Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective

Giannakoulis, Vassilis G.; Dubovan, Peter; Papoutsi, Eleni; Kataki, Agapi; Koskinas, John

doi:10.3390/cancers13184732

Cited by 13 publications

(13 citation statements)

References 113 publications

(146 reference statements)

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“…26 Even though cell senescence is a tumor suppressor mechanism, growing evidence suggests that senescent cells can contribute to cancer including HCC due to the secretion of senescence-associated secretory phenotype that promotes tumor progression. 42 Our study showing that senescence markers were elevated in response to CD-HFD and this effect was reduced in both Ripk3 -/- and Mlkl -/- mice suggests a possible crosstalk between necroptosis and cell senescence. Ripk3 -/- mice showed a sex-specific response in cell senescence inhibition whereas Mlkl -/- mice did not show such an effect.…”

Section: Discussionmentioning

confidence: 67%

Blocking necroptosis reduces inflammation and tumor incidence in a mouse model of diet-induced hepatocellular carcinoma

Mohammed¹,

Thadathil²,

Tran³

et al. 2022

Preprint

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Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. As necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis-induced inflammation contributes to the progression of NAFLD to HCC in a mouse model of diet-induced HCC. Methods: Male and female wild-type (WT) mice or mouse models where necroptosis is blocked (Ripk3-/- or Mlkl-/- mice) were fed a control diet or choline-deficient low fat diet (CD-LFD) or CD-high fat diet (CD-HFD) for 6 months. Changes in inflammation, immune cell infiltration, activation of oncogenic pathways, and tumor incidence were assessed by gene expression analysis, western blotting, and flow cytometry. RNA sequencing (RNA-seq) was performed to assess the changes in liver transcriptome. Results: Blocking necroptosis by deleting either Ripk3 or Mlkl reduced markers of inflammation [proinflammatory cytokines (TNFα, IL-6, and IL-1β), F4/80+ve macrophages, CCR2+ve infiltrating monocytes], inflammation associated oncogenic pathways (JNK, PD-L1/PD-1, β-catenin), and HCC in male mice. In female mice, blocking necroptosis reduced HCC independent of inflammation. Blocking necroptosis reduced cell senescence markers in males and females, suggesting a novel cross-talk between necroptosis and cell senescence. Conclusions: Our data show that hepatic necroptosis promotes recruitment and activation of liver macrophages leading to chronic inflammation, which in turn trigger oncogenic pathways leading to the progression of NAFLD to HCC in male mice. In female mice necroptosis contributes to HCC independent of inflammation. Thus, our study suggests that necroptosis is a valid target for NAFLD-mediated HCC.

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Section: Discussionmentioning

confidence: 67%

Blocking necroptosis reduces inflammation and tumor incidence in a mouse model of diet-induced hepatocellular carcinoma

Mohammed¹,

Thadathil²,

Tran³

et al. 2022

Preprint

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“…Additionally, CD8 + T cells isolated from peripheral blood of HCV-infected subjects show higher levels of DNA damage and hypophosphorylated signal transducer and activator of transcription 1 (STAT1) and STAT5 in response to IL-6 or IL-2 stimulation, respectively ( 202 ). Altogether, these data suggest that chronic HCV infection results in cellular senescence, and since these senescent cells are non-functional, they may predispose HCV-infected individuals to HCC ( 203 ).…”

Section: Drivers Of Immunosenescence and Atherosclerosismentioning

confidence: 98%

Immunosenescence in atherosclerosis: A role for chronic viral infections

Talepoor

Doroudchi

2022

Front. Immunol.

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Immune system is a versatile and dynamic body organ which offers survival and endurance of human beings in their hostile living environment. However, similar to other cells, immune cells are hijacked by senescence. The ageing immune cells lose their beneficial functions but continue to produce inflammatory mediators which draw other immune and non-immune cells to the senescence loop. Immunosenescence has been shown to be associated with different pathological conditions and diseases, among which atherosclerosis has recently come to light. There are common drivers of both immunosenescence and atherosclerosis; e.g. inflammation, reactive oxygen species (ROS), chronic viral infections, genomic damage, oxidized-LDL, hypertension, cigarette smoke, hyperglycaemia, and mitochondrial failure. Chronic viral infections induce inflammaging, sustained cytokine signaling, ROS generation and DNA damage which are associated with atherogenesis. Accumulating evidence shows that several DNA and RNA viruses are stimulators of immunosenescence and atherosclerosis in an interrelated network. DNA viruses such as CMV, EBV and HBV upregulate p16, p21 and p53 senescence-associated molecules; induce inflammaging, metabolic reprogramming of infected cells, replicative senescence and telomere shortening. RNA viruses such as HCV and HIV induce ROS generation, DNA damage, induction of senescence-associated secretory phenotype (SASP), metabolic reprogramming of infected cells, G1 cell cycle arrest, telomere shortening, as well as epigenetic modifications of DNA and histones. The newly emerged SARS-CoV-2 virus is also a potent inducer of cytokine storm and SASP. The spike protein of SARS-CoV-2 promotes senescence phenotype in endothelial cells by augmenting p16, p21, senescence-associated β-galactosidase (SA-β-Gal) and adhesion molecules expression. The impact of SARS-CoV-2 mega-inflammation on atherogenesis, however, remains to be investigated. In this review we focus on the common processes in immunosenescence and atherogenesis caused by chronic viral infections and discuss the current knowledge on this topic.

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“…Several in-depth studies of patients with HCC have established associations between particular microbiome compositions and the development of HCC. For example, genera, such as Bacteroides , Phascolarctobacterium , Enterococcus , Streptococcus , Gemella , Bilophila, are increased in patients with HCC from NAFLD and cirrhosis compared to healthy controls [ 43 ]. On the contrary, Akkermansia , Bifidobacterium , Dialister , and Collinsella were found to be downregulated in these patients [ 43 ].…”

Section: Role Of the Microbiome On Inflammatory Processes In Hccmentioning

confidence: 99%

“…For example, genera, such as Bacteroides , Phascolarctobacterium , Enterococcus , Streptococcus , Gemella , Bilophila, are increased in patients with HCC from NAFLD and cirrhosis compared to healthy controls [ 43 ]. On the contrary, Akkermansia , Bifidobacterium , Dialister , and Collinsella were found to be downregulated in these patients [ 43 ]. Other studies pertaining to cirrhosis mediated HCC have identified genera, such as Klebsiella , Haemophilus, Escherichia - Shigella , Proteus , Subdoligranulum , Prevotella 2 , Barnesiella to be upregulated in patients with HCC, whereas Alistipes, Phascolarctobacterium, Rumnocccus, Buchnera , Megamonas , Lachnospira , and Eubacterumventriosum are downregulated [ 35 , 44 ].…”

Section: Role Of the Microbiome On Inflammatory Processes In Hccmentioning

confidence: 99%

“… Upregulation and downregulation of microbes and their factors related to hepatitis B and C. a Mohamadkhani et al, 2018 [ 32 ], b Palsson McDermott et al, 2014 [ 33 ], c Milosevic et al, 2019 [ 36 ], d Lu et al, 2011 [ 30 ], e Wang et al, 2017 [ 31 ], f Ma et al, 2015 [ 34 ], g Roderburg et al 2014 [ 35 ], h El-Mowafy et al, 2021 [ 39 ], i Aly et al, 2016 [ 40 ], j Qin et al, 2018 [ 41 ]., k Giannakoulis et al, 2021 [ 43 ]. …”

Section: Figurementioning

confidence: 99%

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Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome

Khalyfa

Punatar

Yarbrough

2022

IJMS

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. It is well known that repeated inflammatory insults in the liver can cause hepatic cellular injury that lead to cirrhosis and, ultimately, hepatocellular carcinoma. Furthermore, the microbiome has been implicated in multiple inflammatory conditions which predispose patients to malignancy. With this in mind, we explore the inflammatory implications of the microbiome on pathways that lead to HCC. We also focus on how an understanding of these underlying inflammatory principles lead to a more wholistic understanding of this deadly disease, as well as potential therapeutic implications.

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Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective

Cited by 13 publications

References 113 publications

Blocking necroptosis reduces inflammation and tumor incidence in a mouse model of diet-induced hepatocellular carcinoma

Blocking necroptosis reduces inflammation and tumor incidence in a mouse model of diet-induced hepatocellular carcinoma

Immunosenescence in atherosclerosis: A role for chronic viral infections

Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome

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