Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray.
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.
Suda
Takako
T
Department of Surgery and Bioengineering, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Tsunoda
Takuya
T
Uchida
Naotaka
N
Watanabe
Takeshi
T
Hasegawa
Suguru
S
Satoh
Seiji
S
Ohgi
Shigetsugu
S
Furukawa
Yoichi
Y
Nakamura
Yusuke
Y
Tahara
Hideaki
H
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C471696:SCRN1 protein, human