DOI QR코드

DOI QR Code

Arginase-1 and P-glycoprotein are downregulated in canine hepatocellular carcinoma

  • Kim, Soo-Hyeon (Department of Veterinary Pathology, Small Animal Diagnostic Center, College of Veterinary Medicine, Konkuk University) ;
  • Seung, Byung-Joon (Department of Veterinary Pathology, Small Animal Diagnostic Center, College of Veterinary Medicine, Konkuk University) ;
  • Cho, Seung-Hee (Department of Veterinary Pathology, Small Animal Diagnostic Center, College of Veterinary Medicine, Konkuk University) ;
  • Lim, Ha-Young (Department of Veterinary Pathology, Small Animal Diagnostic Center, College of Veterinary Medicine, Konkuk University) ;
  • Bae, Min-Kyung (Department of Veterinary Pathology, Small Animal Diagnostic Center, College of Veterinary Medicine, Konkuk University) ;
  • Sur, Jung-Hyang (Department of Veterinary Pathology, Small Animal Diagnostic Center, College of Veterinary Medicine, Konkuk University)
  • 투고 : 2021.03.06
  • 심사 : 2021.06.20
  • 발행 : 2021.09.30

초록

Background: Hepatocellular carcinoma is the most common primary hepatic malignancy in humans and dogs. Several differentially expressed molecules have been studied and reported in human hepatocellular carcinoma and non-neoplastic liver lesions. However, studies on the features of canine hepatocellular carcinoma are limited, especially related to the differential characteristics of neoplastic and non-neoplastic lesions. Objectives: The study's objective was 1) to examine and evaluate the expression of arginase-1, P-glycoprotein, and cytokeratin 19 in canine liver tissues and 2) to investigate the differential features of hepatocellular carcinomas, liver tissue with non-neoplastic lesions, and paracancerous liver tissues in dogs. Methods: The expression levels of three markers underwent immunohistochemical analysis in 40 non-neoplastic liver tissues, 32 hepatocellular carcinoma tissues, and 11 paracancerous liver tissues. Scoring of each marker was performed semi-quantitatively. Results: Arginase-1 and P-glycoprotein were significantly downregulated in hepatocellular carcinoma, compared with hepatic tissues with non-neoplastic diseases (p < 0.001). Expression levels of arginase-1 and P-glycoprotein were also significantly lower in hepatocellular carcinoma than in paracancerous liver tissues (arginase-1, p = 0.0195; P-glycoprotein, p = 0.047). Few cytokeratin 19-positive hepatocytes were detected and only in one hepatocellular carcinoma and one cirrhotic liver sample. Conclusions: The results of this study suggest that downregulation of arginase-1 and P-glycoprotein is a feature of canine hepatocellular carcinoma; thus, those markers are potential candidates for use in differentiating hepatocellular carcinomas from non-neoplastic liver lesions in dogs.

키워드

과제정보

We thank Mrs. Eun-Mi Yu for preparing tissue slides.

참고문헌

  1. Patnaik AK, Hurvitz AI, Lieberman PH. Canine hepatic neoplasms: a clinicopathologic study. Vet Pathol. 1980;17(5):553-564. https://doi.org/10.1177/030098588001700504
  2. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47 Suppl:S2-S6. https://doi.org/10.1097/MCG.0b013e3182872f29
  3. Hirose N, Uchida K, Kanemoto H, Ohno K, Chambers JK, Nakayama H. A retrospective histopathological survey on canine and feline liver diseases at the University of Tokyo between 2006 and 2012. J Vet Med Sci. 2014;76(7):1015-1020. https://doi.org/10.1292/jvms.14-0083
  4. Vascellari M, Baioni E, Ru G, Carminato A, Mutinelli F. Animal tumour registry of two provinces in northern Italy: incidence of spontaneous tumours in dogs and cats. BMC Vet Res. 2009;5(1):39. https://doi.org/10.1186/1746-6148-5-39
  5. Partridge BR, O'Brien TJ, Lorenzo MF, Coutermarsh-Ott SL, Barry SL, Stadler K, et al. High-frequency irreversible electroporation for treatment of primary liver cancer: a proof-of-principle study in canine hepatocellular carcinoma. J Vasc Interv Radiol. 2020;31(3):482-491.e4. https://doi.org/10.1016/j.jvir.2019.10.015
  6. Liptak JM, Dernell WS, Monnet E, Powers BE, Bachand AM, Kenney JG, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992-2002). J Am Vet Med Assoc. 2004;225(8):1225-1230. https://doi.org/10.2460/javma.2004.225.1225
  7. Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: a multifaced enzyme important in health and disease. Physiol Rev. 2018;98(2):641-665. https://doi.org/10.1152/physrev.00037.2016
  8. Radwan NA, Ahmed NS. The diagnostic value of arginase-1 immunostaining in differentiating hepatocellular carcinoma from metastatic carcinoma and cholangiocarcinoma as compared to HepPar-1. Diagn Pathol. 2012;7(1):149. https://doi.org/10.1186/1746-1596-7-149
  9. You J, Chen W, Chen J, Zheng Q, Dong J, Zhu Y. The oncogenic role of ARG1 in progression and metastasis of hepatocellular carcinoma. BioMed Res Int. 2018;2018:2109865. https://doi.org/10.1155/2018/2109865
  10. Staud F, Ceckova M, Micuda S, Pavek P. Expression and function of p-glycoprotein in normal tissues: effect on pharmacokinetics. Methods Mol Biol. 2010;596:199-222. https://doi.org/10.1007/978-1-60761-416-6_10
  11. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2011;21(3):152-161. https://doi.org/10.1097/FPC.0b013e3283385a1c
  12. Kong XB, Yang ZK, Liang LJ, Huang JF, Lin HL. Overexpression of P-glycoprotein in hepatocellular carcinoma and its clinical implication. World J Gastroenterol. 2000;6(1):134-135. https://doi.org/10.3748/wjg.v6.i1.134
  13. Takanishi K, Miyazaki M, Ohtsuka M, Nakajima N. Inverse relationship between P-glycoprotein expression and its proliferative activity in hepatocellular carcinoma. Oncology. 1997;54(3):231-237. https://doi.org/10.1159/000227694
  14. Namisaki T, Schaeffeler E, Fukui H, Yoshiji H, Nakajima Y, Fritz P, et al. Differential expression of drug uptake and efflux transporters in Japanese patients with hepatocellular carcinoma. Drug Metab Dispos. 2014;42(12):2033-2040. https://doi.org/10.1124/dmd.114.059832
  15. Vander Borght S, Komuta M, Libbrecht L, Katoonizadeh A, Aerts R, Dymarkowski S, et al. Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin. Liver Int. 2008;28(10):1370-1380. https://doi.org/10.1111/j.1478-3231.2008.01889.x
  16. Zollner G, Wagner M, Fickert P, Silbert D, Fuchsbichler A, Zatloukal K, et al. Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int. 2005;25(2):367-379. https://doi.org/10.1111/j.1478-3231.2005.01033.x
  17. Ng IO, Liu CL, Fan ST, Ng M. Expression of P-glycoprotein in hepatocellular carcinoma. A determinant of chemotherapy response. Am J Clin Pathol. 2000;113(3):355-363. https://doi.org/10.1309/AC1M-4TY4-U0TN-EN7T
  18. Jain R, Fischer S, Serra S, Chetty R. The use of Cytokeratin 19 (CK19) immunohistochemistry in lesions of the pancreas, gastrointestinal tract, and liver. Appl Immunohistochem Mol Morphol. 2010;18(1):9-15. https://doi.org/10.1097/PAI.0b013e3181ad36ea
  19. Kowalik MA, Sulas P, Ledda-Columbano GM, Giordano S, Columbano A, Perra A. Cytokeratin-19 positivity is acquired along cancer progression and does not predict cell origin in rat hepatocarcinogenesis. Oncotarget. 2015;6(36):38749-38763. https://doi.org/10.18632/oncotarget.5501
  20. Feng J, Zhu R, Chang C, Yu L, Cao F, Zhu G, et al. CK19 and glypican 3 expression profiling in the prognostic indication for patients with hepatocellular carcinoma after surgical resection. PLoS One. 2016;11(3):e0151501. https://doi.org/10.1371/journal.pone.0151501
  21. Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, et al. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci. 2003;94(10):851-857. https://doi.org/10.1111/j.1349-7006.2003.tb01366.x
  22. Govaere O, Petz M, Wouters J, Vandewynckel YP, Scott EJ, Topal B, et al. The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma. Oncogene. 2017;36(47):6605-6616. https://doi.org/10.1038/onc.2017.260
  23. van Sprundel RG, van den Ingh TS, Guscetti F, Kershaw O, Kanemoto H, van Gils HM, et al. Classification of primary hepatic tumours in the dog. Vet J. 2013;197(3):596-606. https://doi.org/10.1016/j.tvjl.2013.05.027
  24. Vatnikov Y, Vilkovysky I, Kulikov E, Popova I, Khairova N, Gazin A, et al. Size of canine hepatocellular carcinoma as an adverse prognostic factor for surgery. J Adv Vet Anim Res. 2020;7(1):127-132. https://doi.org/10.5455/javar.2020.g401
  25. Vilkovyskiy IF, Vatnikov YA, Kulikov EV, Sotnikova ED, Yagnikov SA, Seleznev SB, et al. Influence of hepatic neoplasia on life expectancy in dogs. Vet World. 2020;13(3):413-418. https://doi.org/10.14202/vetworld.2020.413-418
  26. Charles JA, Cullen JM, Van den ingh TSGAM, Van winkle T, Desmet VJ. Morphological classification of neoplastic disorders of the canine and feline liver. In: Rothuizen J, Bunch SE, Charles JA, Cullen JM, Desmet VJ, Szatmari V, et al. editors. WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Disease. Amsterdam: W.B. Saunders Company; 2006, 117-124.
  27. Van den ingh TSGAM, Van winkle T, Cullen JM, Charles JA, Desmet VJ. 2006. Morphological classification of parenchymal disorders of the canine and feline liver. In: Rothuizen J, Bunch SE, Charles JA, Cullen JM, Desmet VJ, Szatmari V, et al. editors. WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Disease. Amsterdam: W.B. Saunders Company; 2006, 85-99.
  28. Hewitt SM, Baskin DG, Frevert CW, Stahl WL, Rosa-Molinar E. Controls for immunohistochemistry: the Histochemical Society's standards of practice for validation of immunohistochemical assays. J Histochem Cytochem. 2014;62(10):693-697. https://doi.org/10.1369/0022155414545224
  29. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. https://doi.org/10.1126/science.1260419
  30. Ginn PE. Immunohistochemical detection of P-glycoprotein in formalin-fixed and paraffin-embedded normal and neoplastic canine tissues. Vet Pathol. 1996;33(5):533-541. https://doi.org/10.1177/030098589603300508
  31. Geramizadeh B, Seirfar N. Diagnostic value of arginase-1 and glypican-3 in differential diagnosis of hepatocellular carcinoma, cholangiocarcinoma and metastatic carcinoma of liver. Hepat Mon. 2015;15(7):e30336.
  32. Cao W, Sun B, Feitelson MA, Wu T, Tur-Kaspa R, Fan Q. Hepatitis C virus targets over-expression of arginase I in hepatocarcinogenesis. Int J Cancer. 2009;124(12):2886-2892. https://doi.org/10.1002/ijc.24265
  33. Tashbaeva RE, Hwang DN, Song GS, Choi NH, Lee JH, Lyoo YS, et al. Cellular characterization of multidrug resistance P-glycoprotein, alpha fetoprotein, and neovascular endothelium-associated antigens in canine hepatocellular carcinoma and cirrhotic liver. Vet Pathol. 2007;44(5):600-606. https://doi.org/10.1354/vp.44-5-600
  34. Ramakrishna G, Rastogi A, Trehanpati N, Sen B, Khosla R, Sarin SK. From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence. Liver Cancer. 2013;2(3- 4):367-383. https://doi.org/10.1159/000343852
  35. Ringelhan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philos Trans R Soc Lond B Biol Sci. 2017;372(1732):20160274. https://doi.org/10.1098/rstb.2016.0274
  36. Hepatitis [Internet]. Treasure Island (FL): StatPearls Publishing; https://www.ncbi.nlm.nih.gov/books/NBK554549. Updated 2021. Accessed 2021 May 21.
  37. Zamor PJ, deLemos AS, Russo MW. Viral hepatitis and hepatocellular carcinoma: etiology and management. J Gastrointest Oncol. 2017;8(2):229-242. https://doi.org/10.21037/jgo.2017.03.14
  38. Sykes JE. Infectious Canine Hepatitis. Canine and Feline Infectious Diseases. St. Louis: Elsevier/Saunders; 2014, 182-186.
  39. Moudi B, Mahmoudzadeh-Sagheb H, Heidari Z. Hepatocyte paraffin 1 and arginase-1 are effective panel of markers in HBV-related HCC diagnosis in fine-needle aspiration specimens. BMC Res Notes. 2020;13(1):388. https://doi.org/10.1186/s13104-020-05230-y
  40. Yan BC, Gong C, Song J, Krausz T, Tretiakova M, Hyjek E, et al. Arginase-1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms. Am J Surg Pathol. 2010;34(8):1147-1154. https://doi.org/10.1097/PAS.0b013e3181e5dffa
  41. Kemp SD, Zimmerman KL, Panciera DL, Monroe WE, Leib MS. Histopathologic variation between liver lobes in dogs. J Vet Intern Med. 2015;29(1):58-62. https://doi.org/10.1111/jvim.12520
  42. Cole TL, Center SA, Flood SN, Rowland PH, Valentine BA, Warner KL, et al. Diagnostic comparison of needle and wedge biopsy specimens of the liver in dogs and cats. J Am Vet Med Assoc. 2002;220(10):1483-1490. https://doi.org/10.2460/javma.2002.220.1483
  43. Sanai FM, Keeffe EB. Liver biopsy for histological assessment: The case against. Saudi J Gastroenterol. 2010;16(2):124-132. https://doi.org/10.4103/1319-3767.61244
  44. Dimitroulis D, Damaskos C, Valsami S, Davakis S, Garmpis N, Spartalis E, et al. From diagnosis to treatment of hepatocellular carcinoma: an epidemic problem for both developed and developing world. World J Gastroenterol. 2017;23(29):5282-5294. https://doi.org/10.3748/wjg.v23.i29.5282
  45. Quaglia A. Hepatocellular carcinoma: a review of diagnostic challenges for the pathologist. J Hepatocell Carcinoma. 2018;5:99-108. https://doi.org/10.2147/JHC.S159808
  46. Toth K, Vaughan MM, Peress NS, Slocum HK, Rustum YM. MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors. Am J Pathol 1996;149(3):853-858.
  47. van Sprundel RG, van den Ingh TS, Desmet VJ, Katoonizadeh A, Penning LC, Rothuizen J, et al. Keratin 19 marks poor differentiation and a more aggressive behaviour in canine and human hepatocellular tumours. Comp Hepatol. 2010;9(1):4. https://doi.org/10.1186/1476-5926-9-4