Abstract
This study explored potential biomarkers associated with Lauren classification of gastric cancer. We screened microarray datasets on gastric cancer with information of Lauren classification in gene expression omnibus (GEO) database, and compared differentially expressing genes between intestinal-type or diffuse-type gastric cancer. Four sets of microarray data (GSE2669, GSE2680, GDS3438, and GDS4007) were enrolled into analysis. By differential gene analysis, UBE2C, CDH1, CENPF, ERO1L, SCD, SOX9, CKS1B, SPP1, MMP11, and ANLN were identified as the top genes related to intestinal-type gastric cancer, and MGP, FXYD1, FAT4, SIPA1L2, MUC5AC, MMP15, RAB23, FBLN1, ANXA10, and ADH1B were genes related to diffuse-type gastric cancer. We comprehensively validated the biological functions of the intestinal-type gastric cancer related gene UBE2C and evaluated its clinical significance on 1,868 cases of gastric cancer tissues from multiple medical centers of Shanghai, China. The gain of copy number on 20q was found in 4 out of 5 intestinal-type cancer cell lines, and no similar copy number variation (CNV) was found in any diffuse-type cancer cell line. Interfering UBE2C expression inhibited cell proliferation, migration and invasion in vitro, and tumorigenesis in vivo. Knockdown of UBE2C resulted in G2/M blockage in intestinal-type gastric cancer cells. Overexpression of UBE2C activated ERK signal pathway and promoted cancer cell proliferation. U0126, an inhibitor of ERK signaling pathway reversed the oncogenic phenotypes caused by UBE2C. Moreover, overexpression of UBE2C was identified in human intestinal-type gastric cancer. Overexpression of UBE2C protein predicted poor clinical outcome. Taken together, we characterized a group of Lauren classification-associated biomarkers, and clarified biological functions of UBE2C, an intestinal-type gastric cancer associated gene. Overexpression of UBE2C resulted in chromosomal instability that disturbed cell cycle and led to poor prognosis of intestinal-type gastric cancer.
Highlights
Gastric cancer is one of the most common digestive malignancies, which threats public health worldwide, especially in Asia (Torre et al, 2015)
By searching gene expression omnibus (GEO) database, datasets GSE2669, GSE2680, GSE3438, and GSE4007 were selected because they contain large sample size with detail clinical information including Lauren classification of gastric cancer (Table 1)
40 genes were highly expressed in intestinal-type gastric cancer, and 223 genes were highly expressed in diffuse-type gastric cancer
Summary
Gastric cancer is one of the most common digestive malignancies, which threats public health worldwide, especially in Asia (Torre et al, 2015). Lauren classification is a standard histopathological classification which divides gastric cancer into two subtypes: intestinal-type and diffuse-type (Lauren, 1965). This histological classification was established based on histological observation by a Nordic pathologist half a century ago when there was no evidence at molecular level. With the application of high-throughput gene analysis, many gene expression profiles of gastric cancer have been accumulated and deposited in open accessible database. DNA microarray or gene chip is the first one of the high-throughput technologies applied on molecular classification for cancers (Tusher et al, 2001). A number of datasets come from separated institutes and there is no comparable analysis
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