Defective mitosis-linked DNA damage response and chromosomal instability in liver cancer

Birgani, Maryam Tahmasebi; Ansari, Hossein; Carloni, Vinicio

doi:10.1016/j.bbcan.2019.05.008

Cited by 20 publications

(17 citation statements)

References 47 publications

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“…Evidence shows that hepatocyte apoptosis contributes to a number of liver diseases, including alcohol-induced liver disease, viral hepatitis, cholestatic liver disease, non-alcoholic fatty liver disease, and Wilson’s disease 25 . DDR signalling is another fundamental pathway affecting human and animal diseases, such as liver cancer 26 , and which has been found activated in rodent liver upon feeding with cell-damaging agents 27–29 . The unfolded protein response pathway is also activated upon cellular stress or exposure to certain drugs 30 , and is related to an accumulation of unfolded or wrongly folded proteins within the endoplasmic reticulum (ER) 31 .…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of key pathways in rat liver after a one-year feeding trial with transgenic maize MON810

Stein

Ran

Bohmer

et al. 2019

Sci Rep

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In a recent one-year feeding study, we observed no adverse effects on tissue level in organs of rats fed with the genetically-modified maize MON810. Here, we assessed RNA expression levels of 86 key genes of the apoptosis-, NF-кB-, DNA-damage response (DDR)-, and unfolded-protein response (UPR) pathways by RT-qPCR in the rat liver. Male and female rats were fed either with 33% MON810 (GMO), isogenic- (ISO), or conventional maize (CONV) and RNAs were quantified from eight rats from each of the six feeding groups. Only Birc2 transcript showed a significant (p ≤ 0.05) consistent difference of ≥1.5-fold between the GMO and ISO groups in both sexes. Unsupervised cluster analysis showed a strong separation of male and female rats, but no clustering of the feeding groups. Individual analysis of the pathways did not show any clustering of the male or female feeding groups either, though transcript levels of UPR pathway-associated genes caused some clustering of the male GMO and CONV feeding group samples. These differences were not seen between the GMO and ISO control or within the female cohort. Our data therefore does not support an adverse effect on rat liver RNA expression through the long-term feeding of MON810 compared to isogenic control maize.

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Section: Discussionmentioning

confidence: 99%

Expression profiling of key pathways in rat liver after a one-year feeding trial with transgenic maize MON810

Stein

Ran

Bohmer

et al. 2019

Sci Rep

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“…Interestingly, there were 9 dysregulated proteins in the AN group compared to the DN group but no dysregulation in the HCC group compared to the DN group, and the GO results showed that these dysregulated proteins were mainly involved in desmosome organisation, positive regulation of sister chromatid cohesion, translation, rRNA processing, nuclear-transcribed mRNA catabolic process, translational initiation, and SRP-dependent co-translational protein targeting the membrane. The results also showed that the dysregulated proteins may have affected the incidence and progress of HCC, such as the change of the combination of the protein and the RNA function presenting the disorder of the transcription and translation function, which suggested that the surrounding noncancerous cells might increase the expression of the nucleic acid and enzyme by tumour microenvironment to promote the HCC proliferation and growth [30], and that the changes of telomere and telomerase in the surrounding noncancerous cells revealed the dysregulation on the chromosome stability, repair, and proliferation, which were all closely related to the incidence of HCC development [31,32]. Similarly, the molecular function of these proteins, such as cadherin binding-involved nucleotide binding, RNA binding, calcium ion binding, chromatin binding, transcription regulatory region DNA binding, identical protein binding, etc., also supported this conclusion.…”

Section: Discussionmentioning

confidence: 99%

The isobaric tags for relative and absolute quantification-based quantitative proteomics of fresh tissue-derived secretome in hepatocellular carcinoma

et al. 2021

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IntroductionProteomics technology platforms offer an extremely useful tool for the discovery of new cancer biomarkers. Secreted proteins play important roles in signal transduction, cellular growth, proliferation, differentiation, and apoptosis. This study aimed to investigate the molecular signatures of the hepatocellular carcinoma (HCC) by quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ) with liquid chromatography-tandem mass spectrometry (LC-MS/MS).Material and methodsIn this study, we used an iTRAQ-based quantitative proteomic approach to analyse the secretome of HCC tissues to identify plasma biomarkers. Serum-free conditioned media (CM) were collected from the primary cultures of cancerous tissues, the surrounding noncancerous tissues, and distal noncancerous tissues.ResultsA proteomic analysis of the CM proteins allowed for a total of 5214 identified proteins, of which 190 and 44 proteins were dysregulated in the HCC tissues/distal noncancerous tissues (HCC/DN group) and the adjacent noncancerous tissues/distal noncancerous tissues (AN/DN group) compared with the distal noncancerous tissues. The dysregulated proteins in the HCC/DN group were concentrated in mitogen-activated protein kinase (MAPK) signalling and Janus kinase-signal transducer and activator of the transcription (JAK-STAT) signalling, but the dysregulated proteins in the AN/DN group were more concentrated in the basal material metabolism.ConclusionsThe secretome profile alternations and signalling pathways were associated with HCC incidence and development. The dysregulated proteins in the HCC/DN group were concentrated in the MAPK signalling and JAK-STAT signalling, but the dysregulated proteins in the AN/DN group were more concentrated in the basal material metabolism.

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“…Chromosome instability (CIN) is a typical outcome of defects in DDR and activates DDR [203,204]. Accumulative evidence reveals increases in somatic aneuploidy as a feature of aging [205].…”

Section: Contributions Of Chromosome Instability To Admentioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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Defective mitosis-linked DNA damage response and chromosomal instability in liver cancer

Cited by 20 publications

References 47 publications

Expression profiling of key pathways in rat liver after a one-year feeding trial with transgenic maize MON810

Expression profiling of key pathways in rat liver after a one-year feeding trial with transgenic maize MON810

The isobaric tags for relative and absolute quantification-based quantitative proteomics of fresh tissue-derived secretome in hepatocellular carcinoma

Contributions of DNA Damage to Alzheimer’s Disease

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