Expression of the type 3 InsP 3 receptor is a final common event in the development of hepatocellular carcinoma
Expression of the type 3 InsP 3 receptor is a final common event in the development of hepatocellular carcinoma
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DOI：
10.1136/gutjnl-2018-317811
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发表时间：
2019-09-01
期刊：
影响因子：
24.5
通讯作者：
Leite, Maria Fatima
中科院分区：
文献类型：
--
作者：
Guerra, Mateus T.;Florentino, Rodrigo M.;Leite, Maria Fatima
背景与目的肝细胞癌（HCC）是全球癌症死亡的第二大原因。几种类型的慢性肝病易患HCC，并且几种不同的信号通路与HCC的发病机制有关，但尚未确定共同的分子事件。Ca2+信号传导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Ca2+释放通道在HCC中的作用。设计将肌醇1,4,5 -三磷酸受体（ITPR3） 3型异构体在人肝脏样本、肝癌细胞和小鼠肝脏中的表达分析与肝癌细胞中ITPR3启动子DNA甲基化谱的评估以及ITPR3表达对细胞增殖和凋亡的影响结合起来。研究了ITPR3表达对小鼠肝细胞钙信号传导和肝脏生长的影响。结果ITPR3在正常肝脏的肝细胞中缺失或低量表达，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，其表达水平升高与较差的生存率相关。ITPR3基因在对照肝脏标本中重度甲基化，但在HCC患者标本中多个位点去甲基化。在小鼠模型中使用去甲基化剂导致肝脏离散区域的ITPR3表达，并且这些区域的Ca2+信号传导增强。此外，在小鼠模型中，细胞增殖和肝脏再生得到增强，从人HCC细胞中删除ITPR3增强了细胞凋亡。结论ITPR3的新生表达在HCC中具有典征性，并可能在其发病机制中发挥作用。
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.