Gastroenterology

Gastroenterology

Volume 134, Issue 3, March 2008, Pages 793-802
Gastroenterology

Basic–Liver, Pancreas, and Biliary Tract
Epigenetic Inhibition of Nuclear Receptor Small Heterodimer Partner Is Associated With and Regulates Hepatocellular Carcinoma Growth

https://doi.org/10.1053/j.gastro.2008.01.006Get rights and content

Background & Aims: Aberrant hypermethylation of promoter regions in cytosine-guanine dinucleotides (CpG) islands has been shown to be associated with transcriptional silencing of tumor-suppressor genes in many cancers. This study evaluated the methylation profile and the tumor-suppressive function of the small heterodimer partner (SHP, NR0B2) in the development of human hepatocellular carcinoma (HCC). Methods: Human HCC pathologic specimens and cell lines were used as model systems in this study. Results: The expression of SHP is diminished in HCC pathologic specimens and cell lines by epigenetic silencing owing to SHP promoter hypermethylation. In vitro methylation decreased SHP promoter transactivation and nuclear receptor LRH-1 binding, an event that was reversed by demethylation. Overexpression of SHP inhibited HCC foci formation, arrested HCC tumor growth in xenografted nude mice, and increased the sensitivity of HCC cells to apoptotic stimuli. Further analysis of a total of 19 normal liver and 57 HCC specimens showed that down-regulation of SHP gene expression may be a common denominator of HCC. Conclusions: We propose that SHP functions as a novel tumor suppressor in the development of HCC. These findings provide new insight into the molecular mechanisms leading to this common cancer and may have both diagnostic and therapeutic applications.

Section snippets

HCC Specimens and Cell Lines

HCC specimens were obtained through the National Cancer Institute Cooperative Human Tissue Network and the Liver Tissue Procurement and Distribution System (Minneapolis, Minnesota). Institutional Review Board was approved by the University of Kansas Medical Center human subjects committee. HCC cell lines were obtained from the American Type Culture Collection (Manassas, VA) (HepG2, HB-8065; Hep3B, HB-8064) and the Health Science Research Resources Bank (Saito-Asagi, Osaka, Japan) (Huh7, JCRB

Epigenetic Repression of the SHP Gene in HCC Specimens

To determine if diminished SHP mRNA expression occurs in HCC, we determined the SHP expression profile in 10 pairs of normal human liver and HCC pathologic specimens by Northern blot. The analysis revealed that the expression of SHP mRNA was down-regulated in 9 of 10 HCC specimens as compared with the normal surrounding liver tissue (Figure 1A, left). We further confirmed a correlated down-regulation of SHP protein levels in HCC specimens using immunohistochemistry analysis (Figure 1A, right,

Discussion

HCC often is diagnosed at an advanced stage when therapies have a limited efficacy.23 The fact that HCC is resistant to conventional chemotherapy leaves advanced disease with few therapeutic options and dismal prognosis. The challenges with early diagnosis of HCC emphasize the need for better biomarkers for early stage HCC. HCC tumors are phenotypically and genetically heterogeneous tumors and usually emerge in the presence of chronic liver disease, including hepatitis B or C, and metabolic

References (29)

  • S.M. Dehm et al.

    Molecular regulation of androgen action in prostate cancer

    J Cell Biochem

    (2006)
  • M. Aupperlee et al.

    Progestins and breast cancer

    Breast Dis

    (2005–2006)
  • S. Bandoh et al.

    Mechanical agitation induces gene expression of NOR-1 and its closely related orphan nuclear receptors in leukemic cell lines

    Leukemia

    (1997)
  • J. Auwerx

    Nuclear receptorsI. PPAR gamma in the gastrointestinal tract: gain or pain?

    Am J Physiol

    (2002)
  • Cited by (83)

    • Pleiotropic roles of FXR in liver and colorectal cancers

      2022, Molecular and Cellular Endocrinology
    • The long and the small collide: LncRNAs and small heterodimer partner (SHP) in liver disease

      2021, Molecular and Cellular Endocrinology
      Citation Excerpt :

      SHP expression is down-regulated in hepatocellular carcinoma (HCC). SHP inhibits hepatocyte proliferation and activates apoptosis to suppress tumor growth in HCC (He et al., 2008; Zhang et al, 2008, 2010). A small molecule activator of SHP, 5-(diethylsulfamoyl)-3-hydroxynaphthalene-2-carboxylic acid, has a strong inhibitory effect on HCC cell migration by suppressing CCL2 expression (Z. (Yang et al., 2016)).

    View all citing articles on Scopus

    Supported by a Liver Scholar Award from the American Liver Foundation/American Association for the Study of Liver Diseases, a Junior Faculty Award from the American Diabetes Association, and a BGIA Award from the American Heart Association (L.W.). The Flow Cytometry Core is supported in part by a National Institutes of Health grant (P20 RR016443) from NCRR. HCC specimens were obtained through the Liver Tissue Procurement and Distribution System, which was funded by National Institutes of Health contract N01-DK-9-2310.

    View full text