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Risk of carcinogenesis in the biliary epithelium of children with congenital biliary dilatation through epigenetic and genetic regulation

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Abstract

Purposes

Congenital biliary dilatation (CBD), defined as pancreaticobiliary maljunction (PBM) with biliary dilatation, is a high risk factor for biliary tract cancer (BTC). KRAS and p53 mutations reportedly affect this process, but the mechanisms are unclear, as is the likelihood of BTC later in life in children with CBD. We investigated potential carcinogenetic pathways in children with CBD compared with adults.

Methods

The subjects of this study were nine children with CBD and 13 adults with PBM (10 dilated, 3 non-dilated) without BTC who underwent extrahepatic bile duct resections, as well as four control patients who underwent pancreaticoduodenectomy for non-biliary cancer. We evaluated expressions of Ki-67, KRAS, p53, histone deacetylase (HDAC) and activation-induced cytidine deaminase (AID) in the biliary tract epithelium immunohistochemically.

Results

The Ki-67 labeling index (LI) and expressions of KRAS, p53, HDAC, and AID in the gallbladder epithelium were significantly higher or tended to be higher in both the children with CBD and the adults with PBM than in the controls.

Conclusions

BTC may develop later in children with CBD and in adults with PBM, via HDAC and AID expression and through epigenetic and genetic regulation.

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Abbreviations

AID:

Activation-induced cytidine deaminase

BTC:

Biliary tract cancer

CBD:

Congenital biliary dilatation

HDAC:

Histone deacetylase

HDACs:

Histone deacetylases

LI:

Labeling index

PBM:

Pancreaticobiliary maljunction

SD:

Standard deviation

References

  1. Tashiro S, Imaizumi T, Ohkawa H, Okada A, Katoh T, Kawaharada Y, et al. Pancreaticobiliary maljunction: retrospective and nationwide survey in Japan. J Hepatobiliary Pancreat Surg. 2003;10(5):345–51.

    Article  PubMed  Google Scholar 

  2. Tsuchida A, Itoi T, Aoki T, Koyanagi Y. Carcinogenetic process in gallbladder mucosa with pancreaticobiliary maljunction. Oncol Rep. 2003;10(6):1693–9.

    CAS  PubMed  Google Scholar 

  3. Funabiki T, Matsubara T, Miyakawa S, Ishihara S. Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy. Langenbecks Arch Surg. 2009;394(1):159–69.

    Article  PubMed  Google Scholar 

  4. Tanno S, Obara T, Fujii T, Mizukami Y, Shudo R, Nishino N, et al. Proliferative potential and k-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union. Cancer. 1998;83(2):267–75.

    Article  CAS  PubMed  Google Scholar 

  5. Nagai M, Watanabe M, Iwase T, Yamao K, Isaji S. Clinical and genetic analysis of noncancerous and cancerous biliary epithelium in patients with pancreaticobiliary maljunction. World J Surg. 2002;26(1):91–8.

    Article  PubMed  Google Scholar 

  6. Matsubara T, Sakurai Y, Zhi L-Z, Miura H, Ochiai M, Funabiki T. K-ras and p-53 gene mutations in noncancerous biliary lesions of patients with pancreatico biliary maljunction. J Hepatobiliary Pancreat Surg. 2002;9(3):312–21.

    Article  PubMed  Google Scholar 

  7. Kamisawa T, Funata N, Hayashi Y, Egawa N, Nakajima H, Tsuruta K, et al. Pathologic changes in the non-carcinomatous epithelium of the gallbladder in patients with a relatively long common channel. Gastrointest Endosc. 2004;60(1):56–60.

    Article  PubMed  Google Scholar 

  8. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10(1):32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6(1):38–51.

    Article  CAS  PubMed  Google Scholar 

  10. Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene. 2007;26(37):5420–32.

    Article  CAS  PubMed  Google Scholar 

  11. Patra SK, Patra A, Dahiya R. Histone deacetylase and DNA methyltransferase in human prostate cancer. Biochem Biophys Res Commun. 2001;287(3):705–13.

    Article  CAS  PubMed  Google Scholar 

  12. Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Göttlicher M. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell. 2004;5(5):455–63.

    Article  CAS  PubMed  Google Scholar 

  13. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 1998;391(6669):811–4.

    Article  CAS  PubMed  Google Scholar 

  14. Miyatani T, Kurita N, Mikami C, Kashihara H, Higashijima J, Yoshikawa K, et al. Malignant potential of Barrett’s esophagus: special reference to HDAC-1 and MTA-1 expression. Hepatogastroenterology. 2011;58(106):472–6.

    CAS  PubMed  Google Scholar 

  15. Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature. 2003;424(6944):94–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Honjo T, Kinoshita K, Muramatsu M. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol. 2002;20:165–96.

    Article  CAS  PubMed  Google Scholar 

  17. Wedekind JE, Dance GS, Sowden MP, Smith HC. Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business. Trends Genet. 2003;19(4):207–16.

    Article  CAS  PubMed  Google Scholar 

  18. Cascalho M. Advantages and disadvantages of cytidine deamination. J Immunol. 2004;172(11):6513–8.

    Article  CAS  PubMed  Google Scholar 

  19. Kinoshita K, Nonaka T. The dark side of activation-induced cytidine deaminase: relationship with leukemia and beyond. Int J Hematol. 2006;83(3):201–7.

    Article  CAS  PubMed  Google Scholar 

  20. Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med. 2007;13(4):470–6.

    Article  CAS  PubMed  Google Scholar 

  21. Li M, Liu W, Zhu YF, Chen YL, Zhang BZ, Wang R. Correlation of COX-2 and K-ras expression to clinical outcome in gastric cancer. Acta Oncol. 2006;45(8):1115–9.

    Article  CAS  PubMed  Google Scholar 

  22. Theocharis S, Klijanienko J, Giaginis C, Rodriguez J, Jouffroy T, Girod A, et al. Histone deacetylase-1 and -2 expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. J Oral Pathol Med. 2011;40(9):706–14.

    Article  PubMed  Google Scholar 

  23. Nakanishi Y, Kondo S, Wakisaka N, Tsuji A, Endo K, Murono S, et al. Role of activation-induced cytidine deaminase in the development of oral squamous cell carcinoma. PLoS ONE. 2013;8(4):e62066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gonzalez-Angulo AM, Sneige N, Buzdar AU, Valero V, Kau SW, Broglio K, et al. p53 expression as a prognostic marker in inflammatory breast cancer. Clin Cancer Res. 2004;10(18 Pt 1):6215–21.

    Article  CAS  PubMed  Google Scholar 

  25. Kato T, Matsuda K, Kayaba H, Enomoto S, Hebiguchi T, Koyama K, et al. Pathology of anomalous junction of the pancreaticobiliary ductal system: mutagenicity of the contents of the biliary tract and nuclear atypia of the biliary epithelium. Keio J Med. 1989;38(2):167–76.

    Article  CAS  PubMed  Google Scholar 

  26. Kamisawa T, Kurata M, Honda G, Tsuruta K, Okamoto A. Biliopancreatic reflux-pathophysiology and clinical implications. J Hepatobiliary Pancreat Surg. 2009;16(1):19–24.

    Article  PubMed  Google Scholar 

  27. Shimada K, Yanagisawa J, Nakayama F. Increased lysophosphatidylcholine and pancreatic enzyme content in bile of patients with anomalous pancreaticobiliary ductal junction. Hepatology. 1991;13(3):438–44.

    Article  CAS  PubMed  Google Scholar 

  28. Tsuchida A, Itoi T. Carcinogenesis and chemoprevention of biliary tract cancer in pancreaticobiliary maljunction. World J Gastrointest Oncol. 2010;2(3):130–5.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kamisawa T, Kuruma S, Chiba K, Tabata T, Koizumi S, Kikuyama M. Biliary carcinogenesis in pancreaticobiliary maljunction. J Gastroenterol. 2017;52(2):158–63.

    Article  CAS  PubMed  Google Scholar 

  30. Morine Y, Shimada M, Takamatsu H, Araida T, Endo I, Kubota M, et al. Clinical features of pancreaticobiliary maljunction: update analysis of 2nd Japan-nationwide survey. J Hepatobiliary Pancreat Sci. 2013;20(5):472–80.

    Article  PubMed  Google Scholar 

  31. Hanada K, Itoh M, Fujii K, Tsuchida A, Ooishi H, Kajiyama G. K-ras and p53 mutations in stage I gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct. Cancer. 1996;77(3):452–8.

    Article  CAS  PubMed  Google Scholar 

  32. Singh MK, Chetri K, Pandey UB, Kapoor VK, Mittal B, Choudhuri G. Mutational spectrum of K-ras oncogene among Indian patients with gallbladder cancer. J Gastroenterol Hepatol. 2004;19(8):916–21.

    Article  CAS  PubMed  Google Scholar 

  33. Tazuma S, Kajiyama G. Carcinogenesis of malignant lesions of the gall bladder: the impact of chronic inflammation and gallstones. Langenbecks Arch Surg. 2001;386(3):224–9.

    Article  CAS  PubMed  Google Scholar 

  34. Tomono H, Nimura Y, Aono K, Nakashima I, Iwamoto T, Nakashima N. Point mutations of the c-Ki-ras gene in carcinoma and atypical epithelium associated with congenital biliary dilatation. Am J Gastroenterol. 1996;91(6):1211–4.

    CAS  PubMed  Google Scholar 

  35. Matsubara T, Funabiki T, Jinno O, Sakurai Y, Hasegawa S, Imazu H, et al. p53 gene mutations and overexpression of p53 product in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction. J Hepatobiliary Pancreat Surg. 1999;6(3):286–93.

    Article  CAS  PubMed  Google Scholar 

  36. Wistuba II, Gazdar AF. Gallbladder cancer: lessens from rare tumour. Nat Rev Cancer. 2004;4(9):695–706.

    Article  CAS  PubMed  Google Scholar 

  37. Weichert W. HDAC expression and clinical prognosis in human malignancies. Cancer Lett. 2009;280(2):168–76.

    Article  CAS  PubMed  Google Scholar 

  38. Shukla S, Khan S, Kumar S, Sinha S, Farhan M, Bora HK, et al. Cucurbitacin B alters the expression of tumor-related genes by epigenetic modifications in NSCLC and inhibits NNK-induced lung tumorigenesis. Cancer Prev Res (Phila). 2015;8(6):552–62.

    Article  CAS  Google Scholar 

  39. Tong X, Yin L, Giardina C. Butylrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition. Biochem Biophys Res Commun. 2004;317(2):463–71.

    Article  CAS  PubMed  Google Scholar 

  40. Biran A, Brownstein M, Haklai R, Kloog Y. Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy. Int J Cancer. 2011;128(3):691–701.

    Article  CAS  PubMed  Google Scholar 

  41. Toh Y, Nicolson GL. The role of the MTA family and their encoded proteins in humancancers: molecular functions and clinical implications. Clin Exp Metastasis. 2009;26(3):215–27.

    Article  CAS  PubMed  Google Scholar 

  42. Søreide K, Søreide JA. Bile duct cyst as precursor to biliary tract cancer. Ann Surg Oncol. 2007;14(3):1200–11.

    Article  PubMed  Google Scholar 

  43. Chaudhuri J, Alt FW. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol. 2004;4(7):541–52.

    Article  CAS  PubMed  Google Scholar 

  44. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102(5):553–63.

    Article  CAS  PubMed  Google Scholar 

  45. Endo Y, Marusawa H, Kou T, Nakase H, Fujii S, Fujimori T, et al. Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers. Gastroenterology. 2008;135(3):889–98.

    Article  CAS  PubMed  Google Scholar 

  46. Komori J, Marusawa H, Machimoto T, Endo Y, Kinoshita K, Kou T, et al. Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology. 2008;47(3):888–96.

    Article  CAS  PubMed  Google Scholar 

  47. Morita S, Matsumoto Y, Okuyama S, Ono K, Kitamura Y, Tomori A, et al. Bile acid-induced expression of activationinduced cytidine deaminase during the development of Barrett’s oesophageal adenocarcinoma. Carcinogenesis. 2011;32(11):1706–12.

    Article  CAS  PubMed  Google Scholar 

  48. Kou T, Marusawa H, Kinoshita K, Endo Y, Okazaki IM, Ueda Y, et al. Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis. Int J Cancer. 2007;120(3):469–76.

    Article  CAS  PubMed  Google Scholar 

  49. Morisawa T, Marusawa H, Ueda Y, Iwai A, Okazaki IM, Honjo T, et al. Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. Int J Cancer. 2008;123(12):2735–40.

    Article  CAS  PubMed  Google Scholar 

  50. Ono S, Tokiwa K, Iwai N. Cellular activity in the gallbladder of children with anomalous arrangement of the pancreaticobiliary duct. J pediatr surg. 1999;34(6):962–6.

    Article  CAS  PubMed  Google Scholar 

  51. Saikusa N, Naito S, Iinuma Y, Ohtani T, Yokoyama N, Nitta K. Invasive cholangiocarcinoma identified in congenital biliary dilatation in a 3-year-old boy. J Pediatr Surg. 2009;44(11):2202–5.

    Article  PubMed  Google Scholar 

  52. Nakamura H, Katayose Y, Rikiyama T, Onogawa T, Yamamoto K, Yoshida H, et al. Advanced bile duct carcinoma in a 15-year-old patient with pancreaticobiliary maljunction and congenital biliary cystic disease. J Hepatobiliary Pancreat Surg. 2008;15(5):554–9.

    Article  PubMed  Google Scholar 

  53. Tanaka S, Kubota M, Yagi M, Okuyama N, Ohtaki M, Yamazaki S, et al. An 11-year-old male patient demonstrating cholangiocarcinoma associated with congenital biliary dilatation. J Pediatr Surg. 2006;41(1):e15–9.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Institute of Health Biosciences, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Hiroki Mori, Yuji Morine, Hiroki Ishibashi & Mitsuo Shimada

  2. Department of Pediatric Surgery, Osaka Women’s and Children’s Hospital, Murodoucho 840, Izumi, Osaka, 594-1101, Japan

    Kazunori Masahata, Satoshi Umeda & Noriaki Usui

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  1. Hiroki Mori
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  2. Kazunori Masahata
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Correspondence to Hiroki Mori.

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The protocol for this research project was approved by the Ethics Committee of our institution (No. 3010) and conforms to the provisions of the Declaration of Helsinki.

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Mori, H., Masahata, K., Umeda, S. et al. Risk of carcinogenesis in the biliary epithelium of children with congenital biliary dilatation through epigenetic and genetic regulation. Surg Today 52, 215–223 (2022). https://doi.org/10.1007/s00595-021-02325-2

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