A fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition§

Authors

  • Jae Yeon Seok,

    1. Department of Pathology, Brain Korea 21 Project for Medical Science, Center for Chronic Metabolic Disease, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
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    • *

      Jae Yoon Seok is currently affiliated with the Department of Pathology, Kwandong University College of Medicine, Myongji Hospital, Goyang, Korea. These authors contributed equally.

  • Deuk Chae Na,

    1. Department of Pathology, Brain Korea 21 Project for Medical Science, Center for Chronic Metabolic Disease, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
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    • *

      Jae Yoon Seok is currently affiliated with the Department of Pathology, Kwandong University College of Medicine, Myongji Hospital, Goyang, Korea. These authors contributed equally.

  • Hyun Goo Woo,

    1. Department of Physiology, Ajou University School of Medicine, Suwon, Korea
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    • *

      Jae Yoon Seok is currently affiliated with the Department of Pathology, Kwandong University College of Medicine, Myongji Hospital, Goyang, Korea. These authors contributed equally.

  • Massimo Roncalli,

    1. Department of Pathology, University of Milan School of Medicine and Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Clinical Institute, Rozzano, Milan, Italy
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  • So Mee Kwon,

    1. Department of Physiology, Ajou University School of Medicine, Suwon, Korea
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  • Jeong Eun Yoo,

    1. Department of Pathology, Brain Korea 21 Project for Medical Science, Center for Chronic Metabolic Disease, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
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  • Ei Yong Ahn,

    1. Department of Pathology, Brain Korea 21 Project for Medical Science, Center for Chronic Metabolic Disease, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
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  • Gwang Il Kim,

    1. Department of Pathology, Brain Korea 21 Project for Medical Science, Center for Chronic Metabolic Disease, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
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  • Jin-Sub Choi,

    1. Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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  • Young Bae Kim,

    1. Department of Pathology, Ajou University School of Medicine, Suwon, Korea
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  • Young Nyun Park

    Corresponding author
    1. Department of Pathology, Brain Korea 21 Project for Medical Science, Center for Chronic Metabolic Disease, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
    2. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
    • Department of Pathology, Yonsei University College of Medicine, 250 Seongsanno Seodaemun-gu, Seoul 120-752, Korea
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    • fax: 82-2-362-0860


  • Potential conflict of interest: The authors declare that there are no conflicts of interest.

  • This work was supported by a Korea Science and Engineering Foundation grant funded by the Korean government (MOST; 20100008075), a National Research Foundation of Korea grant funded by the Korean government (MEST; no. 2011-0030707), partly by grants (A101201 and A111574) of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea, and partly by Associazione Italiana Ricerca sul Cancro (AIRC) (grant no. 10247; to M.R.).

  • §

    The raw data of the microarray experiments are available in the GEO database (http://www.ncbi.nlm.nih.gov/geo) with an accession number (GSE31370).

Abstract

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major primary liver cancers in adults. The phenotypic overlap between HCC and CC has been shown to comprise a continuous liver cancer spectrum. As a proof of this concept, a recent study demonstrated a genomic subtype of HCC that expressed CC-like gene expression traits, such as CC-like HCC, which revealed the common genomic trait of stem-cell–like properties and aggressive clinical outcomes. Scirrhous HCC (S-HCC), a rare variant of HCC, is characterized by abundant fibrous stroma and has been known to express several liver stem/progenitor cell markers. This suggests that S-HCC may harbor common intermediate traits between HCC and CC, including stem-cell traits, which are similar to those of CC-like HCC. However, the molecular and pathological characteristics of S-HCC have not been fully evaluated. By performing gene-expression profiling and immunohistochemical evaluation, we compared the morphological and molecular features of S-HCC with those of CC and HCC. S-HCC expresses both CC-like and stem-cell–like genomic traits. In addition, we observed the expression of core epithelial-mesenchymal transition (EMT)-related genes, which may contribute to the aggressive behavior of S-HCC. Overexpression of transforming growth factor beta (TGF-β) signaling was also found, implying its regulatory role in the pathobiology of S-HCC. Conclusion: We suggest that the fibrous stromal component in HCC may contribute to the acquisition of CC-like gene-expression traits in HCC. The expression of stem-cell–like traits and TGF-β/EMT molecules may play a pivotal role in the aggressive phenotyping of S-HCC. (HEPATOLOGY 2012;55:1776–1786)

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