Abstract
Purpose
To investigate the precise function of Cullin1 (CUL1) in colorectal cancer (CRC).
Methods
Immunohistochemistry was performed to test the expression of CUL1 on a CRC tissue microarray containing the tumor and corresponding normal tissues. Simultaneously, the correlation of CUL1 expression with clinicopathological parameters and survival was evaluated. CUL1 was over-expressed or knocked down in HCT116 and SW480 cells, then the cell proliferation, migration and invasion assays in vitro and in vivo were performed.
Results
In this study, we found that CUL1 expression was significantly up-regulated in CRC compared with normal colon tissues. High CUL1 expression was positively associated with lymph node metastasis (P = 0.007) and tumor diameter (P = 0.052). Multivariate Cox regression analysis revealed that high CUL1 expression was an independent unfavorable prognostic factor for CRC patients (HR = 13.9, 95 % confidence interval = 5.89–32.6, P < 0.001). Moreover, we found that CUL1 over-expression induced CRC cell proliferation and the growth of xenografts in nude mice via the changing of cell-cycle proteins. In addition, increased CUL1 expression in CRC cells significantly promoted cell migration and invasion abilities in vitro and peritoneal metastasis in vivo through inducing high expression of MMPs.
Conclusion
Our findings imply that CUL1 may serve as promising prognostic markers in CRC patients.
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Acknowledgments
Research was supported by malignant tumor biomarkers in Jiangsu Province Key Laboratory (#11ZLKF09).
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We declare that we have no conflict of interest.
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Weimin Wang and Yansu Chen have contributed equally to this work.
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432_2015_1931_MOESM2_ESM.tif
Supplementary material 2 Fig. S1: Representative images of CUL1 immunohistochemical staining in human CRC. A, weak positive staining; B, moderate positive staining; C, strong positive staining; (A–C, original magnification, ×200) (TIFF 3509 kb)
432_2015_1931_MOESM3_ESM.tif
Supplementary material 3 Fig. S2: Receiver operating characteristic (ROC) curve is obtained to determine the optimal cutoff value of CUL1 expression. ROC obtains the area under the curves (AUC) at different cutoff values of CUL1 immunoreactivity score (IRS) for 1, 3 and 5 years of overall survival time (TIFF 847 kb)
432_2015_1931_MOESM4_ESM.tif
Supplementary material 4 Fig. S3: CUL1 positively regulated the SW480 cells migration and invasion in vitro. CUL1 over-expression in SW480 cells promoted cell migration and invasion, whereas CUL1 knockdown inhibited cell migration and invasion (A). Numbers of cell migration and invasion per field were counted in five random fields for CUL1 over-expressing/knockdown and control groups (n=3/group) in SW480 cells (B-C). Data were presented as means ± SD, *P < 0.05, **P < 0.001; Student’s t test (TIFF 3728 kb)
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Wang, W., Chen, Y., Deng, J. et al. Cullin1 is a novel prognostic marker and regulates the cell proliferation and metastasis in colorectal cancer. J Cancer Res Clin Oncol 141, 1603–1612 (2015). https://doi.org/10.1007/s00432-015-1931-4
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DOI: https://doi.org/10.1007/s00432-015-1931-4