Role of a Novel Splice Variant of Mitotic Arrest Deficient 1 (MAD1), MAD1β, in Mitotic Checkpoint Control in Liver Cancer

Sze, Karen Man‐Fong; Ching, Yick–Pang; Jin, Dong-Yan; Ng, Irene Oi–Lin

doi:10.1158/0008-5472.can-08-2600

Cited by 21 publications

(31 citation statements)

References 37 publications

(44 reference statements)

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“…Previous studies have shown that reduced expression of MAD1L1 promotes tumor development in mice, which further validates its tumor‐suppressing functions . This gene is over‐expressed in both HCC and breast cancer ; however, it is under‐expressed in chromophobe renal cell cancers . In the present study, only the methylation status of the MAD1L1 intron‐11 was analysed, and the MAD1L1 mRNA level was found to be similar between the MAD1L1 methylation‐low and ‐high HCCs.…”

Section: Discussionsupporting

confidence: 81%

Genome‐wide identification of differential methylation between primary and recurrent hepatocellular carcinomas

Cui

Liu

et al. 2015

Molecular Carcinogenesis

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A biomarker capable of clinically predicting hepatocellular carcinoma (HCC) recurrence has not previously been established. Here genome-wide differential methylation between primary and recurrent HCC cell lines (Hep-11 and Hep-12) from the same patient was characterized. The HCC samples from two independent cohorts, complete with follow-up data, were used to validate the feasibility of the selected methylation biomarkers in predicting HCC prognosis. A methylation array assay identified 30 candidate genes or intergenic-fragments with an absolute methylation fold-change >2.0 between these cell lines; 22 candidates were hypomethylated in Hep-12 cells relative to Hep-11 cells. Bisulfite sequencing confirmed these results. Most importantly, classification of tumors by LINE-2 methylation level was significantly associated with HCC recurrence in both cohorts (P < 0.02). Similarly, MAD1L1 and LINC00682 methylation levels also correlated with HCC recurrence. Survival analysis showed that a combined baseline LINE-2, MAD1L1, and LINC00682 methylation signature was significantly associated with short recurrence-free survival in patients from both cohorts. A synergic effect was observed between these markers on both recurrence-free survival (P< 0.010) and overall survival (P < 0.040). In conclusion, low levels of LINE-2, MAD1L1, and LINC00682 methylation were associated with recurrence and decreased overall survival in HCC patients. © 2015 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 81%

Genome‐wide identification of differential methylation between primary and recurrent hepatocellular carcinomas

Cui

Liu

et al. 2015

Molecular Carcinogenesis

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“…Sze KM et al have shown that all 6 hepatoma cell lines with defective mitotic checkpoint showed significant reduced expression of mitotic arrest deficient 2 ( Mad 2)[13]. Mad 1beta, a novel splicing variant of mitotic arrest deficient 1 ( Mad 1), was expressed at both mRNA and protein levels in the nine hepatoma cell lines tested and was over-expressed in 12 of 50 (24%) human HCC tissues[14]. Jeong SJ et al have shown that transcriptional dysfunction of hsMad 2 is frequently observed in hepatocellular carcinoma cells [15].…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of cenp-e in human hepatocellular carcinoma

Liu

et al. 2009

J Exp Clin Cancer Res

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BackgroundCENP-E, one of spindle checkpoint proteins, plays a crucial role in the function of spindle checkpoint. Once CENP-E expression was interrupted, the chromosomes can not separate procedurally, and may result in aneuploidy which is a hallmark of most solid cancers, such as hepatocellular carcinoma (HCC). We investigate the expression of CENP-E in human hepatocellular carcinoma,. and analyze the effect of low CENP-E expression on chromosome separation in normal liver cell line (LO2).MethodsWe determined its levels in HCC and para-cancerous tissues, human hepatocellular carcinoma-derived cell line (HepG2) and LO2 cell line using real time quantitative PCR (QPCR) and Western blot. Further to know whether reduction in CENP-E expression impairs chromosomes separation in LO2 cells. we knocked down CENP-E using shRNA expressing vector and then count the aneuploid in LO2 cells using chromosomal counts assay.ResultsWe found that both CENP-E mRNA and protein levels were significantly reduced in HCC tissues and HepG2 cells compared with para-cancerous tissues and LO2 cells, respectively. A significantly-increased proportion of aneuploid in these down-knocked LO2 cells compared with those treated with control shRNA vector.ConclusionsTogether with other results, these results reveal that CENP-E expression was reduced in human HCC tissue, and low CENP-E expression result in aneuploidy in LO2 cells.

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“…These transcriptional variants are often over-expressed, causing multipolar mitoses and mis-segregation in cancer cell lines and tissues. The MAD1ß and Aurora B isoforms provide excellent examples [44,45]; these isoforms lead first to errors in the mitotic spindle checkpoint and ultimately to CIN. Centrosome abnormalities are also caused by an imbalance in splice variants of proteins that are key centrosome regulators, like TrkAIII, which is over-expressed in advanced neuroblastoma and primary glioblastoma [46], and NEK2A [47], which has been proposed as a tumour marker and is abnormally expressed in most cancer cell lines and tumours.…”

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confidence: 99%

Differential Signature of the Centrosomal MARK4 Isoforms in Glioma

Magnani

Novielli

Fontana

et al. 2011

Analytical Cellular Pathology

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Abstract.Background: MAP/microtubule affinity-regulating kinase 4 (MARK4) is a serine-threonine kinase expressed in two spliced isoforms, MARK4L and MARK4S, of which MARK4L is a candidate for a role in neoplastic transformation.Methods: We performed mutation analysis to identify sequence alterations possibly affecting MARK4 expression. We then investigated the MARK4L and MARK4S expression profile in 21 glioma cell lines and 36 tissues of different malignancy grades, glioblastoma-derived cancer stem cells (GBM CSCs) and mouse neural stem cells (NSCs) by real-time PCR, immunoblotting and immunohistochemistry. We also analyzed the sub-cellular localisation of MARK4 isoforms in glioma and normal cell lines by immunofluorescence.Results: Mutation analysis rules out sequence variations as the cause of the altered MARK4 expression in glioma. Expression profiling confirms that MARK4L is the predominant isoform, whereas MARK4S levels are significantly decreased in comparison and show an inverse correlation with tumour grade. A high MARK4L/MARK4S ratio also characterizes undifferentiated cells, such as GBM CSCs and NSCs. Accordingly, only MARK4L is expressed in brain neurogenic regions. Moreover, while both MARK4 isoforms are localised to the centrosome and midbody in glioma and normal cells, the L isoform exhibits an additional nucleolar localisation in tumour cells.Conclusions: The observed switch towards MARK4L suggests that the balance between the MARK4 isoforms is carefully guarded during neural differentiation but may be subverted in gliomagenesis. Moreover, the MARK4L nucleolar localisation in tumour cells features this MARK4 isoform as a nucleolus-associated tumour marker.

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Role of a Novel Splice Variant of Mitotic Arrest Deficient 1 (MAD1), MAD1β, in Mitotic Checkpoint Control in Liver Cancer

Cited by 21 publications

References 37 publications

Genome‐wide identification of differential methylation between primary and recurrent hepatocellular carcinomas

Genome‐wide identification of differential methylation between primary and recurrent hepatocellular carcinomas

Reduced expression of cenp-e in human hepatocellular carcinoma

Differential Signature of the Centrosomal MARK4 Isoforms in Glioma

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