Mutational landscape of a chemically-induced mouse model of liver cancer

Connor, Frances; Rayner, Tim; Aitken, Sarah J.; Feig, Christine; Lukk, Margus; Santoyo-López, Javier; Odom, Duncan T.

doi:10.1016/j.jhep.2018.06.009

Cited by 109 publications

(72 citation statements)

References 41 publications

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“…showed that DNA damage was a fundamental factor for the p53 stabilization necessary to degrade HIF‐1α . Since DEN injection could induce DNA damage in this mouse model, it is conceivable that the BCX‐mediated acetylation of p53 inhibited HIF‐1α in a DNA damage‐inducing environment. Moreover, the HIF‐1α signaling pathway plays a vital role in the HCC progression, since it functions as a transcription factor that modulates genes involved in glucose metabolism, cell invasion and migration, and angiogenesis .…”

Section: Discussionmentioning

confidence: 78%

Xanthophyll β‐Cryptoxanthin Inhibits Highly Refined Carbohydrate Diet–Promoted Hepatocellular Carcinoma Progression in Mice

Lim

et al. 2020

Molecular Nutrition Food Res

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Scope: -Cryptoxanthin (BCX) can be cleaved by both -carotene 15,15′-oxygenase (BCO1) and -carotene 9′,10′-oxygenase (BCO2), generating biological active vitamin A and apocarotenoids. We examined whether BCX feeding could inhibit diethylnitrosamine (DEN)-initiated, highly refined carbohydrate diet (HRCD)-promoted hepatocellular carcinoma (HCC) development, dependent or independent of BCO1/BCO2 activity. Methods and results: Two-week-old male wild-type (WT) and BCO1 −/− /BCO2 −/− double knockout (DKO) mice are given a single intraperitoneal injection of DEN (25 mg kg −1 body weight) to initiate hepatic carcinogenesis. At 6 weeks of age, all animals are fed HRCD (66.5% of energy from carbohydrate) with or without BCX for 24 weeks. BCX feeding increases hepatic vitamin A levels in WT mice, but not in DKO mice that shows a significant accumulation of hepatic BCX. Compared to their respective HRCD littermates, both WT and DKO fed BCX have significantly lower HCC multiplicity, average tumor size, and total tumor volume, and the steatosis scores. The chemopreventive effects of BCX are associated with increased p53 protein acetylation and decreased protein levels of lactate dehydrogenase and hypoxia-inducible factor-1 in tumors. Conclusion: This study suggests that BCX feeding may alleviate HRCD-promoted HCC progression by modulating the acetylation of p53, hypoxic tumor microenvironment, and glucose metabolism, independent of BCO1/BCO2.

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Section: Discussionmentioning

confidence: 78%

Xanthophyll β‐Cryptoxanthin Inhibits Highly Refined Carbohydrate Diet–Promoted Hepatocellular Carcinoma Progression in Mice

Lim

et al. 2020

Molecular Nutrition Food Res

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“…We further built the phylogenetic tree by using R package ape ( Paradis et al., 2004 ). In particular, pair-wide distances between samples were calculated as the number of genomic loci where the sample genotypes differ as described by previous study ( Connor et al., 2018 ). As expected, samples in the same groups were closer ( Figure S4 A).…”

Section: Resultsmentioning

confidence: 99%

“…Connor et al. compared mutation signatures between liver tumors for DEN-treated and untreated mice, and human HCCs by using mouse model of DEN-initiated HCC ( Connor et al., 2018 ). They provided insights into the mutational landscape of DEN-initiated HCC mouse model, which facilitated the better understanding of this disease model.…”

Section: Discussionmentioning

confidence: 99%

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model

Chen

Shen

et al. 2020

iScience

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Summary Hepatocellular carcinoma (HCC) initiation is characterized by stepwise accumulation of molecular alterations, during which the early events are largely unknown. Here, we presented a comprehensive genomic and transcriptomic landscape at stages of hepatitis, cirrhosis, and HCC by using a diethylnitrosamine-induced rat HCC model. We observed the early occurrence of gene instability and aberrant cancer associated signaling pathways in liver hepatitis. We further characterized the progressive molecular changes during hepatocarcinogenesis, wherein the intense rivalry between tumor-suppressive and oncogenic strengths occurred in cirrhosis stage. Despite the significant pathological difference, mutation signatures and expression landscape are highly similar between hepatitis and cirrhosis stages. Furthermore, we identified PI3K-Akt signaling pathway as a key pathway in the process of hepatocarcinogenesis through integrative analysis, and PIK3CD is a potential biomarker indicating HCC recurrence. The dynamic immune response during hepatocarcinogenesis, such as continuous decline of monocytes, suggests an immunological intervention strategy beyond chemoprevention for liver cancer.

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“…[128][129][130] While they are useful for studying basic tumour biology, their use as a preclinical platform to evaluate the therapeutic response in HCC is still limited by the lack of systematic cross-species comparative molecular analyses. [131][132][133] New biomarkers While tumour tissue is still the gold standard source for identifying cancer-specific biomarkers, liquid biopsy has become a promising alternative non-invasive procedure, allowing for the isolation and detection of cancer-derived subcellular components that are released in biological fluids such as blood. 134 Thus, it is possible to overcome the difficulties in obtaining tissue biopsies, as in HCC.…”

Section: Precision Oncology In Hccmentioning

confidence: 99%

Advances in molecular classification and precision oncology in hepatocellular carcinoma

Rebouissou

Nault

2020

Journal of Hepatology

379

283

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Hepatocellular carcinoma (HCC) arises from hepatocytes through the sequential accumulation of multiple genomic and epigenomic alterations resulting from Darwinian selection. Genes from various signalling pathways such as telomere maintenance, Wnt/b-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase are frequently mutated in HCC. Several subclasses of HCC have been identified based on transcriptomic dysregulation and genetic alterations that are closely related to risk factors, pathological features and prognosis. Undoubtedly, integration of data obtained from both preclinical models and human studies can help to accelerate the identification of robust predictive biomarkers of response to targeted biotherapy and immunotherapy. The aim of this review is to describe the main advances in HCC in terms of molecular biology and to discuss how this knowledge could be used in clinical practice in the future.

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Mutational landscape of a chemically-induced mouse model of liver cancer

Abstract: Graphical abstract

Cited by 109 publications

References 41 publications

Xanthophyll β‐Cryptoxanthin Inhibits Highly Refined Carbohydrate Diet–Promoted Hepatocellular Carcinoma Progression in Mice

Xanthophyll β‐Cryptoxanthin Inhibits Highly Refined Carbohydrate Diet–Promoted Hepatocellular Carcinoma Progression in Mice

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model

Advances in molecular classification and precision oncology in hepatocellular carcinoma

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