Advertisement

Virchows Archiv

, Volume 474, Issue 1, pp 39–46 | Cite as

EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma

  • Mariko Tanaka
  • Junji Shibahara
  • Shumpei Ishikawa
  • Tetsuo Ushiku
  • Teppei Morikawa
  • Aya Shinozaki-Ushiku
  • Akimasa Hayashi
  • Kento Misumi
  • Atsushi Tanaka
  • Hiroto Katoh
  • Kei Sakuma
  • Takashi Kokudo
  • Yoshinori Inagaki
  • Junichi Arita
  • Yoshihiro Sakamoto
  • Kiyoshi Hasegawa
  • Masashi Fukayama
Original Article
  • 104 Downloads

Abstract

Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.

Keywords

EVI1 Intrahepatic cholangiocarcinoma Type 1 Type 2 Gastric phenotype 

Notes

Acknowledgments

We thank all members of the Department of Pathology of The University of Tokyo especially for Kimiko Takeshita and Aiko Nishimoto. We also thank Dr. Yasunori Sato for the kind advice about statistical analysis.

Author contributions

MT and MF contributed to the design and organization and conducted the study and wrote the manuscript. JS, AH, and KM created the pathological database. SI, TU, TM, AS, AT, and HK advised the direction of study and the interpretation of the data. KS helped in the immunohistochemical process. TK, YI, JA, YS, and KH contributed to provide surgical samples and clinical data. All the authors reviewed and accepted the manuscript.

Compliance with ethical standards

The study was approved by the institutional review board.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2018_2476_Fig4_ESM.png (237 kb)
Supplementary Figure 1

EVI1 was upregulated in cholangiocarcinoma in TCGA database: EVI1 (MECOM) was upregulated in cholangiocarcinoma (CHOL, orange square), pancreatic adenocarcinoma (PAAD), and uterine corpus endometrial carcinoma (UCEC) (black arrows). The bar graph showed RSEM mRNASeq EVI1 expression profiles for each The Cancer Genome Atlas (TCGA) disease chart. ACC; Adrenocortical carcinoma; BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, Cholangiocarcinoma; COAD, Colon adenocarcinoma; COADREAD, Colorectal adenocarcinoma; DLBC, Lymphoid neoplasm diffuse large-B cell lymphoma; ESCA, Esophageal carcinoma; GBM, Glioblastoma multiforme; GBMLGG, Glioma; HNSC, Head and neck squamous cell carcinoma; KICH, Kidney chromophobe; KIPAN, Pan-kidney cohort; KIRC, Kidney renal clear cell carcinoma; KIRP, Kidney renal papillary cell carcinoma; LAML, Acute myeloid leukemia; LGG, Brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, Lung adenocarcinoma; LUSC, Lung squamous cell carcinoma; MESO, Mesothelioma; OV, Ovarian serous cystadenocarcinoma; PAAD, Pancreatic adenocarcinoma; PCPG, Pheochromocytoma and paraganglioma; PRAD, Prostate adenocarcinoma; READ, Rectum adenocarcinoma; SARC, Sarcoma; SKCM, Skin cutaneous melanoma; STAD, Stomach adenocarcinoma; STES, Stomach and esophageal carcinoma; TGCT, Testicular germ cell tumor; THCA, Thyroid carcinoma; THYM, Thymoma; UCEC, Uterine corpus endometrial carcinoma; UCS, Uterine carcinosarcoma; UVM, Uveal melanoma. (Referred to http://firebrowse.org/viewGene.html?gene=MECOM) (PNG 237 kb)

428_2018_2476_MOESM1_ESM.tif (9.6 mb)
High resolution image (TIF 9838 kb)

References

  1. 1.
    Nakanuma Y, Curado MP, Franceschi S, et al. (2010) Intrahepatic cholangiocarcinoma. Albores-Saavedra J, Adsay NV, Crawford JM, et al. Carcinoma of the gallbladder and extrahepatic bile ducts. In: Bosman F, Carneiro F, Hruban R, Theise N eds). WHO Classification of Tumours of the Digestive System. Fourth edn., International Agency for Research on Cancer IARC): Lyon, pp 217–224, 264–273Google Scholar
  2. 2.
    Zaret KS, Grompe M (2008) Generation and regeneration of cells of the liver and pancreas. Science 322(5907):1490–1494.  https://doi.org/10.1126/science.1161431 CrossRefGoogle Scholar
  3. 3.
    Nakanuma Y (2010) A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: is the biliary tract an incomplete pancreas? Pathol Int 60(6):419–429CrossRefGoogle Scholar
  4. 4.
    Gandou C, Harada K, Sato Y, Igarashi S, Sasaki M, Ikeda H, Nakanuma Y (2013) Hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma share similar histopathologies, immunophenotypes, and development-related molecules. Hum Pathol 44(5):811–821CrossRefGoogle Scholar
  5. 5.
    Nakanuma Y, Sato Y (2014) Hilar cholangiocarcinoma is pathologically similar to pancreatic duct adenocarcinoma: suggestions of similar background and development. J hepato-bil-pan sci 21(7):441–447Google Scholar
  6. 6.
    Hsu M, Sasaki M, Igarashi S, Sato Y, Nakanuma Y (2013) KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas. Cancer 119(9):1669–1674CrossRefGoogle Scholar
  7. 7.
    Sobin LH, Gospodarowicz MK, Wittekind C (eds) (2009) UICC TNM classification of malignant tumours, seventh edn. Wiley–Blackwell, New YorkGoogle Scholar
  8. 8.
    Hayashi A, Misumi K, Shibahara J, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Fukayama M (2016) Distinct clinicopathologic and genetic features of 2 histologic subtypes of intrahepatic cholangiocarcinoma. Am J Surg Pathol 40(8):1021–1030CrossRefGoogle Scholar
  9. 9.
    Aishima S, Oda Y (2015) Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type. J hepato-bil-pan sci 22(2):94–100Google Scholar
  10. 10.
    Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Taketomi A, Maehara Y, Tsuneyoshi M (2006) Gastric mucin phenotype defines tumour progression and prognosis of intrahepatic cholangiocarcinoma: gastric foveolar type is associated with aggressive tumour behaviour. Histopathology 49(1):35–44CrossRefGoogle Scholar
  11. 11.
    Shinozaki A, Shibahara J, Noda N, Tanaka M, Aoki T, Kokudo N, Fukayama M (2011) Claudin-18 in biliary neoplasms. Its significance in the classification of intrahepatic cholangiocarcinoma. Virchows Arch 459(1):73–80CrossRefGoogle Scholar
  12. 12.
    Tian F, Li D, Chen J, Liu W, Cai L, Li J, Jiang P, Liu Z, Zhao X, Guo F, Li X, Wang S (2013) Aberrant expression of GATA binding protein 6 correlates with poor prognosis and promotes metastasis in cholangiocarcinoma. Eur J Cancer 49(7):1771–1780CrossRefGoogle Scholar
  13. 13.
    Mall AS, Tyler MG, Ho SB et al (2010) The expression of MUC mucin in cholangiocarcinoma. Pathol Res Pract 206(12):805–809CrossRefGoogle Scholar
  14. 14.
    Abe T, Amano H, Shimamoto F, Hattori M, Kuroda S, Kobayashi T, Tashiro H, Ohdan H (2015) Prognostic evaluation of mucin-5AC expression in intrahepatic cholangiocarcinoma, mass-forming type, following hepatectomy. Eur J Surg Oncol 41(11):1515–1521CrossRefGoogle Scholar
  15. 15.
    Tanaka M, Suzuki HI, Shibahara J, Kunita A, Isagawa T, Yoshimi A, Kurokawa M, Miyazono K, Aburatani H, Ishikawa S, Fukayama M (2014) EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis. Oncogene 33(19):2454–2463CrossRefGoogle Scholar
  16. 16.
    Akita M, Fujikura K, Ajiki T, Fukumoto T, Otani K, Azuma T, Itoh T, Ku Y, Zen Y (2017) Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas. Mod Pathol 30(7):986–997CrossRefGoogle Scholar
  17. 17.
    Sohal DP, Shrotriya S, Abazeed M et al (2016) Molecular characteristics of biliary tract cancer. Crit Rev Oncol Hemat 107:111–118Google Scholar
  18. 18.
    Chong DQ, Zhu AX (2016) The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget 7(29):46750–46767CrossRefGoogle Scholar
  19. 19.
    Moeini A, Sia D, Bardeesy N et al (2016) Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res 22(2):291–300CrossRefGoogle Scholar
  20. 20.
    Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T (2015) Genomic spectra of biliary tract cancer. Nat Genet 47(9):1003–1010CrossRefGoogle Scholar
  21. 21.
    Liu J, Ji S, Liang C, Qin Y et al (2016) Critical role of oncogenic KRAS in pancreatic cancer (review). Mol Med Rep 13(6):4943–4949CrossRefGoogle Scholar
  22. 22.
    Patra KC, Bardeesy N, Mizukami Y (2017) Diversity of precursor lesions for pancreatic cancer: the genetics and biology of intraductal papillary mucinous neoplasm. Clin Transl Gastroen 8(4):e86Google Scholar
  23. 23.
    Kopp JL, Dubois CL, Schaeffer DF et al (2018) Loss of Pten and activation of Kras synergistically induce formation of intraductal papillary mucinous neoplasia from pancreatic ductal cells in mice. Gastroenterology 154(5):1509–1523.e5CrossRefGoogle Scholar
  24. 24.
    Kim GE, Bae HI, Park HU et al (2002) Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas. Gastroenterology 123(4):1052–1060CrossRefGoogle Scholar
  25. 25.
    Moschovis D, Bamias G, Delladetsima I (2016) Mucins in neoplasms of pancreas, ampulla of Vater and biliary system. World J Gastrointest Oncol 8(10):725–734Google Scholar
  26. 26.
    Syed J, Pandian GN, Sato S et al (2014) Targeted suppression of EVI1 oncogene expression by sequence-specific pyrrole-imidazole polyamide. Chem Biol 21(10):1370–1380CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Mariko Tanaka
    • 1
  • Junji Shibahara
    • 2
  • Shumpei Ishikawa
    • 3
  • Tetsuo Ushiku
    • 1
  • Teppei Morikawa
    • 4
  • Aya Shinozaki-Ushiku
    • 1
  • Akimasa Hayashi
    • 1
  • Kento Misumi
    • 1
  • Atsushi Tanaka
    • 1
  • Hiroto Katoh
    • 3
  • Kei Sakuma
    • 1
  • Takashi Kokudo
    • 5
  • Yoshinori Inagaki
    • 5
  • Junichi Arita
    • 5
  • Yoshihiro Sakamoto
    • 6
  • Kiyoshi Hasegawa
    • 5
  • Masashi Fukayama
    • 1
  1. 1.Department of Pathology, Graduate School of MedicineThe University of TokyoTokyoJapan
  2. 2.Department of PathologyKyorin University HospitalTokyoJapan
  3. 3.Department of Genomic PathologyMedical Research Institute Tokyo Medical and Dental UniversityTokyoJapan
  4. 4.Pathology DivisionNTT Medical Center TokyoTokyoJapan
  5. 5.Department of Surgery, Hepato-Biliary-Pancreatic Surgery, Graduate School of MedicineThe University of TokyoTokyoJapan
  6. 6.Department of SurgeryKyorin University HospitalTokyoJapan

Personalised recommendations