Expression of BUB1 protein in gastric cancer correlates with the histological subtype, but not with DNA ploidy or microsatellite instability

Grabsch, Heike; Askham, Jon M.; Morrison, Ewan E.; Pomjanski, Natalja; Lickvers, Kristina; Parsons, Wendy J; Boêcking, A.; Gabbert, Helmut E.; Mueller, Wolfram

doi:10.1002/path.1499

Cited by 31 publications

(27 citation statements)

References 35 publications

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“…BCL6 was highly expressed in differentiated cancers and was remarkably reduced or absent in undifferentiated cancers. Previous studies of gastric cancers have found that genes such as BUB1, eRF3/GSPT1, and hCG-1 were correlated with histological type (Grabsch et al, 2004;Malta-Vacas et al, 2005;Liu et al, 2007). However, the precise mechanism of association between the expression of these genes and the histology of gastric cancer is not well understood.…”

Section: Discussionmentioning

confidence: 97%

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers

et al. 2009

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BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/ proteasome pathway. Real-time RT -PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.

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Section: Discussionmentioning

confidence: 97%

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers

et al. 2009

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“…BRCA1, BRCA2, ATM, MLH1, and MSH2 immunohistochemistry was done on tissue microarrays constructed from the same series as described by Simon et al (33), sampling at random a minimum of three cores of 0.6-mm diameter from each tumor. Antigen retrieval, blocking procedures, and the modified ImmunoMax method used have previously been described (34). For further details of the immunohistochemical procedures, see Table 1.…”

Section: Methodsmentioning

confidence: 99%

Expression of DNA Double-Strand Break Repair Proteins ATM and BRCA1 Predicts Survival in Colorectal Cancer

Grabsch

Dattani

Barker

et al. 2006

Clinical Cancer Research

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Purpose: The double-strand break (DSB) is the major DNA lesion leading to chromosomal aberrations and faithful repair is crucial for maintaining genomic instability. Very little is known about the expression of DNA DSB repair proteins in colorectal cancer. To address this issue, we examined the expression pattern of DSB repair key proteins ATM, BRCA1, BRCA2, Ku70, and Ku80 and their putative role in patients survival in a large series of colorectal cancer. Experimental Design: 342 sporadic colorectal cancer were subjected to immunohistochemistry by using specific antibodies for the various proteins investigated. Staining results were compared with clinicopathologic data, patient survival, as well as expression of mismatch repair proteins MLH1 and MSH2. Results: The expression pattern of both ATM and BRCA1 predicted survival in all colorectal cancer patients as well as in the small subgroup of patients that received adjuvant therapy. Low expression of ATM and BRCA1 was associated with loss of MLH1 or MSH2 expression. Conclusions: This is the first study to show a relationship between the expression of DNA DSB repair proteins ATM and BRCA1 and survival in colorectal cancer patients. Studies in tumors from large randomized trials are now necessary to validate our pilot data and establish the clinical usefulness of the immunohistochemical assay in predicting response to a particular adjuvant therapy regimen. Furthermore, our results indicate a possible link between expression of DNA mismatch repair and DNA DSB repair proteins in sporadic colorectal cancer, which warrants further investigation. Genetic instability has been proposed to be a driving force in colorectal carcinogenesis (1). Two major types of genetic instability have been described in colorectal cancer: chromosomal instability and microsatellite instability (2). Up to 15% of colorectal cancer show a high frequency of microsatellite instability which is caused by a defect of the DNA mismatch repair pathway (3). The vast majority of colorectal cancer, however, shows chromosomal instability, which is characterized by gains and losses of whole chromosomes or large chromosomal regions.Whereas a large number of genes that trigger chromosomal instability have been identified in yeast in the past (reviewed in ref. 4), the underlying mechanisms leading to chromosomal instability in colorectal cancer remain to be characterized. The DNA double-strand break (DSB) is regarded as the most critical of all DNA lesions (5, 6) and it has been shown that defects in the cellular response to DSBs can lead to genetic alteration, chromosomal instability, and ultimately malignant transformation (7).In mammalian cells, DSBs can be repaired by two distinct pathways: homologous recombination and nonhomologous end joining (8). DSB repair by nonhomologous end joining involves the formation of a Ku70/Ku80 protein heterodimer and recruitment of DNA-dependent protein kinase C to the site of DNA damage (9). DSB repair by homologous recombination is mediated by a large number of...

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“…The BubR1 insufficiency affects life span, aging-related aneuploidy, and senescence (39). Mutations of Bub1 and BubR1, along with several mitotic checkpoint genes, were rarely reported clinically (31,40,41). Up-regulation of checkpoint genes Bub1 and BubR1 was reported in several clinical studies on gastric (40) and colorectal malignancies with significantly shorter relapse-free survival rate (12).…”

Section: Discussionmentioning

confidence: 99%

Bub1 Up-Regulation and Hyperphosphorylation Promote Malignant Transformation in SV40 Tag–Induced Transgenic Mouse Models

Guo

Wu²,

Chin³

et al. 2006

Molecular Cancer Research

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Rodents do not naturally develop prostate cancer. Currently, most widely used genetically engineered mouse prostate cancer models use SV40 T/tag oncogene. To understand the mechanism underlying prostate cancer development in transgenic and knock-in SV40 Tag mouse models, we did cDNA microarray analyses, comparing gene expression profiles of prostate cancer tissues from early-, late-, and advance-stage androgen-independent prostate cancers. Of the 67 genes that were up-regulated by z10-fold, 40 are known to be required for chromosome stability. In particular, the spindle checkpoint component Bub1 was persistently up-regulated from early to advanced androgen-independent prostate cancer lesions. Significantly, Bub1, which is required for accurate chromosome segregation during mitosis, has recently been reported to bind SV40 Tag. Consistent with a spindle checkpoint defect, flow cytometry experiments indicate that advanced androgen-independent prostate cancer tumors exhibit aneuploidy, along with up-regulation of levels of both Bub1 mRNA and Bub1 protein or hyperphosphorylation. Importantly, up-regulation and hyperphosphorylation of Bub1 were also observed in established human prostate cancer cell lines and in clinical studies. Furthermore, analysis of human prostate cancer lines showed impaired spindle checkpoint function and endoreduplication following exposure to spindle toxins. Small interfering RNA -mediated repression of Bub1 in the human prostate cancer line PC-3 restrained cell proliferation, an effect mimicked by inhibition of mitogen-activated protein kinase, an upstream activator of Bub1. Thus, by perturbing Bub1 function, our observations suggest a new mechanism whereby the SV40 Tag oncoprotein promotes chromosomal instability and aneuploidy in transgenic mouse prostate cancer models. Whereas the exact details of this mechanism remain unclear, our novel findings raise the possibility of exploiting Bub1 as a new therapeutic target in the treatment of prostate cancer, the most common cancer in adult men in North America. (Mol Cancer Res 2006;4(12):957 -69)

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Expression of BUB1 protein in gastric cancer correlates with the histological subtype, but not with DNA ploidy or microsatellite instability

Cited by 31 publications

References 35 publications

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers

Expression of DNA Double-Strand Break Repair Proteins ATM and BRCA1 Predicts Survival in Colorectal Cancer

Bub1 Up-Regulation and Hyperphosphorylation Promote Malignant Transformation in SV40 Tag–Induced Transgenic Mouse Models

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