo S, Seguin D, Milne R, Rassart E. Modulation of apolipoprotein D and apolipopoptein E mRNA expression by growth arrest and identification of key elements in the promoter. J Biol Chem 2002; 277: 5514–23.
- 32 Hall RE, Horsfall DJ, Stahl J, Vivekanandan S, Ricciardelli C, Stapleton AMF, Scardino PT, Neufing P, Tilley WD. Apolipoprotein D: a novel cellular marker for HGPIN and prostate cancer. Ptostate 2004; 58: 103–8.
- 33 Proteomic analysis to identify breast cancer biomarkers in nipple aspirate fluid. Clin Cancer Res 2004; 10: 7500–10.
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