MAD2 expression and its significance in mitotic checkpoint control in testicular germ cell tumour.
Chromosomal instability (CIN) is a common characteristic in testicular germ cell tumour (TGCT). A functional mitotic checkpoint control is important for accurate chromosome segregation during mitosis. Mitotic arrest deficient 2 (MAD2) is a key component of this checkpoint and inactivation of MAD2 is correlated with checkpoint impairment. The aim of this study was to investigate the function of mitotic checkpoint control in TGCT cells and to study its association with MAD2 expression using 8 TGCT cell lines as well as 23 TGCT tissue samples. We found that in response to microtubule disruption, 6 of 8 TGCT cell lines (75%) failed to arrest in mitosis demonstrated by the decreased mitotic index and aberrant expression of mitosis regulators, indicating that mitotic checkpoint defect is a common event in TGCT cells. This loss of mitotic checkpoint control was correlated with reduced MAD2 protein expression in TGCT cell lines implicating that downregulation of MAD2 may play a critical role in an impaired mitotic checkpoint control in these cells. In addition, immunohistochemistry studies on 23 seminomas and 12 normal testis tissues demonstrated that nuclear expression of MAD2 was much lower in seminomas (p<0.0001) but cytoplasmic MAD2 expression was higher in seminomas (p=0.06) than normal samples. Our results suggest that aberrant MAD2 expression may play an essential role in a defective mitotic checkpoint in TGCT cells, which may contribute to CIN commonly observed in TGCT tumours.
Fung
Maggie K-L
MK
Cancer Biology Group, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China.
Cheung
Hiu-Wing
HW
Wong
Hing-Lok
HL
Yuen
Hiu-Fung
HF
Ling
Ming-Tat
MT
Chan
Kowk-Wah
KW
Wong
Yong-Chuan
YC
Cheung
Annie L-M
AL
Wang
Xianghong
X
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D064246:Mad2 Proteins; D008297:Male; D008875:Middle Aged; D008938:Mitosis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000096:biosynthesis*; D018239:Seminoma / Q000378:metabolism* / Q000473:pathology; D013736:Testicular Neoplasms / Q000378:metabolism* / Q000473:pathology; D013737:Testis / Q000378:metabolism / Q000473:pathology
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins