p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

Tschaharganeh, Darjus F.; Xue, Wei; Calvisi, Diego F.; Evert, Matthias; Michurina, Tatyana V.; Dow, Lukas E.; Banito, Ana; Katz, Sarah–Fee; Kastenhuber, Edward R.; Weissmueller, Susann; Huang, Chun‐Hao; Lechel, André; Andersen, Jesper B.; Capper, David; Zender, Lars; Longerich, Thomas; Enikolopov, Grigori; Lowe, Scott W.

doi:10.1016/j.cell.2016.05.058

Cited by 57 publications

(89 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since 2012 we have observed that Nestin protein was mainly expressed in endothelial cells of activated arteries/arterioles and – in HCC – in intratumoral sinusoids and neoarteries, but never in neoplastic hepatocytes . Of note, two papers in the literature described Nestin expression in hepatocytes in a percentage of HCC; in our experience using the monoclonal antibody anti‐Nestin clone 10C2, we never observed Nestin expression in hepatocytes. This negative pattern is in keeping with that reported in the Human Atlas with another four clones of anti‐Nestin antibody (https://www.proteinatlas.org/ENSG00000132688-NES/pathology).…”

Section: Discussionmentioning

confidence: 60%

“…demonstrated that TP53 normally represses the Nestin protein transcription independently from the oncogenic‐driven mutation in cell cultures and in mouse models. Moreover, TP53 mutation induces high levels of Nestin expression [demonstrated by IHC and polymerase chain reaction (PCR)] in liver tumours . The mechanism of this phenomenon is not yet fully understood, and it is hypothesised that TP53 can act through the binding of the Sp1 gene.…”

Section: Discussionmentioning

confidence: 99%

“…As reported in the literature, PLC can originate from both progenitor cells and mature cells through de‐differentiation and/or trans‐differentiation: according to recent work on a mouse model, the loss of TP53 in mature hepatocytes increased the number of Nestin‐positive progenitor cells in PLC via the Sp1/3 pathway …”

Section: Introductionmentioning

confidence: 86%

See 2 more Smart Citations

Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate‐cell carcinoma?

et al. 2019

View full text Add to dashboard Cite

Aims Primary mixed liver cancers (PLCs), combined hepatocellular‐cholangiocellular (cHCC‐CC) and intermediate‐cell carcinomas are rare tumours characterised by different molecular mechanisms. Nestin is a marker of progenitor cells with a promising application in human tumours. The aims of the present paper are (i) to determine the expression of Nestin in mixed PLCs; and (ii) to correlate the PLC immunoprofile with the gene expression in each tumour component. Methods and results We selected 28 mixed PLCs, 13 (46.4%) cHCC‐CC and 15 (53.6%) intermediate‐cell carcinomas. The immunohistochemistry panel consisted of keratin 7, keratin 19, CD56 and Nestin. Next‐generation sequencing analysis was performed on 17 cases (27 specimens) using a multi‐gene custom panel. The differentiated HCC and CC components of cHCC‐CC were negative for Nestin in all cases. The intermediate areas of cHCC‐CC were immunoreactive for Nestin in 92.3% of cases, for CD56 in 76.9% and for K7/K19 in all cases. The immunoprofile of the intermediate‐cell carcinomas showed 73.3% of cases positive for Nestin and 66.7% for CD56. TP53 and TERT were the most frequently mutated genes (31.3% and 17.6% of samples, respectively). Mutations were also found in IDH1, IDH2, PIK3CA and NRAS genes. Intermediate and HCC areas of cHCC‐CC seemed to share the same mutational profile, and both harboured different mutations than the CC component. Conclusions According to our preliminary data, Nestin was not expressed by hepatocellular or cholangiocellular‐cell components, but was expressed by most of the intermediate cells in PLCs, and therefore could be considered in the differential diagnosis of PLCs, together with mutational profile.

show abstract

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate‐cell carcinoma?

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Several activities of p53 help to block reprogramming, including the induction of p21 and PUMA 47 . p53 can also repress the expression of nestin (a stem cell marker) in differentiated cells, thereby limiting cell plasticity and inhibiting tumorigenesis in response to oncogenic stress 48 . This work supports the hypothesis that p53-mediated tumour suppression is in part dependent on its capacity to maintain a differentiated cell fate.…”

Section: Box 1 | Apoptosismentioning

confidence: 99%

p53 in survival, death and metabolic health: a lifeguard with a licence to kill

Kruiswijk

Labuschagne

Vousden

2015

Nat Rev Mol Cell Biol

932

792

View full text Add to dashboard Cite

The function of p53 as a tumour suppressor has been attributed to its ability to promote cell death or permanently inhibit cell proliferation. However, in recent years, it has become clear that p53 can also contribute to cell survival. p53 regulates various metabolic pathways, helping to balance glycolysis and oxidative phosphorylation, limiting the production of reactive oxygen species, and contributing to the ability of cells to adapt to and survive mild metabolic stresses. Although these activities may be integrated into the tumour suppressive functions of p53, deregulation of some elements of the p53-induced response might also provide tumours with a survival advantage.

show abstract

“…The role of p53 as the barrier for CSC formation was recently reviewed [42]. Indeed, in the liver, p53 restricts cellular plasticity by repressing the expression of the hepatic progenitor marker, Nestin, which plays a role in liver tumorigenesis [43].…”

Section: Activation Of Wtp53 Promotes Fatty Liver Pathologiesmentioning

confidence: 99%

p53 in liver pathologies—taking the good with the bad

Charni¹,

Rivlin²,

Molchadsky³

et al. 2014

J Mol Med

View full text Add to dashboard Cite

The distinct physiology of the liver makes it a unique ground with respect to its cross talk with p53, the "guardian of the genome." The stressful environment in the liver frequently leads to the activation of p53, which is associated with alterations in metabolic pathways and induction of apoptosis. The latter serves as a mechanism that controls the deposal of DNA-damaged cells. However, accentuated apoptosis may eventually lead to liver pathologies, mainly steatosis, which can develop into a more severe disease such as steatohepatitis, fibrosis, and cirrhosis. These pathologies, together with other apoptosis outcome such as chronic inflammation, may pave the way toward cancer development. In addition to this unique scenario that connects the ongoing response of wild-type (WT) p53 to stress and cancer development, hepatocarcinoma may develop in other well-described mechanisms involving p53. One such example is hepatitis virus-induced liver cancer whereby p53 is inactivated upon the binding of a specific viral protein, leading to the loss of its tumor suppressive activity. Furthermore, the accumulations of carcinogens such as aflatoxin were shown to yield an oncogenic mutated p53 protein. In this review, we will demonstrate the diverse activities of p53 in the liver. Interestingly, some of these activities may protect the liver from cancer in the short term, yet in the long term, p53 may lead to malignant transformation. A better understanding of the complex clinical outcome of p53 function in the liver may shed light on future therapies.

show abstract

p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

Cited by 57 publications

References 0 publications

Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate‐cell carcinoma?

Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate‐cell carcinoma?

p53 in survival, death and metabolic health: a lifeguard with a licence to kill

p53 in liver pathologies—taking the good with the bad

Contact Info

Product

Resources

About