Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Gut. 2019 Sep;68(9):1676-1687. doi: 10.1136/gutjnl-2018-317811. Epub 2019 Jul 17.
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. Ca signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca release channels in HCC.
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 ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice.
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 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 Ca signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of from human HCC cells enhanced apoptosis.
These results provide evidence that expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.
肝细胞癌（HCC）是全球癌症死亡的第二大主要原因。几种类型的慢性肝病可导致 HCC，几种不同的信号通路已被牵涉到其发病机制中，但尚未确定共同的分子事件。钙信号调节正常肝细胞和肝癌细胞的增殖，因此我们研究了细胞内钙释放通道在 HCC 中的作用。
对人肝组织样本、肝癌细胞和小鼠肝中 1,4,5-三磷酸肌醇受体（ITPR3）的 3 型同工型的表达分析，结合对 HCC 中 ITPR3 启动子 DNA 甲基化图谱的评估以及 ITPR3 表达对细胞增殖和凋亡的影响进行综合分析。评估了 ITPR3 表达对小鼠肝细胞钙信号和肝脏生长的影响。
ITPR3 在正常肝的肝细胞中缺失或低表达，但在来自三个独立患者队列的 HCC 标本中表达，无论慢性肝病的潜在原因如何，其表达水平的增加与较差的生存相关。在对照肝标本中，该基因高度甲基化，但在 HCC 标本中的多个位点去甲基化。在小鼠模型中给予去甲基化剂可导致 ITPR3 在肝脏的离散区域表达，并增强这些区域的钙信号。此外，在小鼠模型中增强了细胞增殖和肝脏再生，并且从人 HCC 细胞中删除 ITPR3 增强了细胞凋亡。
这些结果提供了证据表明 ITPR3 的表达通常发生在 HCC 中，并可能在其发病机制中发挥作用。
