<i>MSH2</i> Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development

Eso, Yuji; Takai, Atsushi; Matsumoto, Tomonori; Inuzuka, Tadashi; Horie, Takahiro; Ono, Koh; Üemoto, Shinji; Lee, Kyeryoung; Edelmann, Winfried; Chiba, Tsutomu; Marusawa, Hiroyuki

doi:10.1158/0008-5472.can-15-2926

Cited by 28 publications

(25 citation statements)

References 50 publications

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“…Taking advantage of the lack of differentiation of PDCs into hepatocytes in the DDC-induced liver injury model, we investigated whether Epcam-positive PDCs could directly give origin to liver cancer. AID is upregulated in both hepatocytes and cholangiocytes in response to inflammatory stimulation (31,39,40) and elicits liver carcinogenesis through the induction of somatic mutations (34,41). AID-mediated mutagenesis in epithelial cells under inflammatory conditions is also attributed to inflammation-associated carcinogenesis in various organs (42,43).…”

Section: Discussionmentioning

confidence: 99%

“…As a representative model of hepatocyte-derived HCC, we also examined HCCs developed in Alb Cre /AID cTg mice (Alb-derived HCCs) in which HCCs originated from albumin-expressing hepatocytes through AID-mediated mutagenesis (34). All of the Albderived HCCs were histologically consistent with well-to-moderately differentiated HCCs, and none of those tumors contained ductule-like components ( Supplementary Fig.…”

Section: Pdc-derived Hcc Displayed a Divergent Lineage Of Differentiamentioning

confidence: 99%

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Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma

et al. 2017

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Hepatocellular carcinoma (HCC) originates from regenerating liver cells with genetic alterations in chronically inflamed liver. Ductal cells and hepatocytes proliferate for liver regeneration, and proliferating ductal cells (PDC) derived from bile ductules have long been considered putative liver stem/progenitor cells and candidate cellular origins of HCC. The potential of PDC as tumor-originating cells, however, remains controversial in contrast to accumulating evidence that HCC originates from hepatocytes. Here, we demonstrate that PDCs expressing the established surface and cancer stem cell marker EpCAM give rise to HCC in inflamed liver. EpCAM-expressing PDCs were specifically labeled in newly developed Epcam mice and traced in a chemically induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. Lineage-tracing experiments revealed that labeled PDC differentiated into cholangiocytes, but not into hepatocytes, in the chemically damaged liver. Nevertheless, EpCAM-positive PDC with genetic alterations gave rise to HCC after 8 months of chemical administration. PDC-derived HCC showed histologic characteristics of concomitant ductule-like structures resembling human cholangiolocellular carcinoma (CLC) and exhibited serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. The Wnt signaling pathway was specifically upregulated in the CLC components of PDC-derived HCC. Our findings provide direct experimental evidence that EpCAM-expressing PDC could be a cellular origin of HCC, suggesting the existence of stem/progenitor-derived hepatocarcinogenesis. .

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Section: Discussionmentioning

confidence: 99%

Section: Pdc-derived Hcc Displayed a Divergent Lineage Of Differentiamentioning

confidence: 99%

Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma

et al. 2017

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“…Some degree of MSI is known to be induced by chronic inflammation, as reported in pancreatitis [71] and ulcerative colitis [72]. We previously demonstrated that proinflammatory cytokine stimulation induced transcriptional downregulation of MSH2 via inflammation-mediated microRNA-21 expression in hepatocytes [14]. Furthermore, hepatocyte-specific disruption of MSH2 in mice results in the development of liver tumors with the histologic features of HCC.…”

Section: Msi Status and Treatment With Icis For Hepatocellular Carcinomamentioning

confidence: 94%

“…MSI reflects the condition of genetic hypermutability that results from impaired DNA MMR, and is accompanied by a 100-to 1000-fold increase in the mutation rate [10,12]. The presence of MSI is a sign of either sporadic or hereditary dysfunction of the MMR pathway caused by various factors, including mutations in MMR-related genes, inactivation of MMR gene transcription due to hypermethylation of its promoter region, or inflammation-mediated transcriptional repression [12][13][14].…”

Section: Microsatellite Instability and Cancer Predispositionmentioning

confidence: 99%

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

et al. 2019

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Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.

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“…In fact, several types of congenital and acquired human cancers contain mutations or exhibit methylated silencing of DNA repair genes, including MLH1 and polymerase e (POLE) [132,133]. We recently demonstrated that the expression level of MSH2, a representative mismatch repair protein, is downregulated by tumor necrosis factor-a in inflamed hepatocytes [134]. In addition, hepatocyte-specific defects of MSH2 result in the development of liver tumors with the histologic features of HCC.…”

Section: Genetic Alterations Accumulated In Hepatitis Virusinfected Lmentioning

confidence: 99%

Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis

et al. 2016

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Hepatitis virus infection is a leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Although anti-viral therapies against hepatitis B virus (HBV) and hepatitis C virus (HCV) have dramatically progressed during the past decade, the estimated number of people chronically infected with HBV and/or HCV is *370 million, and hepatitis virus-associated hepatocarcinogenesis is a serious health concern worldwide. Understanding the mechanism of virus-associated carcinogenesis is crucial toward both treatment and prevention, and the recently developed whole genome/exome sequencing analysis using next-generation sequencing technologies has contributed to unveiling the landscape of genetic and epigenetic aberrations in not only tumor tissues but also the background liver tissues underlying chronic liver damage caused by hepatitis virus infection. Several major mechanisms underlie the genetic and epigenetic aberrations in the hepatitis virus-infected liver, such as the generation of reactive oxidative stress, ectopic expression of DNA mutator enzymes, and dysfunction of the DNA repair system. In addition, direct oncogenic effects of hepatitis virus, represented by the integration of HBV-DNA, are observed in infected hepatocytes. Elucidating the whole picture of genetic and epigenetic alterations, as well as the mechanisms of tumorigenesis, will facilitate the development of efficient treatment and prevention strategies for hepatitis virus-associated HCC.

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MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development

Cited by 28 publications

References 50 publications

Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma

Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis

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