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A potential role for the homeoprotein Hhex in hepatocellular carcinoma progression

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Abstract

Hepatocellular carcinoma (HCC), the most common primary malignant tumor of the liver, often associated with the dysregulation of transcriptional pathways involved in cell growth and differentiation. The hematopoietically expressed homeobox protein (Hhex) is an important transcription factor throughout liver development and is essential to liver bud formation and hepatoblast differentiation. Here, we report a relationship between Hhex expression and HCC. First, adenovirus-mediated Hhex delivery into the hepatoma cell line, Hepa1-6, resulted in decreased expression of several proto-oncogenes (c-Jun and Bcl2), increased expression of some tumor suppressor genes (P53 and Rb), and enhanced expression of a cluster of hepatocytic and bile ductular markers. Second, Hhex expression significantly attenuated Hepa1-6 tumorigenicity in nude mice. Third, we report a correlation between Hhex expression and the differentiation state of human HCC. In 24 cases of clinical specimens, there was a significant difference in Hhex expression between poorly differentiated HCC and well-differentiated HCC (P < 0.001). Taken together, these results indicate that Hhex is a potential candidate molecular marker for HCC pathological evaluation, suggesting a need to evaluate Hhex as a potential target for therapeutic intervention.

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References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  PubMed  CAS  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  3. Wilson RE, Antman KH, Brodsky G, Greenberger JS. Tumor-cell heterogeneity in soft tissue sarcomas as defined by chemoradiotherapy. Cancer. 1984;53:1420–5.

    Article  PubMed  CAS  Google Scholar 

  4. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11:259–73.

    Article  PubMed  CAS  Google Scholar 

  5. Ishiyama T, Kano J, Minami Y, Iijima T, Morishita Y, Noguchi M. Expression of HNFs and C/EBP alpha is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytes. Cancer Sci. 2003;94:757–63.

    Article  PubMed  CAS  Google Scholar 

  6. Lazarevich NL, Cheremnova OA, Varga EV, Ovchinnikov DA, Kudrjavtseva EI, Morozova OV, Fleishman DI, Engelhardt NV, Duncan SA. Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors. Hepatology. 2004;39:1038–47.

    Article  PubMed  CAS  Google Scholar 

  7. Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandl S, Bachmann MH, Borowsky AD, Ruebner B, Cardiff RD, Yang Q, Bishop JM, Contag CH, Felsher DW. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004;431:1112–7.

    Article  PubMed  CAS  Google Scholar 

  8. Yin C, Lin Y, Zhang X, Chen YX, Zeng X, Yue HY, Hou JL, Deng X, Zhang JP, Han ZG, Xie WF. Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4 alpha gene. Hepatology. 2008;48:1528–39.

    Article  PubMed  CAS  Google Scholar 

  9. Kubo A, Chen V, Kennedy M, Zahradka E, Daley GQ, Keller G. The homeobox gene HEX regulates proliferation and differentiation of hemangioblasts and endothelial cells during ES cell differentiation. Blood. 2005;105:4590–7.

    Article  PubMed  CAS  Google Scholar 

  10. Bogue CW, Zhang PX, McGrath J, Jacobs HC, Fuleihan RL. Impaired B cell development and function in mice with a targeted disruption of the homeobox gene Hex. Proc Natl Acad Sci USA. 2003;100:556–61.

    Article  PubMed  CAS  Google Scholar 

  11. Foley AC, Mercola M. Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Genes Dev. 2005;19:387–96.

    Article  PubMed  CAS  Google Scholar 

  12. Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, Fraenkel E, Bell GI, Young RA. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303:1378–81.

    Article  PubMed  CAS  Google Scholar 

  13. Hunter MP, Wilson CM, Jiang X, Cong R, Vasavada H, Kaestner KH, Bogue CW. The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev Biol. 2007;308:355–67.

    Article  PubMed  CAS  Google Scholar 

  14. Martinez-Barbera JP, Clements M, Thomas P, Rodriguez T, Meloy D, Kioussis D, Beddington RS. The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development. 2000;127:2433–45.

    PubMed  CAS  Google Scholar 

  15. Tanaka T, Inazu T, Yamada K, Myint Z, Keng VW, Inoue Y, Taniguchi N, Noguchi T. cDNA cloning and expression of rat homeobox gene, Hex, and functional characterization of the protein. Biochem J. 1999;339:111–7.

    Article  PubMed  CAS  Google Scholar 

  16. Guo Y, Chan R, Ramsey H, Li W, Xie X, Shelley WC, Martinez-Barbera JP, Bort B, Zaret K, Yoder M, Hromas R. The homeoprotein Hex is required for hemangioblast differentiation. Blood. 2003;102:2428–35.

    Article  PubMed  CAS  Google Scholar 

  17. Soufi A, Jayaraman PS. PRH/Hex: an oligomeric transcription factor and multifunctional regulator of cell fate. Biochem J. 2008;412:399–413.

    Article  PubMed  CAS  Google Scholar 

  18. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA. 1998;95:2509–14.

    Article  PubMed  CAS  Google Scholar 

  19. Kanegae Y, Makimura M, Saito I. A simple and efficient method for purification of infectious recombinant adenovirus. Jpn J Med Sci Biol. 1994;47:157–66.

    PubMed  CAS  Google Scholar 

  20. Talarico LB, Pujol CA, Zibetti RGM, Faría PCS, Noseda MD, Duarte MER, Damonte EB. The antiviral activity of sulfated polysaccharides against dengue virus is dependent on virus serotype and host cell. Antivir Res. 2005;66:103–10.

    Article  PubMed  CAS  Google Scholar 

  21. Cong R, Jiang X, Wilson CM, Hunter MP, Vasavada H, Bogue CW. Hhex is a direct repressor of endothelial cell-specific molecule 1 ESM-1. Biochem Biophys Res Commun. 2006;346:535–45.

    Article  PubMed  CAS  Google Scholar 

  22. Li WL, Su J, Yao YC, Tao XR, Yan YB, Yu HY, Wang XM, Li JX, Yang YJ, Lau JT, Hu YP. Isolation and characterization of bipotent liver progenitor cells from adult mouse. Stem cells. 2006;24:322–32.

    Google Scholar 

  23. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-Delta Delta C T method. Methods. 2001;25:402–8.

    Article  PubMed  CAS  Google Scholar 

  24. Li Y, Zhu Z, Zhang S, Yu D, Yu H, Liu L, Cao X, Wang L, Gao H, Zhu M. ShRNA-Targeted centromere protein A inhibits hepatocellular carcinoma growth. PLoS ONE. 2011;6:e17794.

    Google Scholar 

  25. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–24.

    Article  PubMed  CAS  Google Scholar 

  26. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, Budhu A, Zanetti KA, Chen Y, Qin LX, Tang ZY, Wang XW. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008;68:1451–61.

    Article  PubMed  CAS  Google Scholar 

  27. Ghosh B, Ganea GR, Denson LA, Iannucci R, Jacobs HC, Bogue CW. Immunocytochemical characterization of murine Hex, a homeobox-containing protein. Pediatr Res. 2000;48:634–8.

    Article  PubMed  CAS  Google Scholar 

  28. D’Elia AV, Tell G, Russo D, Arturi F, Puglisi F, Manfioletti G, Gattei V, Mack DL, Cataldi P, Filetti S, Di Loreto C, Damante G. Expression and localization of the homeodomain-containing protein HEX in human thyroid tumors. J Clin Endocrinol Metab. 2002;87:1376–83.

    Article  PubMed  Google Scholar 

  29. Gonzalez-Crespo S, Morata G. Genetic evidence for the subdivision of the arthropod limb into coxopodite and telopodite. Development. 1996;122:3921–8.

    PubMed  CAS  Google Scholar 

  30. Casares F, Mann RS. Control of antennal versus leg development in Drosophila. Nature. 1998;392:723–6.

    Article  PubMed  CAS  Google Scholar 

  31. Gonzalez-Crespo S, Abu-Shaar M, Torres M, Martinez AC, Mann RS, Morata G. Antagonism between extradenticle function and Hedgehog signalling in the developing limb. Nature. 1998;394:196–200.

    Article  PubMed  CAS  Google Scholar 

  32. Ilia M, Bazigou E, Price J. Expression of the POU domain transcription factor, Oct-6, is attenuated in the adult mouse telencephalon, but increased by neurotoxic damage. Exp Neurol. 2003;181:159–69.

    Article  PubMed  CAS  Google Scholar 

  33. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3:895–902.

    Article  PubMed  CAS  Google Scholar 

  34. Jordan CT. Cancer stem cell biology: from leukemia to solid tumors. Curr Opin Cell Biol. 2004;16:708–12.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank Dr. Joseph T.Y. Lau (Roswell Park Cancer Institute, Buffalo, New York, NY 10021, United States) for help in the preparation of the manuscript. This work was supported by National Basic Research Program of China (Grant 2009CB941100, 2010CB945600), National Natural Science Foundation of China (Grant 30971426, 30772045, 30700400), and National Key Technology R&D Program (Grant 2008BAI60B03).

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Authors and Affiliations

  1. Department of Cell Biology, Second Military Medical University, 800 Xiangyin Rd., Shanghai, 200433, People’s Republic of China

    Juan Su, Pu You, Jun-Peng Zhao, Li-Wei Ye, Xiao-Yuan Zi, Dong-Fu Xie & Yi-Ping Hu

  2. Department of Pathology, Changhai Hospital, Second Military Medical University, 168 Changhai Rd., Shanghai, 200433, People’s Republic of China

    Ming-Hua Zhu

  3. Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, 415 Fengyang Rd., Shanghai, 200003, People’s Republic of China

    Shou-Long Zhang, Shao-Hua Song & Zhi-Ren Fu

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  1. Juan Su
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Correspondence to Ming-Hua Zhu or Yi-Ping Hu.

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J. Su, P. You and J.-P. Zhao contributed equally to this study.

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Su, J., You, P., Zhao, JP. et al. A potential role for the homeoprotein Hhex in hepatocellular carcinoma progression. Med Oncol 29, 1059–1067 (2012). https://doi.org/10.1007/s12032-011-9989-6

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