DOI QR코드

DOI QR Code

Association of CYP39A1, RUNX2 and Oxidized Alpha-1 Antitrypsin Expression in Relation to Cholangiocarcinoma Progression

  • Khenjanta, Chakkaphan (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Thanan, Raynoo (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Jusakul, Apinya (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Techasen, Anchalee (Center for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University) ;
  • Jamnongkan, Wassana (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Namwat, Nisana (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Loilome, Watcharin (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Pairojkul, Chawalit (Department of Pathology, Faculty of Medicine, Khon Kaen University) ;
  • Yongvanit, Puangrat (Department of Biochemistry, Faculty of Medicine, Khon Kaen University)
  • Published : 2015.01.06

Abstract

Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2) in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker, was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally, immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.

Keywords

CYP39A1;RUNX2;oxidized alpha-1 antitrypsin;cholangiocarcinoma

References

  1. Alexandrov P, Cui JG, Zhao Y, et al (2005). 24S-hydroxycholesterol induces inflammatory gene expression in primary human neural cells. Neuroreport, 16, 909-13. https://doi.org/10.1097/00001756-200506210-00007
  2. Bjorkhem I (2009). Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med, 260, 493-508.
  3. Bjorkhem I, Heverin M, Leoni V, et al (2006). Oxysterols and Alzheimer's disease. Acta Neurol Scand, 114, 43-49. https://doi.org/10.1111/j.1600-0404.2006.00684.x
  4. Bjorkhem I, Lutjohann D, Diczfalusy U, et al (1998). Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res, 39, 1594-600.
  5. Chimge N-O, Baniwal SK, Luo J, et al (2012). Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness. Clin Cancer Res, 8, 901-11.
  6. Crawford EL, Weaver DA, DeMuth JP, et al (1998). Measurement of cytochrome P450 2A6 and 2E1 gene expression in primary human bronchial epithelial cells. Carcinogenesis, 19, 1867-71. https://doi.org/10.1093/carcin/19.10.1867
  7. de Groen PC, Gores GJ, LaRusso NF, et al (1999). Biliary tract cancers. N Engl J Med, 341, 1368-78. https://doi.org/10.1056/NEJM199910283411807
  8. Godoy W, Albano RM, Moraes EG, et al (2002). CYP2A6/2A7 and CYP2E1 expression in human oesophageal mucosa: regional and inter-individual variation in expression and relevance to nitrosamine metabolism. Carcinogenesis, 23, 611-16. https://doi.org/10.1093/carcin/23.4.611
  9. Ho JC, Cheung ST, Leung KL, et al (2004). Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma. Int J Cancer, 111, 494-500. https://doi.org/10.1002/ijc.20282
  10. Huang Y-W, Jansen RA, Fabbri E, et al (2009). Identification of candidate epigenetic biomarkers for ovarian cancer detection. Oncol Rep, 22, 853-61.
  11. Hunsawong T, Singsuksawat E, In-chon N, et al (2012). Estrogen is increased in male cholangiocarcinoma patients' serum and stimulates invasion in cholangiocar cinoma cell lines in vitro. J Cancer Res Clin Oncol, 138, 1311-20. https://doi.org/10.1007/s00432-012-1207-1
  12. Jaiswal M, LaRusso NF, Burgart LJ, et al (2012). Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res, 60, 184-90.
  13. Jamnongkan W, Techasen A, Thanan R, et al (2013). Oxidized alpha-1 antitrypsin as a predictive risk marker of opisthorchiasis-associated cholangiocarcinoma. Tumor Biol, 34, 695-704. https://doi.org/10.1007/s13277-012-0597-7
  14. Joffre C, LeclereL, Buteau B, et al (2007). Oxysterols induced inflammation and oxidation in primary porcine retinal pigment epithelial cells. Curr Eye Res, 32, 271-80. https://doi.org/10.1080/02713680601187951
  15. Khan SA, Toledano MB, Taylor Robinson SD (2008). Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB, 10, 77-82. https://doi.org/10.1080/13651820801992641
  16. Kunlabut K, Vaeteewoottacharn K, Wongkham C, et al (2012). Aberrant expression of CD44 in bile duct cancer correlates with poor prognosis. Asian Pac J Cancer Prev, 13, 95-99.
  17. Li-Hawkins J, Lund EG, Bronson AD, et al (2000). Expression cloning of an oxysterol 7alpha-hydroxylase selective for 24-hydroxycholesterol. J Biol Chem, 275, 16543-16549. https://doi.org/10.1074/jbc.M001810200
  18. Lutjohann D, Breuer O, Ahlborg G, et al (1996). Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A, 93, 9799-804. https://doi.org/10.1073/pnas.93.18.9799
  19. Murata M, Thanan R, Ma N, et al (2012). Role of nitrative and oxidative DNA damage in inflammation-related carcinogenesis. J Biomed Biotechnol, 2012, 623019.
  20. Namwat N, Chusorn P, Loilome W, et al (2012). Expression profiles of oncomir miR-21 and tumor suppressor let-7a in the progression of opisthorchiasis-associated cholangiocarcinoma. Asian Pac J Cancer Prev, 13, 65-69.
  21. Pinlaor S, Yongvanit P, Hiraku Y, et al (2003). 8-Nitroguanine formation in the liver of hamsters infected with Opisthorchis viverrini. Biochem Biophys Res Commun, 309, 567-71. https://doi.org/10.1016/j.bbrc.2003.08.039
  22. Raunio H, Juvonen R, Pasanen M, et al (1998). Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma. Hepatology, 27, 427- 32. https://doi.org/10.1002/hep.510270217
  23. Satarug S, Lang MA, Yongvanit P, et al (1996). Induction of cytochrome P450 2A6 expression in humans by the carcinogenic parasite infection, opisthorchiasis viverrini. Cancer Epidemiol Biomarkers Prev, 5, 795-800.
  24. Shin H-R, Oh J-K, Masuyer E, et al (2012). Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci, 101, 579-85.
  25. Simpson (1997). The cytochrome P450 4 (CYP4) family. Gen Pharmacol, 28, 351-59. https://doi.org/10.1016/S0306-3623(96)00246-7
  26. Teplyuk NM, Zhang Y, Lou Y, et al (2009). The osteogenic transcription factor runx2 controls genes involved in sterol/ steroid metabolism, including CYP11A1 in osteoblasts. J Mol Endocrinol, 23, 849-61. https://doi.org/10.1210/me.2008-0270
  27. Thanan R, Ma N, Iijima K, Abe Y, et al (2012a). Proton pump inhibitors suppress iNOS-dependent DNA damage in Barretts esophagus by increasing Mn-SOD expression. Biochem Biophys Res Commun, 421, 280-85. https://doi.org/10.1016/j.bbrc.2012.03.152
  28. Thanan R, Murata M, Pinlaor S, et al (2008). Urinary 8-oxo-7, 8-dihydro-2'-deoxyguanosine in patients with parasite infection and effect of antiparasitic drug in relation to cholangiocarcinogenesis. Cancer Epidemiol Biomarkers Prev, 17, 518-24. https://doi.org/10.1158/1055-9965.EPI-07-2717
  29. Thanan R, Oikawa S, Yongvanit P, et al (2012b). Inflammationinduced protein carbonylation contributes to poor prognosis for cholangiocarcinoma. Free Radic Biol Med, 52, 1465-72. https://doi.org/10.1016/j.freeradbiomed.2012.01.018
  30. Thongchot S, Yongvanit P, Loilome W, et al (2014). High expression of HIF-1${\alpha}$, BNIP3 and PI3KC3: hypoxiainduced autophagy predicts cholangiocarcinoma survival and metastasis. Asian Pac J Cancer Prev, 15, 5873-5878. https://doi.org/10.7314/APJCP.2014.15.14.5873
  31. Vatanasapt V, Sriamporn S, Vatanasapt P (2002). Cancer control in Thailand. Jpn J Clin Oncol, 32, 82-91. https://doi.org/10.1093/jjco/hye134
  32. Yongvanit P, Phanomsri E, Namwat N, et al (2012a). Hepatic cytochrome P450 2A6 and 2E1 status in peri-tumor tissues of patients with opisthorchis viverrini associated cholangiocarcinoma. Parasitology Int, 61, 162-66. https://doi.org/10.1016/j.parint.2011.06.026
  33. Yongvanit P, Pinlaor S, Bartsch H (2012b). Oxidative and nitrative DNA damage: key events in opisthorchiasisinduced carcinogenesis. Parasitology Int, 61, 130-35. https://doi.org/10.1016/j.parint.2011.06.011

Cited by

  1. Microarray Analysis of Differentially-Expressed Genes Encoding CYP450 and Phase II Drug Metabolizing Enzymes in Psoriasis and Melanoma vol.8, pp.1, 2016, https://doi.org/10.3390/pharmaceutics8010004
  2. Liver fluke infection and cholangiocarcinoma: a review vol.116, pp.1, 2017, https://doi.org/10.1007/s00436-016-5276-y
  3. A transcriptome-based protein network that identifies new therapeutic targets in colorectal cancer vol.18, pp.1, 2017, https://doi.org/10.1186/s12864-017-4139-y
  4. Expression of oxysterol pathway genes in oestrogen-positive breast carcinomas vol.86, pp.6, 2017, https://doi.org/10.1111/cen.13337