Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray

Abstract

Despite the discovery of multiple TAAs, only a limited number is available for clinical application, particularly against epithelial malignancies. In this study we searched for novel TAAs using expression profiles of gastric cancer examined with cDNA microarray, and identified the SCRN1 gene as a candidate. SCRN1 was confirmed to be expressed in five out of seven gastric cancers with semiquantitative RT-PCR. With Northern blot analysis, it was detected abundantly in the testis and ovary, but it was barely detectable in 14 other normal human adult organs. Colony formation assay revealed that its augmented expression is associated with promoted cell growth. As these expression profiles and functional features of SCRN1 appeared to be compatible with the characteristics of the hypothesized ideal TAAs, we examined whether SCRN1 protein contains antigenic epitope peptides restricted to HLA-A*0201. We synthesized the candidate peptides derived from SCRN1, and tried to induce CTLs with each peptide. The CTL clones were successfully induced with a peptide SCRN1-196 (KMDAEHPEL), and they lyzed not only the peptide-pulsed targets but also the tumor cells expressing both SCRN1 and HLA-A*0201 endogenously. These results strongly suggest that SCRN1-196 is an epitope peptide restricted to HLA-A*0201. Furthermore, we synthesized an anchor-modified peptide SCRN1-9 V (KMDAEHPEV), in which leucine at position 9 was substituted for valine to increase the binding affinity to the HLA-A*0201 molecules. The CTL clones induced by SCRN1-9 V also recognized tumor cells expressing its natural SCRN1 protein endogenously. These results strongly suggest that SCRN1 is a novel TAA and these peptides, both native and modified, may be applicable for cancer vaccines to treat gastric cancer. (Cancer Sci 2006; 97: 411-419)

SCRN1 is a novel marker for prognosis in colorectal cancer

“…Scrn1 is a 50-kDa cytosolic protein involved in the regulation of exocytosis in mast cells, and previous reports show that the SCRN1 gene is expressed in normal organs such as the brain, prostate, thymus, and intestine [7,8,12]. SCRN1 is reportedly upregulated in tumor tissues of the stomach and prostate [8,12]. Especially in gastric cancer, a cDNA microarray exhibited SCRN1 expression in cancer tissues and the cell lines, and SCRN1 was reported to be a novel immunotherapy target [8].…”

“…Secernin 1 is located on chromosome 7 (7p14.3-p14.1), and the others are located on chromosomes 17 (17q21.3) and 2 (2p14-q14.3), respectively [7]. Scrn1 is a 50-kDa cytosolic protein involved in the regulation of exocytosis in mast cells, and previous reports show that the SCRN1 gene is expressed in normal organs such as the brain, prostate, thymus, and intestine [7,8,12]. SCRN1 is reportedly upregulated in tumor tissues of the stomach and prostate [8,12].…”

“…The human secernin 1 (SCRN1) gene is a member of the secernin family and is reported to be a tumor-associated antigen in gastric cancer [7,8]. Previous reports have shown that SCRN1 is upregulated in gastric cancer cell lines and is a novel immunotherapy target, whereas the expression and its significance of prognosis in CRC is not yet understood.…”

Concise Review: Cancer/Testis Antigens, Stem Cells, and Cancer

“…Some CTAs can be expressed in nongametogenic tissues such as the pancreas, liver, and spleen at levels far below that observed in germ cells [39]; 2) their expression programs are strictly regulated by epigenetic mechanisms such as DNA methylation [40]; and 3) they are immunogenic. To date, nearly 40 distinct CTAs have been identified based on immunogenic properties [41], expression profiles [42], and by bioinformatic methods [43]. However, little is known about their specific functions, and their functional connection with stem cell biology and cancer is widely unexplored.…”

Phase I Clinical Trial of Peptide Vaccination with KIF20A and VEGFR1 Epitope Peptides in Patients with Advanced Pancreatic Cancer

“…Recently, analyses of gene expression profiles of cancer and normal cells using cDNA microarray technologies have provided an effective approach for the identification of tumor-associated antigens [10][11][12][13][14][15][16][17].…”