The online version of this article (doi:10.1186/1476-4598-11-39) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
Li W and Juan Du made the microarrays, performed the real-time, western-blot and immunohistochemical staining, collected the clinical data and contributed to the writing of the manuscript. Qinghui Z analyzed the statistical data and participated in writing the manuscript. Binbin C and Jun L participated in collecting the clinical data. Changquan L and Denghai Z participated in designing and coordinating the study, and in writing the manuscript. All of the authors read and approved the final manuscript.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Frequent tumor recurrence after surgery is related to its poor prognosis. Although gene expression signatures have been associated with outcome, the molecular basis of HCC recurrence is not fully understood, and there is no method to predict recurrence using peripheral blood mononuclear cells (PBMCs), which can be easily obtained for recurrence prediction in the clinical setting.
According to the microarray analysis results, we constructed a co-expression network using the k-core algorithm to determine which genes play pivotal roles in the recurrence of HCC associated with the hepatitis B virus (HBV) infection. Furthermore, we evaluated the mRNA and protein expressions in the PBMCs from 80 patients with or without recurrence and 30 healthy subjects. The stability of the signatures was determined in HCC tissues from the same 80 patients. Data analysis included ROC analysis, correlation analysis, log-lank tests, and Cox modeling to identify independent predictors of tumor recurrence.
The tumor-associated proteins cyclin B1, Sec62, and Birc3 were highly expressed in a subset of samples of recurrent HCC; cyclin B1, Sec62, and Birc3 positivity was observed in 80%, 65.7%, and 54.2% of the samples, respectively. The Kaplan-Meier analysis revealed that high expression levels of these proteins was associated with significantly reduced recurrence-free survival. Cox proportional hazards model analysis revealed that cyclin B1 (hazard ratio [HR], 4.762; p = 0.002) and Sec62 (HR, 2.674; p = 0.018) were independent predictors of HCC recurrence.
These results revealed that cyclin B1 and Sec62 may be candidate biomarkers and potential therapeutic targets for HBV-related HCC recurrence after surgery.
Additional file 1: Figure S1. Unsupervised hierarchical clustering based on the set of 615 differentially expressed genes in response to recurrent HCC patients and non-recurrent samples. The relative gene log 2 expression changes are expressed by a color gradient intensity scale, as shown in the upside. Green color indicates down-regulation, and red color indicates up-regulation of gene expression. Each row represents a separate sample and each column a single gene. (TIFF 1 MB)12943_2011_1014_MOESM1_ESM.tiff
Additional file 2: Figure S2. The mRNA levels of cyclin B1, Sec62 and Birc3 in 6 HCC patients were analysed by RT-PCR. To validate the microarray analysis findings, we analyzed their mRNA expression using real-time PCR in 6 samples. The expression of cyclin B1, Sec62 and Birc3 in recurrence HCC Patients were significantly higher than non-reucrrence samples (p < 0.05). Cyclin B1 (left), Sec62 (median), and Birc3 (right). * compared with non-recurrence group. (TIFF 680 KB)12943_2011_1014_MOESM2_ESM.tiff
Additional file 3: Table S1. Primers for selected genes analyzed by RT-PCR. (DOC 47 KB)12943_2011_1014_MOESM3_ESM.doc
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- Identification of cyclin B1 and Sec62 as biomarkers for recurrence in patients with HBV-related hepatocellular carcinoma after surgical resection
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