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Gut. 2019 Sep;68(9):1676-1687. doi: 10.1136/gutjnl-2018-317811. Epub 2019 Jul 17.

Expression of the type 3 InsP3 receptor is a final common event in the development of hepatocellular carcinoma.

Author information

1
Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
3
Centro Nacional de Pesquisa em Energia e Materiais, Campinas, Brazil.
4
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
5
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
6
Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut, USA.
7
Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, China.
8
Department of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
9
Department of Pathological Anatomy and Forensic Medicine, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
#
Contributed equally

Abstract

BACKGROUND & OBJECTIVES:

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC.

DESIGN:

Expression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice.

RESULTS:

ITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis.

CONCLUSIONS:

These results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.

KEYWORDS:

apoptosis; calcium signaling; cell growth; liver cancer; methylation

PMID:
31315892
DOI:
10.1136/gutjnl-2018-317811

Conflict of interest statement

Competing interests: None declared.

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