Bak deficiency inhibits liver carcinogenesis: A causal link between apoptosis and carcinogenesis

Hikita, Hayato; Kodama, Tatsuhiko; Shimizu, Satoshi; Li, Wei; Shigekawa, Minoru; Tanaka, Satoshi; Hosui, Atsushi; Miyagi, Takuya; Tatsumi, Tomohide; Kanto, Tatsuya; Hiramatsu, Naoki; Morii, Eiichi; Hayashi, Norio; Takehara, Tetsuo

doi:10.1016/j.jhep.2012.01.027

Cited by 57 publications

(60 citation statements)

References 42 publications

(56 reference statements)

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“…As a mouse model with continuous activation of the mitochondrial apoptotic pathway in hepatocytes, we previously reported hepatocyte-specific Bcl-xL or Mcl-1 KO mice, which display spontaneous apoptosis in hepatocytes scattered throughout the liver and increased serum ALT levels over time after birth (8,9). We also reported that oxidative stress as well as hepatocyte regeneration and liver fibrosis increased in hepatocyte-specific Bcl-xL or Mcl-1 KO mice (10). To further examine whether suppression of the mitochondrial pathway of apoptosis reduces oxidative damage, we generated Bax/Mcl-1 double KO mice by crossing Bax KO mice and hepatocyte-specific Mcl-1 KO mice.…”

Section: Activation Of the Mitochondrial Pathway Of Apoptosis Increasmentioning

confidence: 84%

“…We previously reported that among the antiapoptotic bcl-2 family proteins, Bcl-xL and Mcl-1, are critical molecules that protect hepatocytes from apoptosis because hepatocyte-specific Bcl-xL or Mcl-1 knockout (KO) mice displayed hepatocyte apoptosis over time after birth (8,9). Recently, we and another group reported that these mice spontaneously develop HCC without any extra stimuli (10,11). These results strongly support the idea that continuous hepatocyte apoptosis is mechanistically linked to liver tumor development.…”

Section: Introductionmentioning

confidence: 99%

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Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis

Kodama

Tanaka

Saito

et al. 2015

Cancer Prevention Research

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Section: Activation Of the Mitochondrial Pathway Of Apoptosis Increasmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis

Kodama

Tanaka

Saito

et al. 2015

Cancer Prevention Research

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“…The tumor-promoting effects of hepatocyte apoptosis have been clearly shown by hepatocyte-specific deletion of the antiapoptotic proteins Mcl-1 or Bcl-xl, which not only increased the rate of hepatocyte apoptosis 62, 63 and 64 but also resulted in spontaneous development of HCC. 64 and 153 In the Bcl-xl liver knockout model, hepatocarcinogenesis could be suppressed by additional knockout of Bak, thus providing a direct link between hepatocyte apoptosis and HCC. 153 Similar evidence comes from models in which NF-κB inhibition through conditional deletion of Nemo in hepatocytes leads to massively increased cell death and spontaneous development of HCC.…”

Section: Response Pathways To Cell Deathmentioning

confidence: 99%

“…64 and 153 In the Bcl-xl liver knockout model, hepatocarcinogenesis could be suppressed by additional knockout of Bak, thus providing a direct link between hepatocyte apoptosis and HCC. 153 Similar evidence comes from models in which NF-κB inhibition through conditional deletion of Nemo in hepatocytes leads to massively increased cell death and spontaneous development of HCC. 151 Increasing carcinogen-induced apoptosis and compensatory proliferation through hepatocyte-specific IKKβ deletion promotes formation of HCC, 151 whereas decreasing it through knockout of Bcl-2 family member p53 up-regulated modulator of apoptosis (PUMA) decreases it.…”

Section: Response Pathways To Cell Deathmentioning

confidence: 99%

“…Despite the widely held belief that apoptosis represents an “unreactive” form of cell death, aforementioned evidence from mouse models with increased hepatocyte apoptosis 64, 90, 152, 153 and 167 and interventions that reduce apoptosis 105, 153, 155 and 156 strongly suggest that apoptosis is the primary driver of HCC development. Accordingly, co-deletion experiments in TAK1-knockout mice showed that apoptosis but not necroptosis promoted carcinogenesis in this model.…”

Section: Response Pathways To Cell Deathmentioning

confidence: 99%

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Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance

2014

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Summary Hepatocellular death is present in almost all types of human liver disease and is used as a sensitive parameter for the detection of acute and chronic liver disease of viral, toxic, metabolic, or autoimmune origin. Clinical data and animal models suggest that hepatocyte death is the key trigger of liver disease progression, manifested by the subsequent development of inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Modes of hepatocellular death differ substantially between liver diseases. Different modes of cell death such as apoptosis, necrosis, and necroptosis trigger specific cell death responses and promote progression of liver disease through distinct mechanisms. In this review, we first discuss molecular mechanisms by which different modes of cell death, damage-associated molecular patterns, and specific cell death responses contribute to the development of liver disease. We then review the clinical relevance of cell death, focusing on biomarkers; the contribution of cell death to drug-induced, viral, and fatty liver disease and liver cancer; and evidence for cell death pathways as therapeutic targets.

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Apoptosis and Necrosis in the Liver

Guicciardi

Malhi

Mott

et al. 2013

Comprehensive Physiology

324

248

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Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.

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Bak deficiency inhibits liver carcinogenesis: A causal link between apoptosis and carcinogenesis

Cited by 57 publications

References 42 publications

Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis

Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis

Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance

Apoptosis and Necrosis in the Liver

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