Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Fukuda K, Kin S, Nakase Y, Shimomura K, Oue N, Yasui W, Hayasizaki H, Okazaki Y, Yamagishi H, Hagiwara A, Otsuji E
Department of Surgery and Regenerative Medicine, Division of Surgery and Physiology of Digestive System, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
Anticancer Res. 2008 Mar-Apr;28(2B):1169-79.
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.
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.
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.
These findings suggest that RegIV mRNA expression has the potential to serve as a novel marker for detecting peritoneal dissemination in gastric cancer.
再生基因IV型（RegIV）是癌症和炎症性肠病的候选标志物。在本研究中，检测了其作为检测胃癌腹膜微转移新标志物的潜力。
采用实时逆转录聚合酶链反应（RT-PCR）定量检测95例胃癌患者和22例良性疾病患者腹腔灌洗液中RegIV mRNA水平。为检测RegIV表达是否增强致瘤性，将TMK-1细胞的RegIV转染子、亲本TMK-1细胞或新霉素对照转染子腹腔内或皮下注射到32只小鼠体内。
与无腹膜转移的患者相比，有腹膜转移的患者RegIV表达明显更高。胃癌患者RegIV mRNA水平与胃壁浸润深度有关。基于对良性疾病阴性对照患者的分析确定RegIV阳性表达的临界值，高于该临界值的胃癌患者构成微转移（MM+）组。根据该标准，43例T1或T2期病例中有3例为MM+（特异性93%）。在15例腹膜播散患者中（15例中有7例细胞学检查阳性），14例RegIV表达阳性（敏感性93%），而癌胚抗原（CEA）mRNA分析未能检测出4例微转移（敏感性73%）。CEA和RegIV联合分析将诊断准确性提高到100%。RegIV阳性病例的预后明显差于RegIV阴性病例。使用Cox比例风险模型进行多因素分析表明，RegIV可能是一个独立的预后因素。在胃癌动物模型中，RegIV的稳定表达显著增强了腹膜转移。
这些发现表明，RegIV mRNA表达有可能作为检测胃癌腹膜播散的新标志物。
