Abstract
Gastric adenocarcinoma is a common form of cancer associated with a poor prognosis. We analyzed microarray profiling data from 48 patients with gastric adenocarcinoma to characterize gastric cancer subtypes and identify biomarkers associated with prognosis. We identified two major subtypes of gastric adenocarcinoma differentially associated with overall survival (P = 0.025). Genes that were differentially expressed were identified using specific criteria (P < 0.001 and >1.5-fold); expression of 294 and 116 genes was enriched in good and poor prognosis subtypes, respectively. Genes related to translational elongation and cell cycle were upregulated in the poor prognosis group. Of these genes, upregulation of proteasome subunit beta type 8 PSMB8 and PDZ binding kinase PBK was confirmed by real-time reverse transcription-PCR analysis. PSMB8 or PBK knockdown had no effect on gastric cancer cell proliferation but suppressed cell migration and invasion, respectively. Furthermore, immunohistochemistry analysis of 385 gastric cancer patients revealed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion, lymph node metastasis, and lower survival rates. Taken together, two gastric adenocarcinoma subtypes were predictive of prognosis. PSMB8 and PBK were predictive of gastric cancer prognosis and could be potential gastric cancer subtype-specific biomarkers.
Highlights
Gastric cancer is a common form of cancer with the second highest cancer-related mortality rate [1]
Multivariate analysis showed that nuclear expression of PSMB8 and PBK were borderline significant predictors of overall survival (P = 0.085, P = 0.083, respectively) (Supplementary Table 3 and 4). These findings indicate that nuclear PSMB8 and PBK overexpression in tumor cells correlates with gastric cancer progression, especially aspects relating to tumor invasion depth and lymph node metastasis
Using an unsupervised clustering approach, we found that gastric cancer patients were divided into two distinct subtypes that significantly differed with respect to overall survival, underscoring the clinical relevance of these subtypes
Summary
Gastric cancer is a common form of cancer with the second highest cancer-related mortality rate [1]. Advanced gastric cancer is generally refractory to chemotherapy, leading to a poor prognosis, with five-year survival rates of only 20-30% [2]. It is important to understand the molecular heterogeneity of tumors and to identify clinically useful biomarkers to identify gastric cancer patients with a poor prognosis for alternative treatment strategies. Previous studies have been focused on discovering novel biomarkers or gene signatures associated with gastric cancer using gene expression profiling [4, 5]. In the present study, we analyzed gene expression profiling data from 48 patients with gastric cancer and identified two subtypes that were clinically relevant in predicting prognosis based on their unique gene expression signatures using an unsupervised hierarchical clustering. We identified and validated two specific biomarkers associated with prognosis
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