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. 2001 Apr;158(4):1289-99.
doi: 10.1016/S0002-9440(10)64080-1.

c-Myb and Bcl-x overexpression predicts poor prognosis in colorectal cancer: clinical and experimental findings

A Biroccio  1 , B Benassi, I D'Agnano, C D'Angelo, S Buglioni, M Mottolese, A Ricciotti, G Citro, M Cosimelli, R G Ramsay, B Calabretta, G Zupi
Affiliations

c-Myb and Bcl-x overexpression predicts poor prognosis in colorectal cancer: clinical and experimental findings

A Biroccio et al. Am J Pathol. 2001 Apr.

Abstract

The aim of this study was twofold: to assess the relationship between c-Myb and Bcl-x expression and to evaluate the prognostic significance of their expression in colorectal carcinoma (CRC) patients. Analysis of tumors from 91 CRC patients for expression of c-Myb and Bcl-x revealed a significant relationship between these two proteins. Kaplan-Meier's analysis showed an increased risk of relapse and death in patients whose tumor specimens displayed high c-Myb levels and Bcl-x positivity. Similar results were also observed excluding Dukes' D patients. Molecular analysis using three c-Myb-overexpressing LoVo clones indicated that c-Myb overexpression was accompanied by up-regulation of Bcl-x(L) protein and mRNA. Tumors originating from these clones injected in nude mice were significantly larger than those formed in mice injected with parental or vector-transfected LoVo cells. Moreover, tumors derived from parental and control vector-transfected but not from c-Myb-overexpressing LoVo cells showed high frequency of apoptotic cells. These results provide direct evidence of an association between c-Myb and Bcl-x expression and suggest that expression of both molecules might be a useful prognostic marker in CRC.

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Figures

Figure 1.
Figure 1.
Two-parameter FCM analysis in four representative samples of normal mucosa (NM) and primary tumor (T). The number reported represents the percentage of c-Myb-positive cells. The threshold (▾) was set to the negative control of each sample. Windows 1 and 2 indicate the diploid and aneuploid cell populations, respectively.
Figure 2.
Figure 2.
Expression of Bcl-x protein, as revealed by streptavidin-biotin immunoperoxidase staining, in two representative colon adenocarcinomas displaying positive (score 9, see MM) (a) and negative (score 1, see MM) (b) cytoplasmic reactivity. Original magnification, ×400.
Figure 3.
Figure 3.
DFS and OS (81 cases) for patients with CRC categorized according to the c-Myb (a and b) and Bcl-x expression (c and d). Survival curves were generated according to the Kaplan-Meier method; statistical comparisons were made using the log-rank method.
Figure 4.
Figure 4.
DFS and OS (54 cases obtained by excluding the Dukes’ D patients) for patients with CRC categorized according to the c-Myb (a and b) and Bcl-x expression (c and d). Survival curves were generated according to the Kaplan-Meier method; statistical comparisons were made using the log-rank method.
Figure 5.
Figure 5.
DFS and OS (71 cases) for patients with CRC categorized according to the combinations of c-Myb and Bcl-x expression (a and b) and DFS and OS (49 cases obtained by excluding Dukes’ D patients) for patients with CRC categorized according to the combinations of c-Myb and Bcl-x expression (c and d). Survival curves were generated according to the Kaplan-Meier method; statistical comparisons were made using the log-rank method.
Figure 6.
Figure 6.
Western blot analysis of c-Myb expression in LoVo parental line, LoVo/neo control clone, and several c-Myb transfectants (M11, M15, M18, and M30). HL60 cells was used as positive control. Expression of HSP 72/73 was measured as control of equal proteins loading.
Figure 7.
Figure 7.
A: Cell lysates from the LoVo/neo clone, and M18, M30, and M11 c-Myb-overexpressing clones were loaded on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, blotted, and incubated with rabbit anti-Bcl-x polyclonal antibody (top), nonspecific purified rabbit IgG (middle) and mouse anti-HSP mAb (bottom). Expression of HSP 72/73 was measured as control of equal proteins loading. B: Northern blot analysis of bcl-xL expression in LoVo/neo clone, M18, M30, and M11 c-Myb-overexpressing clones. Glyceraldehyde-3-phosphate dehydrogenase was measured as control of equal RNA loading.
Figure 8.
Figure 8.
In vitro growth curves of LoVo cells, LoVo/neo clone, and three c-Myb-overexpressing clones (M11, M18, and M30).
Figure 9.
Figure 9.
A: In vivo growth curves of tumors from injected LoVo cells (•), LoVo/neo clone (▿), and M11 (▪), M18 (○), M30 (▴) c-Myb-overexpressing clones. B: Detection of apoptosis (TUNEL) in LoVo/neo (a) and M30 (b) tumor cells grown in nude mice. Original magnification, ×200.
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