Inhibitor of caspase-activated DNase expression enhances caspase-activated DNase expression and inhibits oxidative stress-induced chromosome breaks at the mixed lineage leukaemia gene in nasopharyngeal carcinoma cells

Boon, Siaw Shi; Sim, Sai‐Peng

doi:10.1186/s12935-015-0205-1

Cited by 10 publications

(6 citation statements)

References 54 publications

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“…DFFA plays an essential role in apoptosis. When cleaved by caspase-3, it induces the release of its partner DFFB, which in turn triggers DNA fragmentation by its nuclease activity [ 165 ]. Hence, absence of this protein could result in aberrant apoptosis, invasive growth, and metastasis [ 166 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma

Toraih

Ibrahiem

Fawzy

et al. 2017

Oxidative Medicine and Cellular Longevity

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Renal cell carcinoma (RCC) incidence has increased over the past two decades. Recent studies reported microRNAs as promising biomarkers for early cancer detection, accurate prognosis, and molecular targets for future treatment. This study aimed to evaluate the expression levels of miR-34a and 11 of its bioinformatically selected target genes and proteins to test their potential dysregulation in RCC. Quantitative real-time PCR for miR-34a and its targets; MET oncogene; gene-regulating apoptosis (TP53INP2 and DFFA); cell proliferation (E2F3); and cell differentiation (SOX2 and TGFB3) as well as immunohistochemical assay for VEGFA, TP53, Bcl2, TGFB1, and Ki67 protein expression have been performed in 85 FFPE RCC tumor specimens. Clinicopathological parameter correlation and in silico network analysis have also implicated. We found RCC tissues displayed significantly higher miR-34a expression level than their corresponding noncancerous tissues, particularly in chromophobic subtype. MET and E2F3 were significantly upregulated, while TP53INP2 and SOX2 were downregulated. ROC analysis showed high diagnostic performance of miR-34a (AUC = 0.854), MET (AUC = 0.765), and E2F3 (AUC = 0.761). The advanced pathological grade was associated with strong TGFB1, VEGFA, and Ki67 protein expression and absent Tp53 staining. These findings indicate miR-34a along with its putative target genes could play a role in RCC tumorigenesis and progression.

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Section: Discussionmentioning

confidence: 99%

MicroRNA‐34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma

Toraih

Ibrahiem

Fawzy

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…ICAD is a downstream molecule of the caspases, usually inhibiting nuclear DNA fragmentation induced by CAD during apoptosis. ICAD is often located in cell nuclei and functions in the cytoplasm as an anchor for CAD or as a factor that enters the nucleus following caspase cleavage ( 6 , 7 , 14 ). In the current TMA analysis, Figure 1A demonstrates ICAD protein expression in normal kidney.…”

Section: Resultsmentioning

confidence: 99%

“…CAD is normally inhibited by the inhibitor of CAD (ICAD). During apoptosis, the effector caspase, caspase-3, cleaves ICAD, causing CAD to become activated and degradation of nuclear DNA into nucleosomal units to occur ( 6–8 ).…”

Section: Introductionmentioning

confidence: 99%

Decreased Expression of Inhibitor of Caspase-Activated DNase (ICAD) in Renal Cell Carcinoma –Tissue Microarray of Human Samples

Rajandram

Razack

et al. 2016

jkcvhl

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Although primary localised tumours of renal cell carcinoma (RCC) can be treated relatively successfully with surgery, metastatic RCC has poor prognosis because of late diagnosis and resistance to therapies. In the present study, we were interested in profiling the protein expression of “inhibitor of caspase-activated DNase” (ICAD), an apoptosis inhibitor, in kidney cancer and its paired normal kidney. Immunohistochemistry with automated batch staining and morphometry using digital pathology were used to compare ICAD in 121 RCC specimens with their paired normal kidney tissue. Tissue microarray of formalin-fixed, paraffin-embedded archival tissue was used. Intensity and localisation of ICAD were compared between normal and cancer samples, and against grading within the cancers. The results demonstrated that, in this cohort, ICAD was highly expressed in the proximal tubular epithelium of normal kidney, and significantly decreased in clear cell RCC tissue (p < 0.05) as well as other subtypes of RCC (p < 0.01) compared with normal kidney. There was a tendency towards nuclear localisation of ICAD in clear cell RCC, but not in other subtypes of RCC. No significant association was found between ICAD intensity and grade of RCC. In summary, down-regulation of ICAD occurs in RCC. ICAD normally inhibits DNA fragmentation and apoptosis; thus, its down-regulation was unexpected in a cancer known for its resistance to apoptosis. However, these RCC samples were from primary, not metastatic, RCC sites, and down-regulated ICAD may be part of a progressive pathway that promotes RCC metastasis.

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“…Indeed, our previous study had demonstrated that, overexpression of ICAD resulted in expression of CAD and also inhibited H 2 O 2 -induced MLL gene cleavages. The observations of our previous study suggested a role for CAD in mediating H 2 O 2 -induced chromosome breaks [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Matrix association region/scaffold attachment region (MAR/SAR) sequence: its vital role in mediating chromosome breakages in nasopharyngeal epithelial cells via oxidative stress-induced apoptosis

2018

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BackgroundOxidative stress is known to be involved in most of the aetiological factors of nasopharyngeal carcinoma (NPC). Cells that are under oxidative stress may undergo apoptosis. We have previously demonstrated that oxidative stress-induced apoptosis could be a potential mechanism mediating chromosome breakages in nasopharyngeal epithelial cells. Additionally, caspase-activated DNase (CAD) may be the vital player in mediating the chromosomal breakages during oxidative stress-induced apoptosis. Chromosomal breakage occurs during apoptosis and chromosome rearrangement. Chromosomal breakages tend to cluster in certain regions, such as matrix association region/scaffold attachment region (MAR/SAR). We hypothesised that oxidative stress-induced apoptosis may result in chromosome breaks preferentially at the MAR/SAR sites. The AF9 gene at 9p22 was targeted in this study because 9p22 is a deletion site commonly found in NPC.ResultsBy using MAR/SAR recognition signature (MRS), potential MAR/SAR sites were predicted in the AF9 gene. The predicted MAR/SAR sites precisely match to the experimentally determined MAR/SARs. Hydrogen peroxide (H2O2) was used to induce apoptosis in normal nasopharyngeal epithelial cells (NP69) and NPC cells (HK1). Nested inverse polymerase chain reaction was employed to identify the AF9 gene cleavages. In the SAR region, the gene cleavage frequency of H2O2-treated cells was significantly higher than that of the non-treated cells. A few chromosomal breakages were detected within the AF9 region which was previously found to be involved in the mixed lineage leukaemia (MLL)-AF9 translocation in an acute lymphoblastic leukaemia patient. As for the non-SAR region, no significant difference in the gene cleavage frequency was found between the untreated control and H2O2-treated cells. Furthermore, H2O2-induced cleavages within the SAR region were reduced by caspase-3 inhibitor, which indirectly inhibits CAD.ConclusionsThese results reaffirm our previous findings that oxidative stress-induced apoptosis could be one of the potential mechanisms underlying chromosome breakages in nasopharyngeal epithelial cells. MAR/SAR may play a vital role in defining the location of chromosomal breakages mediated by oxidative stress-induced apoptosis, where CAD is the major nuclease.Electronic supplementary materialThe online version of this article (10.1186/s12867-018-0116-5) contains supplementary material, which is available to authorized users.

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Inhibitor of caspase-activated DNase expression enhances caspase-activated DNase expression and inhibits oxidative stress-induced chromosome breaks at the mixed lineage leukaemia gene in nasopharyngeal carcinoma cells

Cited by 10 publications

References 54 publications

MicroRNA‐34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma

MicroRNA‐34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma

Decreased Expression of Inhibitor of Caspase-Activated DNase (ICAD) in Renal Cell Carcinoma –Tissue Microarray of Human Samples

Matrix association region/scaffold attachment region (MAR/SAR) sequence: its vital role in mediating chromosome breakages in nasopharyngeal epithelial cells via oxidative stress-induced apoptosis

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