The p53 family in hepatocellular carcinoma

Kunst, C; Haderer, M; Heckel, S; Schlosser, S; Müller, Martina

doi:10.21037/tcr.2016.11.79

Cited by 29 publications

(38 citation statements)

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“…It is well established that tumor suppressor p53 is highly sensitive to DNA damage and cellular stress and regulates cell fate by directing damaged cells down the cell cycle arrest or apoptosis (Kastenhuber and Lowe 2017). Therefore, p53 signalling plays a central role in tumorigenesis and prognosis of hepatocellular carcinoma (Kunst et al 2016). Considering that PCTS were prepared from cirrhotic livers that had considerable pre-existing DNA and cellular damage, culture induced activation of p53 pathway in these slices.…”

Section: Organ-and Pathology-specificity In the Effect Of Culturementioning

confidence: 99%

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

et al. 2019

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Our knowledge of complex pathological mechanisms underlying organ fibrosis is predominantly derived from animal studies. However, relevance of animal models for human disease is limited; therefore, an ex vivo model of human precision-cut tissue slices (PCTS) might become an indispensable tool in fibrosis research and drug development by bridging the animal-human translational gap. This study, presented as two parts, provides comprehensive characterization of the dynamic transcriptional changes in PCTS during culture by RNA sequencing. Part I investigates the differences in culture-induced responses in murine and human PCTS derived from healthy liver, kidney and gut. Part II delineates the molecular processes in cultured human PCTS generated from diseased liver, kidney and ileum. We demonstrated that culture was associated with extensive transcriptional changes and impacted PCTS in a universal way across the organs and two species by triggering an inflammatory response and fibrosis-related extracellular matrix (ECM) remodelling. All PCTS shared mRNA upregulation of IL-11 and ECM-degrading enzymes MMP3 and MMP10. Slice preparation and culturing activated numerous pathways across all PCTS, especially those involved in inflammation (IL-6, IL-8 and HMGB1 signalling) and tissue remodelling (osteoarthritis pathway and integrin signalling). Despite the converging effects of culture, PCTS display species-, organ-and pathologyspecific differences in the regulation of genes and canonical pathways. The underlying pathology in human diseased PCTS endures and influences biological processes like cytokine release. Our study reinforces the use of PCTS as an ex vivo fibrosis model and supports future studies towards its validation as a preclinical tool for drug development.

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Section: Organ-and Pathology-specificity In the Effect Of Culturementioning

confidence: 99%

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

et al. 2019

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“…The preferred site for TP53 mutations is in the DNA-binding domains, which decreases the binding affinity to responsive elements, leading to reduced activity of the p53 protein. (31,32) Etiological factors, in addition to AFB 1 ,such as HBV, HCV and alcohol have been implicated in generating TP53 mutations in HCC. (31,33) Inactivation of p53 by core proteins produced by HBV (e.g.…”

Section: Discussionmentioning

confidence: 99%

Analysis of TP53 gene mutations demonstrates that aflatoxin is a risk factor for hepatocellular carcinoma in Guatemala

Álvarez¹,

Ortiz

Bendfeldt-Avila

et al. 2019

Preprint

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Background Guatemala has the highest incidence of hepatocellular carcinoma (HCC), the dominant type of liver cancer, in the Western Hemisphere. The major risk factors in Guatemala are not well-characterized, but the prevalence of hepatitis B (HBV) and hepatitis C virus (HCV) appear to be low, while the prevalence of aflatoxin (AFB 1 ) exposure appears to be high. To examine whether AFB 1 could be a risk factor for HCC in Guatemala, this study examined the frequency of the AFB 1 -signature mutation in the TP53 gene (R249S) as well as other somatic mutations.Methods Ninety-one formalin-fixed, paraffin-embedded (FFPE) HCC tissues were obtained from three hospitals in Guatemala City. An additional, eighteen tumor tissues preserved in RNAlater were also obtained. Targeted sequencing of TP53 was successfully performed in 89 of the FFPE samples, and a panel of 245 genes were sequenced in the RNAlater samples.Results Overall, 47% of HCCs had a TP53 mutation. The AFB 1 -signature R249S mutation was present in 24%. Among the RNAlater samples, 44% had any TP53 mutation and 33% had the R249S mutation. Other somatic mutations were identified in known HCC driver genes such as ARID1A , ARID2 , and CTNNB1 .Conclusions The presence of the TP53 R249S mutation indicates that AFB 1 is a risk factor for HCC in Guatemala. The proportion of HBV positive tumors was low, suggesting that AFB 1 is associated with HCC in the absence of concomitant HBV infection. To decrease the risk of HCC in Guatemala, AFB 1 abatements efforts are warranted.

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“…[20][21][22] Mutant genes found in subjects with large and extra large tumors were in line with HCC behavior. [9][10][11] Those with overexpressed p53 suggested poorly and moderately differentiated tumors, microvascular invasion, and necrotic area, thereby indicating poor prognosis. 23 Among these behaviors, necrosis was predominantly found in this study, which suggested the nature of lesions present in surrounding tissues.…”

Section: Discussionmentioning

confidence: 99%

“…This p53 or "the guardian of genome" is known as a tumor suppressor gene that controls cellular growth after deoxyribonucleic acid (DNA) damage through mechanisms involving growth arrest and apoptosis; such mechanisms trigger a variety of antiproliferative programs by activating or repressing key effector genes. 5,8,9 Mutation of p53 found in HCC has been reported after 2013. 10 Patients with HCC managed in Cipto Mangunkusumo General Hospital (CMGH), Jakarta, have different characteristics from patients in studies published abroad.…”

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confidence: 99%

Overexpression of p53 in extra large (more than 10 cm) hepatocellular carcinoma

et al. 2018

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Background: Extra large hepatocellular carcinoma (HCC) of >10 cm managed in our center shows a specific characteristic in tropical regions. This type of HCC exhibits distinct p53 expression. This study aimed to determine the association between p53 expression and tumor size and behavior. Method: Subjects with HCC who underwent surgical resection in our hospital during 2012–2015 were enrolled in thisstudy. Subject’s characteristics, tumor size, histopathology findings, and tumor behavior were variables observed. Animmunohistochemical study on p53 expression was conducted to determine its association with those variables.Results: This study involved 38 subjects with tumor size ranging from 3 cm to 25 cm in diameter and 20 subjects (52.8%) with tumor size ranging from 10 cm to 25 cm in diameter. Only 13 samples were evaluated for p53 expression. Five subjects with >10 cm (extra large) tumor showed highly/overexpressed p53 (intensity>50%), two subjects with strong p53 expression (intensity>5%–50%), and two subjects with weak expression. Three subjects with <10 cm (large) tumor showed strong expression of p53 (5%–9%) and a subject with 3 cm tumor showed weak p53 expression (<5%). Highly expressed p53 was found in patients with microvascular invasion, inflammatory response, mitosis, and necrosis.Conclusion: Overexpression of p53 was associated with extra large and poorly differentiated HCC.

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The p53 family in hepatocellular carcinoma

Cited by 29 publications

References 0 publications

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

Analysis of TP53 gene mutations demonstrates that aflatoxin is a risk factor for hepatocellular carcinoma in Guatemala

Overexpression of p53 in extra large (more than 10 cm) hepatocellular carcinoma

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