Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4.
Pancreatic ductal adenocarcinoma (PDAC) shows the worst mortality rate among common malignancies, with a 5-year survival rate of only 4%, and the majority of PDAC patients are diagnosed at an advanced stage in which no effective therapy is available at present. Although the proportion of curable cases is still not so high, surgical resection of early stage PDAC is the only way to cure the disease. Hence, establishment of a screening strategy to detect early stage PDAC by novel serological markers is required urgently, and development of novel molecular therapies for PDAC treatment is also eagerly expected. We here report overexpression of REG4, a new member of the regenerating islet-derived (REG) family, in PDAC cells on the basis of genome-wide cDNA microarray analysis as well as reverse transcription-polymerase chain reaction and immunohistochemical analysis. We also detected significant elevation of REG4 in the serum of some patients with early-stage PDAC using our enzyme-linked immunosorbent assay system, indicating the possibility of REG4 as a new serological marker of PDAC. Furthermore, we found that knockdown of endogenous REG4 expression in PDAC cell lines with small interfering RNA caused a decrease in cell viability. Concordantly, addition of recombinant REG4 to the culture medium enhanced growth of a PDAC cell line in a dose-dependent manner. A monoclonal antibody against REG4 neutralized its growth-promoting effects and attenuated significantly the growth of PDAC cells. These findings indicate that REG4 is a promising tumor marker to screen early-stage PDAC, and also that neutralization of REG4 by the antibody may offer novel potential tools for the treatment of PDAC.
Takehara
Akio
A
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Eguchi
Hidetoshi
H
Ohigashi
Hiroaki
H
Ishikawa
Osamu
O
Kasugai
Tsutomu
T
Hosokawa
Masayo
M
Katagiri
Toyomasa
T
Nakamura
Yusuke
Y
Nakagawa
Hidewaki
H
D000230:Adenocarcinoma / Q000097:blood / Q000276:immunology / Q000628:therapy; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000276:immunology / Q000628:therapy; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005240:Feasibility Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000097:blood* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D020411:Oligonucleotide Array Sequence Analysis; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000276:immunology / Q000628:therapy*; D000073718:Pancreatitis-Associated Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D009363:Neoplasm Proteins; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051057:Proto-Oncogene Proteins c-akt