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Tumor-Related Gene Changes in Immunosuppressive Syrian Hamster Cholangiocarcinoma

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Pathology & Oncology Research

Abstract

The results of a previous study demonstrated that prednisolone enhanced cholangiocarcinogenesis. Therefore, to clarify molecular changes during immunosuppressive cholangiocarcinogenesis, Syrian hamsters were divided into 8 groups: uninfected controls; immunosuppressed Syrian hamsters using prednisolone (P); normal Syrian hamsters administered N-nitrosodimethylamine (ND); immunosuppressed Syrian hamsters administered N-nitrosodimethylamine (NDis); normal Syrian hamsters infected with Opisthorchis viverrini (OV); immunosuppressed Syrian hamsters infected with O. viverrini (OVis); normal Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCA); and immunosuppressed Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCAis). Syrian hamster livers were used for analysis of tumor-related gene expression and immunohistochemistry through cytokeratin 19 (CK19) and proliferating cell nuclear antigen (PCNA) staining. The tumor-related gene expression results show that CCAis groups at all time points exhibited upregulation of COX-2, IL-6, SOD1, CAT and iNOS and downregulation of p53, which correlated with the predominant expression of CK19 and PCNA in liver tissue. These results suggest that prednisolone enhances cholangiocarcinoma development, which was confirmed by molecular changes.

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References

  1. Juasook A, Boonmars T, Wu Z, Loilome W, Veteewuthacharn K, Namwat N, Sudsarn P, Wonkchalee O, Sriraj P, Aukkanimart R (2013) Immunosuppressive prednisolone enhances early cholangiocarcinoma in Syrian hamsters with liver fluke infection and administration of N-nitrosodimethylamine. Pathol Oncol Res 19(1):55–62

    Article  PubMed  CAS  Google Scholar 

  2. Boonmars T, Srirach P, Kaewsamut B, Srisawangwong T, Pinlaor S, Pinlaor P, Yongvanit P, Sithithaworn P (2008) Apoptosis-related gene expression in hamster opisthorchiasis post praziquantel treatment. Parasitol Res 102(3):447–455

    Article  PubMed  CAS  Google Scholar 

  3. Boonmars T, Wu Z, Boonjaruspinyo S, Pinlaor S, Nagano I, Takahashi Y, Kaewsamut B, Yongvanit P (2009) Alterations of gene expression of RB pathway in Opisthorchis viverrini infection-induced cholangiocarcinoma. Parasitol Res 105(5):1273–1281

    Article  PubMed  Google Scholar 

  4. Boonmars T, Wu Z, Boonjaruspinyo S, Puapairoj A, Kaewsamut B, Nagano I, Pinlaor S, Yongvanit P, Wonkchalee O, Juasook A, Sudsarn P, Srisawangwong T (2010) Involvement of c-Ski oncoprotein in carcinogenesis of cholangiocacinoma induced by Opisthorchis viverrini and N-nitrosodimethylamine. Pathol Oncol Res 17(2):219–227

    Article  PubMed  Google Scholar 

  5. Trune DR, Kempton JB, Gross ND (2006) Mineralocorticoid receptor mediates glucocorticoid treatment effects in the autoimmune mouse ear. Hear Res 212(1–2):22–32

    Article  PubMed  CAS  Google Scholar 

  6. Boonjaraspinyo S, Boonmars T, Aromdee C, Puapairoj A, Wu Z (2011) Indirect effect of a turmeric diet: enhanced bile duct proliferation in Syrian hamsters with a combination of partial obstruction by Opisthorchis viverrini infection and inflammation by N-nitrosodimethylamine administration. Parasitol Res 108(1):7–14

    Article  PubMed  Google Scholar 

  7. Laothong U, Pinlaor P, Hiraku Y, Boonsiri P, Prakobwong S, Khoontawad J, Pinlaor S (2010) Protective effect of melatonin against Opisthorchis viverrini-induced oxidative and nitrosative DNA damage and liver injury in hamsters. J Pineal Res 49(3):271–282

    Article  PubMed  CAS  Google Scholar 

  8. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899

    Article  PubMed  CAS  Google Scholar 

  9. Barth H, Robinet E, Liang TJ, Baumert TF (2008) Mouse models for the study of HCV infection and virus-host interactions. J Hepatol 49(1):134–142

    Article  PubMed  CAS  Google Scholar 

  10. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197–208

    Article  PubMed  CAS  Google Scholar 

  11. IARC (2011) A review of human carcinogens part B: biological agents (Opisthorchis viverrini and Clonorchis sinensis). IARC Monogr Eval Carcinog Risks Hum 100:347–376

    Google Scholar 

  12. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59(13):3128–3133

    PubMed  CAS  Google Scholar 

  13. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404(6776):398–402

    Article  PubMed  CAS  Google Scholar 

  14. de Martel C, Llosa AE, Farr SM, Friedman GD, Vogelman JH, Orentreich N, Corley DA, Parsonnet J (2005) Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma. J Infect Dis 191(5):761–767

    Article  PubMed  Google Scholar 

  15. Zamarron BF, Chen W (2011) Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 7(5):651–658

    Article  PubMed  CAS  Google Scholar 

  16. Pinlaor S, Hiraku Y, Ma N, Yongvanit P, Semba R, Oikawa S, Murata M, Sripa B, Sithithaworn P, Kawanishi S (2004) Mechanism of NO-mediated oxidative and nitrative DNA damage in hamsters infected with Opisthorchis viverrini: a model of inflammation-mediated carcinogenesis. Nitric Oxide 11(2):175–183

    Article  PubMed  CAS  Google Scholar 

  17. Pinlaor S, Ma N, Hiraku Y, Yongvanit P, Semba R, Oikawa S, Murata M, Sripa B, Sithithaworn P, Kawanishi S (2004) Repeated infection with Opisthorchis viverrini induces accumulation of 8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanine in the bile duct of hamsters via inducible nitric oxide synthase. Carcinogenesis 25(8):1535–1542

    Article  PubMed  CAS  Google Scholar 

  18. Wu Z, Boonmars T, Boonjaraspinyo S, Nagano I, Pinlaor S, Puapairoj A, Yongvanit P, Takahashi Y (2011) Candidate genes involving in tumorigenesis of cholangiocarcinoma induced by Opisthorchis viverrini infection. Parasitol Res 109(3):657–673

    Article  PubMed  Google Scholar 

  19. Loilome W, Yongvanit P, Wongkham C, Tepsiri N, Sripa B, Sithithaworn P, Hanai S, Miwa M (2006) Altered gene expression in Opisthorchis viverrini-associated cholangiocarcinoma in hamster model. Mol Carcinog 45(5):279–287

    Article  PubMed  CAS  Google Scholar 

  20. Howe LR, Subbaramaiah K, Brown AM, Dannenberg AJ (2001) Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocr Relat Cancer 8(2):97–114

    Article  PubMed  CAS  Google Scholar 

  21. Lakatos PL, Lakatos L (2008) Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol 14(25):3937–3947

    Article  PubMed  Google Scholar 

  22. Dolcet X, Llobet D, Pallares J, Matias-Guiu X (2005) NF-kB in development and progression of human cancer. Virchows Arch 446(5):475–482

    Article  PubMed  CAS  Google Scholar 

  23. Sakamoto K, Maeda S, Hikiba Y, Nakagawa H, Hayakawa Y, Shibata W, Yanai A, Ogura K, Omata M (2009) Constitutive NF-kappaB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth. Clin Cancer Res 15(7):2248–2258

    Article  PubMed  CAS  Google Scholar 

  24. Fernandez-Majada V, Aguilera C, Villanueva A, Vilardell F, Robert-Moreno A, Aytes A, Real FX, Capella G, Mayo MW, Espinosa L, Bigas A (2007) Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proc Natl Acad Sci U S A 104(1):276–281

    Article  PubMed  CAS  Google Scholar 

  25. Leong KG, Karsan A (2006) Recent insights into the role of Notch signaling in tumorigenesis. Blood 107(6):2223–2233

    Article  PubMed  CAS  Google Scholar 

  26. Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K, Harada M, Kusaba T, Tanaka M, Kimura R, Nakashima Y, Nakashima O, Kojiro M, Kurohiji T, Sata M (1999) Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology 29(3):688–696

    Article  PubMed  CAS  Google Scholar 

  27. Martin-Sanz P, Mayoral R, Casado M, Bosca L (2010) COX-2 in liver, from regeneration to hepatocarcinogenesis: what we have learned from animal models? World J Gastroenterol 16(12):1430–1435

    Article  PubMed  CAS  Google Scholar 

  28. Kundu JK, Surh YJ (2008) Inflammation: gearing the journey to cancer. Mutat Res 659(1–2):15–30

    PubMed  CAS  Google Scholar 

  29. Burstein E, Fearon ER (2008) Colitis and cancer: a tale of inflammatory cells and their cytokines. J Clin Invest 118(2):464–467

    PubMed  CAS  Google Scholar 

  30. McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244(22):6049–6055

    PubMed  CAS  Google Scholar 

  31. Cobbs CS, Levi DS, Aldape K, Israel MA (1996) Manganese superoxide dismutase expression in human central nervous system tumors. Cancer Res 56(14):3192–3195

    PubMed  CAS  Google Scholar 

  32. Izutani R, Asano S, Imano M, Kuroda D, Kato M, Ohyanagi H (1998) Expression of manganese superoxide dismutase in esophageal and gastric cancers. J Gastroenterol 33(6):816–822

    Article  PubMed  CAS  Google Scholar 

  33. Toh Y, Kuninaka S, Oshiro T, Ikeda Y, Nakashima H, Baba H, Kohnoe S, Okamura T, Mori M, Sugimachi K (2000) Overexpression of manganese superoxide dismutase mRNA may correlate with aggressiveness in gastric and colorectal adenocarcinomas. Int J Oncol 17(1):107–112

    PubMed  CAS  Google Scholar 

  34. Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S (1995) Nitric oxide synthase activity in human breast cancer. Br J Cancer 72(1):41–44

    Article  PubMed  CAS  Google Scholar 

  35. Cobbs CS, Brenman JE, Aldape KD, Bredt DS, Israel MA (1995) Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res 55(4):727–730

    PubMed  CAS  Google Scholar 

  36. Masri FA, Comhair SA, Koeck T, Xu W, Janocha A, Ghosh S, Dweik RA, Golish J, Kinter M, Stuehr DJ, Erzurum SC, Aulak KS (2005) Abnormalities in nitric oxide and its derivatives in lung cancer. Am J Respir Crit Care Med 172(5):597–605

    Article  PubMed  Google Scholar 

  37. Klotz T, Bloch W, Volberg C, Engelmann U, Addicks K (1998) Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82(10):1897–1903

    Article  PubMed  CAS  Google Scholar 

  38. Lagares-Garcia JA, Moore RA, Collier B, Heggere M, Diaz F, Qian F (2001) Nitric oxide synthase as a marker in colorectal carcinoma. Am Surg 67(7):709–713

    PubMed  CAS  Google Scholar 

  39. Hajri A, Metzger E, Vallat F, Coffy S, Flatter E, Evrard S, Marescaux J, Aprahamian M (1998) Role of nitric oxide in pancreatic tumour growth: in vivo and in vitro studies. Br J Cancer 78(7):841–849

    Article  PubMed  CAS  Google Scholar 

  40. Ekmekcioglu S, Ellerhorst J, Smid CM, Prieto VG, Munsell M, Buzaid AC, Grimm EA (2000) Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res 6(12):4768–4775

    PubMed  CAS  Google Scholar 

  41. Calvisi DF, Pinna F, Ladu S, Pellegrino R, Muroni MR, Simile MM, Frau M, Tomasi ML, De Miglio MR, Seddaiu MA, Daino L, Sanna V, Feo F, Pascale RM (2008) Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease. Carcinogenesis 29(8):1639–1647

    Article  PubMed  CAS  Google Scholar 

  42. Cahlin C, Gelin J, Delbro D, Lonnroth C, Doi C, Lundholm K (2000) Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids. Cancer Res 60(6):1742–1749

    PubMed  CAS  Google Scholar 

  43. van der Woude CJ, Kleibeuker JH, Jansen PL, Moshage H (2004) Chronic inflammation, apoptosis and (pre-)malignant lesions in the gastro-intestinal tract. Apoptosis 9(2):123–130

    Article  PubMed  Google Scholar 

  44. Mates JM (2000) Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology 153(1–3):83–104

    Article  PubMed  CAS  Google Scholar 

  45. Marra M, Sordelli IM, Lombardi A, Lamberti M, Tarantino L, Giudice A, Stiuso P, Abbruzzese A, Sperlongano R, Accardo M, Agresti M, Caraglia M, Sperlongano P (2011) Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: an overview. J Transl Med. doi:10.1186/1479-5876-9-171

    PubMed  Google Scholar 

  46. Min JY, Lim SO, Jung G (2010) Downregulation of catalase by reactive oxygen species via hypermethylation of CpG island II on the catalase promoter. FEBS Lett 584(11):2427–2432

    Article  PubMed  CAS  Google Scholar 

  47. Sen S, Kawahara B, Chaudhuri G (2012) Maintenance of higher H2O2 levels, and its mechanism of action to induce growth in breast cancer cells: important roles of bioactive catalase and PP2A. Free Radic Biol Med 53(8):1541–1551

    Article  PubMed  CAS  Google Scholar 

  48. Alawadi S, Ghabreau L, Alsaleh M, Abdulaziz Z, Rafeek M, Akil N, Alkhalaf M (2011) P53 gene polymorphisms and breast cancer risk in Arab women. Med Oncol 28(3):709–715

    Article  PubMed  Google Scholar 

  49. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253(5015):49–53

    Article  PubMed  CAS  Google Scholar 

  50. O’Dell MR, Huang JL, Whitney-Miller CL, Deshpande V, Rothberg P, Grose V, Rossi RM, Zhu AX, Land H, Bardeesy N, Hezel AF (2012) Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma. Cancer Res 72(6):1557–1567

    Article  PubMed  Google Scholar 

  51. Kishimoto T, Akira S, Narazaki M, Taga T (1995) Interleukin-6 family of cytokines and gp130. Blood 86(4):1243–1254

    PubMed  CAS  Google Scholar 

  52. Chung YC, Chang YF (2003) Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol 83(4):222–226

    Article  PubMed  Google Scholar 

  53. Schneider MR, Hoeflich A, Fischer JR, Wolf E, Sordat B, Lahm H (2000) Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells. Cancer Lett 151(1):31–38

    Article  PubMed  CAS  Google Scholar 

  54. Park J, Tadlock L, Gores GJ, Patel T (1999) Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 30(5):1128–1133

    Article  PubMed  CAS  Google Scholar 

  55. Meng F, Yamagiwa Y, Ueno Y, Patel T (2006) Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol 44(6):1055–1065

    Article  PubMed  CAS  Google Scholar 

  56. Frampton G, Invernizzi P, Bernuzzi F, Pae HY, Quinn M, Horvat D, Galindo C, Huang L, McMillin M, Cooper B, Rimassa L, DeMorrow S (2012) Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism. Gut 61(2):268–277

    Article  PubMed  CAS  Google Scholar 

  57. Alvaro D (2009) Serum and bile biomarkers for cholangiocarcinoma. Curr Opin Gastroenterol 25(3):279–284

    Article  PubMed  CAS  Google Scholar 

  58. Okada K, Shimizu Y, Nambu S, Higuchi K, Watanabe A (1994) Interleukin-6 functions as an autocrine growth factor in a cholangiocarcinoma cell line. J Gastroenterol Hepatol 9(5):462–467

    Article  PubMed  CAS  Google Scholar 

  59. Sugawara H, Yasoshima M, Katayanagi K, Kono N, Watanabe Y, Harada K, Nakanuma Y (1998) Relationship between interleukin-6 and proliferation and differentiation in cholangiocarcinoma. Histopathology 33(2):145–153

    Article  PubMed  CAS  Google Scholar 

  60. Sripa B, Thinkhamrop B, Mairiang E, Laha T, Kaewkes S, Sithithaworn P, Periago MV, Bhudhisawasdi V, Yonglitthipagon P, Mulvenna J, Brindley PJ, Loukas A, Bethony JM (2012) Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini. PLoS Negl Trop Dis 6(5):e1654

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by grant from under the program Strategic Scholarships for Frontier Research Network for the Ph.D. Program Thai Doctoral degree from the Office of the Higher Education Commission, Thailand. The authors also gratefully acknowledge financial support from the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, through the Health Cluster (SHep-GMS), Khon Kaen University. We also wish to thank the Department of Research affair (AS54301), Animal Experimental Unit, Faculty of Medicine, Khon Kaen University, for their assistance.

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Authors and Affiliations

  1. Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Amornrat Juasook, Ratchadawan Aukkanimart, Thidarut Boonmars, Pakkayanee Sudsarn, Nadchanan Wonkchalee, Porntip Laummaunwai & Pranee Sriraj

  2. Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, 40002, Thailand

    Amornrat Juasook, Ratchadawan Aukkanimart, Thidarut Boonmars, Pakkayanee Sudsarn, Nadchanan Wonkchalee & Pranee Sriraj

  3. Faculty of Veterinary Sciences, Mahasarakham University, Mahasarakham, 44000, Thailand

    Amornrat Juasook

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  1. Amornrat Juasook
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Correspondence to Thidarut Boonmars.

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Juasook, A., Aukkanimart, R., Boonmars, T. et al. Tumor-Related Gene Changes in Immunosuppressive Syrian Hamster Cholangiocarcinoma. Pathol. Oncol. Res. 19, 785–794 (2013). https://doi.org/10.1007/s12253-013-9645-x

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