Overexpression of RegIV in peritoneal dissemination of gastric cancer and its potential as A novel marker for the detection of peritoneal micrometastasis.
BACKGROUND
Regenerating gene type IV (RegIV) is a candidate marker for cancer and inflammatory bowel disease. In this study, its potential as a novel marker for the detection of gastric cancer peritoneal micrometastases was examined.


METHODS
RegIV mRNA levels in the peritoneal washes of 95 gastric cancer patients and 22 with benign disease were quantified by real-time RT-PCR. To examine whether expression of RegIV enhance tumorigenicity or not, thirty two mice were injected intraperitoneally or subcutaneously with RegIV transfectants of TMK-1 cells, parental TMK-1 cells, or neomycin control transfectants.


RESULTS
RegIV expression was markedly higher in patients with peritoneal metastases compared to those without. The level of RegIV mRNA in gastric cancer patients was related to the extent of wall penetration. A cut-off value for RegIV-positive expression was based on an analysis of negative control patients with benign disease, and gastric cancer patients above the cut-off value constituted the micrometastasis (MM+) group. Based on this criteria, 3 out of 43 T1 or T2 cases were MM+ (93% specificity). Among 15 patients with peritoneal dissemination (7 out of 15 cases were positive by cytology), 14 cases were positive for RegIV expression (93% sensitivity), while analysis of carcinoembryonic antigen (CEA) mRNA failed to detect micrometastases in 4 cases (73% sensitivity). Combined analysis of CEA and RegIV improved the accuracy of diagnosis to 100%. The prognosis of RegIV-positive cases was significantly worse than that of RegIV-negative cases. Multivariate analysis using the Cox proportional hazards model suggested that RegIV may be an independent prognostic factor. Stable expression of RegIV significantly enhanced peritoneal metastasis in an animal model of gastric cancer.


CONCLUSIONS
These findings suggest that RegIV mRNA expression has the potential to serve as a novel marker for detecting peritoneal dissemination in gastric cancer.
Miyagawa
K
K
Department of Surgery and Regenerative Medicine, Division of Surgery and Physiology of Digestive System, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan. k-miya@koto.kpu-m.ac.jp
Sakakura
C
C
Nakashima
S
S
Yoshikawa
T
T
Fukuda
K
K
Kin
S
S
Nakase
Y
Y
Shimomura
K
K
Oue
N
N
Yasui
W
W
Hayasizaki
H
H
Okazaki
Y
Y
Yamagishi
H
H
Hagiwara
A
A
Otsuji
E
E
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D005753:Gastric Mucosa / Q000378:metabolism / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000073718:Pancreatitis-Associated Proteins; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection
D000199:Actins; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human; D012333:RNA, Messenger