Proteins of the mitotic checkpoint and spindle are related to chromosomal instability and unfavourable prognosis in patients with myelodysplastic syndrome

Genga, Kelly Roveran; Filho, Francisco Dário Rocha; Ferreira, Francisco Valdeci de Almeida; Sousa, Jorge Rodrigues de; Studart, Fernando S.; Magalhães, Sílvia Maria Meira; Heredia, Fabiola Fernandes; Pinheiro, Ronald Feitosa

doi:10.1136/jclinpath-2014-202728

Cited by 20 publications

(17 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inversely, there is a correlation between age and expression of the checkpoint genes Mad2, Aurora B and Cdc20 in myelodysplastic syndrome (MDS), an characteristic aging-associated dysplasia of the blood-forming system. The same study also demonstrated a correlation of expression levels of these genes and the developmental stage of MDS, as already discussed in the previous paragraph [ 45 ].…”

Section: Changes Of Mitotic Checkpoint Signaling During the Aging Prosupporting

confidence: 76%

“…Further on, expression levels of the SAC components Aurora A/B have been reported for AML cells [ 43 ], whereas upregulation of Aurora A has also been connected to the initiation of myelodysplastic syndrome (MDS) [ 44 ]. This heterogeneous class of various blood cancers also in most cases emerges from transformed HSPCs [ 45 , 46 ]. The van Deursen laboratory showed that overexpression of the MCC regulator Bub1 in mice induced tumor formation [ 47 ], while the level of expression of the gene was reduced in AML specimens and cell lines, such as K562 and HL60 [ 48 , 49 ].…”

Section: Changes In Sac Signaling In Cancermentioning

confidence: 99%

“…Interestingly, each MDS subtype was reported to have its own expression profile of SAC genes. High expression, especially of Mad2 and Cdc20 was associated with thrombocytopenia and an overall poor survival rate [ 45 ]. That implies that the level of impairment of the SAC triggered by Cdc20 and Mad2 mis-regulation might directly contribute to the severity of the disease.…”

Section: Changes In Sac Signaling In Cancermentioning

confidence: 99%

See 2 more Smart Citations

Chromosome integrity checkpoints in stem and progenitor cells: transitions upon differentiation, pathogenesis, and aging

Brown

Geiger

2018

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Loss of chromosome integrity is a major contributor to cancer. Checkpoints within the cell division cycle that facilitate the accuracy and outcome of chromosome segregation are thus critical pathways for preserving chromosome integrity and preventing chromosomal instability. The spindle assembly checkpoint, the decatenation checkpoint and the post-mitotic tetraploidy checkpoint ensure the appropriate establishment of the spindle apparatus, block mitotic entry upon entanglement of chromosomes or prevent further progression of post-mitotic cells that display massive spindle defects. Most of our knowledge on these mechanisms originates from studies conducted in yeast, cancer cell lines and differentiated cells. Considering that in many instances cancer derives from transformed stem and progenitor cells, our knowledge on these checkpoints in these cells just started to emerge. With this review, we provide a general overview of the current knowledge of these checkpoints in embryonic as well as in adult stem and progenitor cells with a focus on the hematopoietic system and outline common mis-regulations of their function associated with cancer and leukemia. Most cancers are aging-associated diseases. We will thus also discuss changes in the function and outcome of these checkpoints upon aging of stem and progenitor cells.

show abstract

Section: Changes Of Mitotic Checkpoint Signaling During the Aging Prosupporting

confidence: 76%

Section: Changes In Sac Signaling In Cancermentioning

confidence: 99%

Section: Changes In Sac Signaling In Cancermentioning

confidence: 99%

See 1 more Smart Citation

Chromosome integrity checkpoints in stem and progenitor cells: transitions upon differentiation, pathogenesis, and aging

Brown

Geiger

2018

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Among these 5 hub genes, MAD2L1 and FANCD2 are associated with ovarian cancer. As a component of the mitotic checkpoint, high levels of MAD2L1 are related to increased cellular proliferation, migration, and metastasis, which can lead to shorter survival in various cancers [22][23][24][25][26]. However, in ovarian cancer, the role of MAD2L1 did not agree with previous findings that patients with lower MAD2L1 levels were less sensitive to paclitaxel and had shorter progression-free survival (PFS) and overall survival (OS) [27,28].…”

Section: Discussionmentioning

confidence: 82%

Identification of Hub Genes in High-Grade Serous Ovarian Cancer Using Weighted Gene Co-Expression Network Analysis

Sun

et al. 2020

Med Sci Monit

View full text Add to dashboard Cite

Background: High-grade serous ovarian cancer (HGSOC) is the most malignant gynecologic tumor. This study reveals biomarkers related to HGSOC incidence and progression using the bioinformatics method. Material/Methods: Five gene expression profiles were downloaded from GEO. Differentially-expressed genes (DEGs) in HGSOC and normal ovarian tissue samples were screened using limma and the function of DEGs was annotated by KEGG and GO analysis using clusterProfiler. A co-expression network utilizing the WGCNA package was established to define several hub genes from the key module. Furthermore, survival analysis was performed, followed by expression validation with datasets from TCGA and GTEx. Finally, we used single-gene GSEA to detect the function of prognostic hub genes. Results: Out of the 1874 DEGs detected from 114 HGSOC versus 49 normal tissue samples, 956 were upregulated and 919 were downregulated. The functional annotation indicated that upregulated DEGs were mostly enriched in cell cycle, whereas the downregulated DEGs were enriched in the MAPK or Ras signaling pathway. Two modules significantly associated with HGSOC were excavated through WGCNA. After survival analysis and expression validation of hub genes, we found that 2 upregulated genes (MAD2L1 and PKD2) and 3 downregulated genes (DOCK5, FANCD2 and TBRG1) were positively correlated with HGSOC prognosis. GSEA for single-hub genes revealed that MAD2L1 and PKD2 were associated with proliferation, while DOCK5, FANCD2, and TBRG1 were associated with immune response. Conclusions: We found that FANCD2, PKD2, TBRG1, and DOCK5 had prognostic value and could be used as potential biomarkers for HGSOC treatment.

show abstract

“…Similarly in breast cancer, where p53 and BRCA1 are also regularly mutated, high MAD2 levels are associated with improved breast cancer specific survival [ 53 ]. Additionally, high grade serous ovarian cancers express lower levels of E-cadherin and higher levels of N-cadherin compared to mucinous which is suggestive of a more epithelial-mesenchymal transition phenotype which in-turn triggers tumour metastasis and possibly reduce the requirement of MAD2 for tumour spread [ 54 , 55 ]. However, due to the limited number of studies on MAD2 expression in ovarian cancer, we cannot conclude if different ovarian subtypes have different survival rates depending on MAD2 expression.…”

Section: Discussionmentioning

confidence: 99%

The association between MAD2 and prognosis in cancer: a systematic review and meta-analyses

et al. 2017

View full text Add to dashboard Cite

This systematic review and meta-analyses investigates the expression of the cell checkpoint regulator, mitotic arrest deficiency protein 2 (MAD2) in cancerous tissue and examines whether an association exists between MAD2 levels and cancer survival and recurrence. Studies investigating MAD2 expression in cancer tissue utilising immunohistochemistry (IHC) were identified by systematic literature searches of Medline, Embase and Web of Science databases by October 2015. Random effects meta-analyses were performed to generate pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of overall and progression-free survival according to MAD2 expression. Forty-three studies were included in the overall review. In 33 studies investigating MAD2 expression by IHC in cancer tissue, a wide range of expression positivity (11–100%) was reported. Higher MAD2 expression was not associated with an increased risk of all-cause mortality in a range of cancers (pooled HR 1.35, 95% CI 0.97–1.87; P = 0.077, n = 15). However, when ovarian cancer studies were removed, a significant pooled HR of 1.59 for risk of all-cause mortality in other cancer patients with higher expressing MAD2 tumours was evident (95% CI, 1.17–2.17; P = 0.003, n = 12). In contrast, higher MAD2 expression was associated with significant decreased risk of all-cause mortality in ovarian cancer patients (pooled HR = 0.50, 95% CI, 0.25–0.97; P = 0.04, n = 3). In conclusion, with the exception of ovarian cancer, increased MAD2 expression is associated with increased risk of all-cause mortality and recurrence in cancer. For ovarian cancer, reduced levels of MAD2 are associated with poorer outcome. Further studies are critical to assess the clinical utility of a MAD2 IHC biomarker.

show abstract

Proteins of the mitotic checkpoint and spindle are related to chromosomal instability and unfavourable prognosis in patients with myelodysplastic syndrome

Abstract: To the best of our knowledge, this is the first report to demonstrate that these proteins are associated with chromosomal abnormalities and poor prognosis in patients with MDS.

Cited by 20 publications

References 32 publications

Chromosome integrity checkpoints in stem and progenitor cells: transitions upon differentiation, pathogenesis, and aging

Chromosome integrity checkpoints in stem and progenitor cells: transitions upon differentiation, pathogenesis, and aging

Identification of Hub Genes in High-Grade Serous Ovarian Cancer Using Weighted Gene Co-Expression Network Analysis

The association between MAD2 and prognosis in cancer: a systematic review and meta-analyses

Contact Info

Product

Resources

About