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Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Hepatocellular carcinoma (HCC) frequently exhibits biliary differentiation, which is typically overlooked. Hepatocyte nuclear factor 1β (HNF1β), a bile duct-specific transcription factor expressed in bile ducts but not in the normal hepatocytes, is also expressed in HCC.

Materials and Methods

The expression of HNF1β and the biliary differentiation marker cytokeratin 19 (CK19) were retrospectively evaluated using immunohistochemistry in 159 surgically resected primary HCCs.

Results

A significant correlation was observed between HNF1β protein expression and younger age (p = 0.0293), high serum α-fetoprotein levels (p = 6 × 10−4), and high tumor grade (p = 0.0255). However, HNF1β expression exhibited no correlation with tumor stage. Patients with HCCs and HNF1β expression were more likely to exhibit early tumor recurrence (ETR; p = 0.0048) and a lower 5-year survival rate (p = 0.0001). A multivariate analysis indicated HNF1β expression as an independent prognostic factor in HCC (p = 0.0048). A combinatorial analysis revealed additive adverse effects of HNF1β when concomitant with CK19 expression and p53 mutation. Furthermore, HNF1β expression can predict poor prognosis in patients with ETR.

Conclusion

Our results indicated that HNF1β expression is a crucial predictor of poor prognosis in HCC and is independent of tumor stage. Moreover, concomitant HNF1β and CK19 expressions exhibited additive adverse effects in HCC, confirming that HCC with biliary differentiation has a poor prognosis.

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References

  1. El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 2002;35:S72–S78

    Article  PubMed  Google Scholar 

  2. Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 2002;122:1609–1619

    Article  PubMed  Google Scholar 

  3. Pan HW, Ou YH, Peng SY, Liu SH, Lai PL, Lee PH, Sheu JC, Chen CL, Hsu HC. Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer 2003;98:119–127

    Article  PubMed  CAS  Google Scholar 

  4. Blumenfeld M, Maury M, Chouard T, Yaniv M, Condamine H. Hepatic nuclear factor 1 (HNF1) shows a wider distribution than products of its known target genes in developing mouse. Development 1991;113:589–599

    PubMed  CAS  Google Scholar 

  5. Barbacci E, Reber M, Ott MO, Breillat C, Huetz F, Cereghini S. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development 1999;126:4795–4805

    PubMed  CAS  Google Scholar 

  6. Coffinier C, Barra J, Babinet C, Yaniv M. Expression of the vHNF1/HNF1beta homeoprotein gene during mouse organogenesis. Mech Dev 1999;89:211–213

    Article  PubMed  CAS  Google Scholar 

  7. Coffinier C, Gresh L, Fiette L, Tronche F, Schütz G, Babinet C, Pontoglio M, Yaniv M, Barra J. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. Development 2002;129:1829–1838

    PubMed  CAS  Google Scholar 

  8. Maeda T, Adachi E, Kajiyama K, Sugimachi K, Tsuneyoshi M. Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Hum Pathol 1995;26:956–964

    Article  PubMed  CAS  Google Scholar 

  9. Koh KC, Lee H, Choi MS, Lee JH, Paik SW, Yoo BC, Rhee JC, Cho JW, Park CK, Kim HJ. Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Am J Surg 2005;189:120–125

    Article  PubMed  Google Scholar 

  10. Zhang F, Chen XP, Zhang W, Dong HH, Xiang S, Zhang WG, Zhang BX. Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: immunohistochemical and double-fluorescence immunostaining evidence. Histopathology 2008;52:224–232

    Article  PubMed  CAS  Google Scholar 

  11. Ding SJ, Li Y, Tan YX, Jiang MR, Tian B, Liu YK, Shao XX, Ye SL, Wu JR, Zeng R, Wang HY, Tang ZY, Xia QC. From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics 2004;3:73–81

    Article  PubMed  CAS  Google Scholar 

  12. Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, Tanaka S, Kaneda K, Hirohashi K. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci 2003;94:851–857

    Article  PubMed  CAS  Google Scholar 

  13. Yang XR, Xu Y, Shi GM, Fan J, Zhou J, Ji Y, Sun HC, Qiu SJ, Yu B, Gao Q, He YZ, Qin WZ, Chen RX, Yang GH, Wu B, Lu Q, Wu ZQ, Tang ZY. Cytokeratin 10 and cytokeratin 19: predictive markers for poor prognosis in hepatocellular carcinoma patients after curative resection. Clin Cancer Res 2008;14:3850–3859

    Article  PubMed  CAS  Google Scholar 

  14. Yuan RH, Jeng YM, Hu RH, Lai PL, Lee PH, Cheng CC, Hsu HC. Role of p53 and β-catenin mutations in conjunction with CK19 expression on early tumor recurrence and prognosis of hepatocellular carcinoma. J Gastrointest Surg 2011;15:321–329

    Article  PubMed  Google Scholar 

  15. Wang W, Hayashi Y, Ninomiya T, Ohta K, Nakabayashi H, Tamaoki T, Itoh H. Expression of HNF-1 alpha and HNF-1 beta in various histological differentiations of hepatocellular carcinoma. J Pathol 1998;184:272–278

    Article  PubMed  CAS  Google Scholar 

  16. Yuan RH, Jeng YM, Chen HL, Hsieh FJ, Yang CY, Lee PH, Hsu HC. Opposite roles of human pancreatitis-associated protein and REG1A expression in hepatocellular carcinoma: association of pancreatitis-associated protein expression with low-stage hepatocellular carcinoma, beta-catenin mutation, and favorable prognosis. Clin Cancer Res 2005;11:2568–2575

    Article  PubMed  CAS  Google Scholar 

  17. Yuan RH, Jeng YM, Chen HL, Lai PL, Pan HW, Hsieh FJ, Lin CY, Lee PH, Hsu HC. Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol 2006;209:549–558

    Article  PubMed  CAS  Google Scholar 

  18. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 489,000 necropsies. Cancer 1954;7:462–503

    Article  PubMed  CAS  Google Scholar 

  19. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer staging manual, 7th ed. New York: Springer, 2010

    Google Scholar 

  20. Hsu HC, Huang AM, Lai PL, Chien WM, Peng SY, Lin SW. Genetic alterations at the splice junction of p53 gene in human hepatocellular carcinoma. Hepatology 1994;19:122–128

    Article  PubMed  CAS  Google Scholar 

  21. Peng SY, Chen WJ, Lai PL, Jeng YM, Sheu JC, Hsu HC. High alpha-fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: significance of hepatitis virus infection, age, p53 and beta-catenin mutations. Int J Cancer 2004;112:44–50

    Article  PubMed  CAS  Google Scholar 

  22. Lai YS, Thung SN, Gerber MA, Chen ML, Schaffner F. Expression of cytokeratins in normal and diseased livers and in primary liver carcinomas. Arch Pathol Lab Med 1989;113:134–138

    PubMed  CAS  Google Scholar 

  23. Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J Hepatol 1998;29:455–463

    Article  PubMed  CAS  Google Scholar 

  24. Hsu HC, Tseng HJ, Lai PL, Lee PH, Peng SY. Expression of p53 gene in 184 unifocal hepatocellular carcinomas: association with tumor growth and invasiveness. Cancer Res 1993;53:4691–4694

    PubMed  CAS  Google Scholar 

  25. Hsu HC, Peng SY, Lai PL, Chu JS, Lee PH. Mutations of p53 gene in hepatocellular carcinoma (HCC) correlate with tumor progression and patient prognosis—a study of 138 patients with unifocal HCC. Int J Oncol 1994;4:1341–1347

    PubMed  CAS  Google Scholar 

  26. Hu YL, Zhong D, Pang F, Ning QY, Zhang YY, Li G, Wu JZ, Mo ZN. HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes. Genet Mol Res 2013;12:1327–1335

    Article  PubMed  CAS  Google Scholar 

  27. Shen H, Fridley BL, Song H, Lawrenson K, Cunningham JM, Ramus SJ, Cicek MS, Tyrer J, Stram D, Larson MC, Köbel M. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nat Commun 2013;4:1628. doi: 10.1038/ncomms2629.

    Article  PubMed  Google Scholar 

  28. Buchner A, Castro M, Hennig A, Popp T, Assmann G, Stief CG, Zimmermann W. Downregulation of HNF-1B in renal cell carcinoma is associated with tumor progression and poor prognosis. Urology 2010;76:e6–e11

    Article  PubMed  Google Scholar 

  29. Elliott KS, Zeggini E, McCarthy MI, Gudmundsson J, Sulem P, Stacey SN, Thorlacius S, Amundadottir L. Evaluation of association of HNF1B variants with diverse cancers: collaborative analysis of data from 19 genome-wide association studies. PLoS One 2010;5:e10858. doi: 10.1371/journal.pone.0010858.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shim JH, Lee HC, Han S, Kang HJ, Yu E, Lee SG. Hepatocyte nuclear factor 1β is a novel prognostic marker independent of the Milan criteria in transplantable hepatocellular carcinoma: a retrospective analysis based on tissue microarrays. Liver Transpl 2013;19:336–345

    Article  PubMed  Google Scholar 

  31. Ninomiya T, Hayashi Y, Saijoh K, Ohta K, Yoon S, Nakabayashi H, Tamaoki T, Kasuga M, Itoh H. Expression ratio of hepatocyte nuclear factor-1 to variant hepatocyte nuclear factor-1 in differentiation of hepatocellular carcinoma and hepatoblastoma. J Hepatol 1996;25:445–453

    Article  PubMed  CAS  Google Scholar 

  32. Tsuchiya A, Sakamoto M, Yasuda J, Chuma M, Ohta T, Ohki M, Yasugi T, Taketani Y, Hirohashi S. Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma. Am J Pathol 2003;163:2503–2512

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer 2000;89:500–507

    Article  PubMed  CAS  Google Scholar 

  34. Yuan RH, Chang KT, Chen YL, Hsu HC, Lee PH, Lai PL, Jeng YM. S100P Expression is a novel prognostic factor in hepatocellular carcinoma and predicts survival in patients with high tumor stage or early recurrent tumors. PLoS One 2013;8:e65501doi:10.1371/journal.pone.0065501.

  35. Peng SY, Ou YH, Chen WJ, Li HY, Liu SH, Pan HW, Lai PL, Jeng YM, Chen DC, Hsu HC. Aberrant expressions of annexin A10 short isoform, osteopontin and alpha-fetoprotein at chromosome 4q cooperatively contribute to progression and poor prognosis of hepatocellular carcinoma. Int J Oncol 2005;26:1053–1061

    PubMed  CAS  Google Scholar 

  36. Lee JI, Lee JW, Kim JM, Kim JK, Chung HJ, Kim YS. Prognosis of hepatocellular carcinoma expressing cytokeratin 19: comparison with other liver cancers. World J Gastroenterol 2012;18:4751–4757

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lu XY, Xi T, Lau WY, Dong H, Zhu Z, Shen F, Wu MC, Cong WM. Hepatocellular carcinoma expressing cholangiocyte phenotype is a novel subtype with highly aggressive behavior. Ann Surg Oncol 2011;18:2210–2217

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Miss Eunice J. Yuan for her secretarial assistance.

Conflicts of Interest

The authors declare no conflicts of interest regarding the subject of this study and no commercial interest.

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Authors and Affiliations

  1. Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10051, Taiwan, Republic of China

    Ray-Hwang Yuan & Hong-Shiee Lai

  2. Department of Surgery, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan, Republic of China

    Ray-Hwang Yuan & Hong-Shiee Lai

  3. Department of Diagnostics and Therapeutics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10051, Taiwan, Republic of China

    Ray-Hwang Yuan

  4. Department of Pathology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10051, Taiwan, Republic of China

    Hey-Chi Hsu, Po-Lin Lai & Yung-Ming Jeng

  5. Department of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan, Republic of China

    Hey-Chi Hsu & Yung-Ming Jeng

  6. Graduate Institute of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan, Republic of China

    Yung-Ming Jeng

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Correspondence to Yung-Ming Jeng.

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Yuan, RH., Lai, HS., Hsu, HC. et al. Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma. J Gastrointest Surg 18, 1784–1794 (2014). https://doi.org/10.1007/s11605-014-2596-z

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  • DOI: https://doi.org/10.1007/s11605-014-2596-z

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