Increased Expression of Hepatocyte Nuclear Factor 4 Alpha Transcribed by Promoter 2 Indicates a Poor Prognosis in Hepatocellular Carcinoma

Overview

Journal Therap Adv Gastroenterol

Publisher Sage Publications

Specialty Gastroenterology

Date 2017 Oct 21

PMID 29051787

Citations 42

Authors

Shao-Hang Cai

Shi-Xun Lu

Li-Li Liu

Chris Zhiyi Zhang

Jing-Ping Yun

Affiliations

Soon will be listed here.

Abstract

Background: Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear.

Methods: A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan-Meier analysis was conducted to assess the prognostic value of P2-HNF4α.

Results: The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression ( = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC ( = 0.002) and vascular invasion ( = 0.017). Kaplan-Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group ( = 0.01), validation group ( = 0.034), and overall group of patients with HCC ( < 0.001).

Conclusions: Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

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References

Hanawa M, Takayama K, Sakurai F, Tachibana M, Mizuguchi H . Hepatocyte Nuclear Factor 4 Alpha Promotes Definitive Endoderm Differentiation from Human Induced Pluripotent Stem Cells. Stem Cell Rev Rep. 2016; 13(4):542-551. DOI: 10.1007/s12015-016-9709-x. View

Sel S, Ebert T, Ryffel G, Drewes T . Human renal cell carcinogenesis is accompanied by a coordinate loss of the tissue specific transcription factors HNF4 alpha and HNF1 alpha. Cancer Lett. 1996; 101(2):205-10. DOI: 10.1016/0304-3835(96)04136-5. View

Yi C, Wang Q, Wang L, Huang Y, Li L, Liu L . MiR-663, a microRNA targeting p21(WAF1/CIP1), promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma. Oncogene. 2012; 31(41):4421-33. DOI: 10.1038/onc.2011.629. View

Hwang-Verslues W, Sladek F . HNF4α--role in drug metabolism and potential drug target?. Curr Opin Pharmacol. 2010; 10(6):698-705. PMC: 2981672. DOI: 10.1016/j.coph.2010.08.010. View

Tanaka T, Jiang S, Hotta H, Takano K, Iwanari H, Sumi K . Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. J Pathol. 2006; 208(5):662-72. DOI: 10.1002/path.1928. View

Ning B, Ding J, Yin C, Zhong W, Wu K, Zeng X . Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res. 2010; 70(19):7640-51. DOI: 10.1158/0008-5472.CAN-10-0824. View

Harries L, Locke J, Shields B, Hanley N, Piper Hanley K, Steele A . The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development. Diabetes. 2008; 57(6):1745-52. DOI: 10.2337/db07-1742. View

Drewes T, Senkel S, Holewa B, Ryffel G . Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol. 1996; 16(3):925-31. PMC: 231074. DOI: 10.1128/MCB.16.3.925. View

Oshima T, Kawasaki T, Ohashi R, Hasegawa G, Jiang S, Umezu H . Downregulated P1 promoter-driven hepatocyte nuclear factor-4alpha expression in human colorectal carcinoma is a new prognostic factor against liver metastasis. Pathol Int. 2007; 57(2):82-90. DOI: 10.1111/j.1440-1827.2006.02061.x. View

10.

Duncan S, Nagy A, Chan W . Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(-/-) embryos. Development. 1997; 124(2):279-87. DOI: 10.1242/dev.124.2.279. View

11.

Mizuguchi T, Mitaka T, Hirata K, Oda H, Mochizuki Y . Alteration of expression of liver-enriched transcription factors in the transition between growth and differentiation of primary cultured rat hepatocytes. J Cell Physiol. 1998; 174(3):273-84. DOI: 10.1002/(SICI)1097-4652(199803)174:3<273::AID-JCP1>3.0.CO;2-L. View

12.

Chen W, Manova K, Weinstein D, Duncan S, Plump A, Prezioso V . Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev. 1994; 8(20):2466-77. DOI: 10.1101/gad.8.20.2466. View

13.

Li J, Ning G, Duncan S . Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev. 2000; 14(4):464-74. PMC: 316377. View

14.

Darsigny M, Babeu J, Seidman E, Gendron F, Levy E, Carrier J . Hepatocyte nuclear factor-4alpha promotes gut neoplasia in mice and protects against the production of reactive oxygen species. Cancer Res. 2010; 70(22):9423-33. DOI: 10.1158/0008-5472.CAN-10-1697. View

15.

Lazarevich N, Shavochkina D, Fleishman D, Kustova I, Morozova O, Chuchuev E . Deregulation of hepatocyte nuclear factor 4 (HNF4)as a marker of epithelial tumors progression. Exp Oncol. 2011; 32(3):167-71. View

16.

Iacob R, Rudrich U, Rothe M, Kirsch S, Maasoumy B, Narain N . Induction of a mature hepatocyte phenotype in adult liver derived progenitor cells by ectopic expression of transcription factors. Stem Cell Res. 2011; 6(3):251-61. DOI: 10.1016/j.scr.2011.02.002. View

17.

Babeu J, Boudreau F . Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks. World J Gastroenterol. 2014; 20(1):22-30. PMC: 3886012. DOI: 10.3748/wjg.v20.i1.22. View

18.

Eeckhoute J, Moerman E, Bouckenooghe T, Lukoviak B, Pattou F, Formstecher P . Hepatocyte nuclear factor 4 alpha isoforms originated from the P1 promoter are expressed in human pancreatic beta-cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms. Endocrinology. 2003; 144(5):1686-94. DOI: 10.1210/en.2002-0024. View

19.

Saandi T, Baraille F, Derbal-Wolfrom L, Cattin A, Benahmed F, Martin E . Regulation of the tumor suppressor homeogene Cdx2 by HNF4α in intestinal cancer. Oncogene. 2012; 32(32):3782-8. DOI: 10.1038/onc.2012.401. View

20.

Lenburg M, Liou L, Gerry N, Frampton G, Cohen H, Christman M . Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data. BMC Cancer. 2003; 3:31. PMC: 317310. DOI: 10.1186/1471-2407-3-31. View