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HAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for

Edmund Kwok-Kwan Tung1, Chun-Ming Wong, Tai-On Yau

  • 1Department of Pathology, Faculty of Medicine, Liver Cancer and Hepatitis Research Laboratory and S H Ho Foundation Research Laboratories, The University of Hong Kong, Pokfulam, Hong Kong.

International Journal of Cancer
|December 25, 2008
PubMed

Insights

Hepatocellular carcinoma (HCC) often shows low expression of HGF activator inhibitor 2 (HAI-2), a potential tumor suppressor. Promoter hypermethylation silences HAI-2, and restoring its expression inhibits HCC cell invasion and tumor growth, particularly via its KD-1 domain.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Pharmacological demethylation aids in identifying epigenetically silenced tumor suppressor genes.
  • HGF activator inhibitor 2 (HAI-2) is a candidate tumor suppressor gene in human hepatocellular carcinoma (HCC).

Purpose of the Study:

  • To characterize the epigenetic status and tumor suppressive function of HAI-2 in HCC.
  • To investigate the role of HAI-2's Kunitz domains in its anti-tumor activity.

Main Methods:

  • Gene expression analysis and pharmacological demethylation (5-Aza-2'-deoxycytidine).
  • Bisulfite DNA sequencing and methylation-specific PCR to assess promoter methylation.
  • In vitro cell migration/invasion assays and in vivo tumor xenograft models.
  • Site-directed mutagenesis to inactivate Kunitz domains (KD-1, KD-2).

Main Results:

  • HAI-2 expression was low/absent in HCC cell lines and human HCCs, frequently restored by demethylation.
  • Frequent promoter hypermethylation of HAI-2 was observed in HCC.
  • Ectopic HAI-2 expression inhibited HCC cell migration, invasion, and tumor growth.
  • The KD-1 domain, but not KD-2, was essential for HAI-2's anti-invasive function.

Conclusions:

  • HAI-2 is a frequently hypermethylated and underexpressed tumor suppressor gene in HCC.
  • HAI-2 suppresses HCC cell invasiveness and tumorigenicity.
  • The KD-1 domain is critical for HAI-2's anti-invasive tumor suppressor function.

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