Prospective study of the patients with cancer according to MRP-1/CD9 status and regulation of metastastasis of cancer by means of MRP-1/CD9 control

根据MRP-1/CD9状态对癌症患者进行前瞻性研究以及通过MRP-1/CD9控制调节癌症转移

• 批准号: 07557253
• 负责人: MIYAKE Masayuki
• 金额: $ 4.42万
• 依托单位: TAZUKE KOFOKAI MEDICAL RESEARCH INSTITUTE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557253/
• 关键词: MRP-1; CD9; Iung cancer; breast cancer; pancreatic cancer; coloncancer; metastasis; prognosis; KAI1; CD82; TM4SF; 予後; 肺癌; 乳癌; 転移; 再発

In our previous studies we showed that motility related protein-1 (MRP-1) is a glycoprotein recognized by monoclonal antibody (MAb) M31-15, and that the sequence of MRP-1 is identical to that of CD9, a while cell differentiation antigen. Transfection of MRP-1/CD9 cDNA into cultured non-hematopoietic cells suppresses cell motility. The extent of suppression is derectly related to the level of MRP-1/CD9 expression. In addition the metastatic potential of MRP-1/CD9-transfected melanoma cells BL6 is lower than that of control BL6 cells. To determine whether these experimental results are of relevance with respect to actual human tumors, we performed the prospective study of patients with non-small cell lung cancers, breast cancers, pancreatic cancers and colon cancers using quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry. Of patients with lung cancers, the overall survival rate of the 108 patients (57.7%) with MRP-1/CD9-positive tumors was strikingly h … More igher than that of the 79 patients (42.3%) with MRP-1/CD9-reduced tumors.(57.6% vs.25.9%, p=0.0001). Cox multivariate regression analysis showed that nodal status, and MRP-1/CD9 status were significant factors for a prognosis (p<0.0001 and p=0.0083, respectively). Of 109 patients with breast cancers, 73 tumors (67.0%) were MRP-1/CD9 positive, and 36 tumors (33.0%) were MRP-1/CD9 negative. The discase-free survival rate and the 5-year survival rate of patients with MRP-1/CD9-negative tumors were both significantly lower than patients with MRP-1/CD9-positive tumors (P=0.0005 and P=0.0380, respectively). Cox regression analysis also demonstrated that MRP-1/CD9 status was a significant factor for a prognosis (p=0.0016). In pancreatic cancers, the overall survival rate for the 17 patients whose tumors had reduced MRP-1/CD9 gene expression was strikingly lower than that of the 18 patients with MRP-1/CD9-positive tumors (p=0.0015). In a multivariate analysis using the Cox proportional hazard model, MRP-1/CD9 status was found to be the only significant prognostic factor for survival. However, of patients with colon cancers, no signicicant difference is found due to the short observation time. Our data suggest that low MRP-1/CD9 expression by malignant tumors may be associated with a poor prognosis. On the other hand, sequence analysis with lung cancer revealed that MRP-1/CD9 have the hot spots at codon 143 and 163, both of which change from A to G.The former aminoacid changes are from LYS to ARG,and the latter from ASN to ASP.However, these mutant MRP-1/CD9 DNA transfection had no effect of the functions. Down-regulation due to abnormal promotor rather than mutation may be a more common mechanism in the progression of cancer. Less

在我们之前的研究中，我们发现运动相关蛋白-1 （MRP-1）是单克隆抗体（MAb） M31-15识别的糖蛋白，并且MRP-1的序列与细胞分化抗原CD9的序列相同。将MRP-1/CD9 cDNA转染培养的非造血细胞可抑制细胞运动。抑制程度与MRP-1/CD9表达水平直接相关。此外，MRP-1/ cd9转染的黑色素瘤细胞BL6的转移潜能低于对照BL6细胞。为了确定这些实验结果是否与实际的人类肿瘤相关，我们使用定量逆转录酶聚合酶链反应和免疫组织化学对非小细胞肺癌、乳腺癌、胰腺癌和结肠癌患者进行了前瞻性研究。在肺癌患者中，MRP-1/ cd9阳性肿瘤患者108例（57.7%）的总生存率显著高于MRP-1/ cd9降低肿瘤患者79例（42.3%）（57.6% vs.25.9%, p=0.0001）。Cox多因素回归分析显示，淋巴结状态和MRP-1/CD9状态是影响预后的重要因素（p<0.0001和p=0.0083）。109例乳腺癌患者中MRP-1/CD9阳性73例（67.0%），MRP-1/CD9阴性36例（33.0%）。MRP-1/ cd9阴性肿瘤患者的无病生存率和5年生存率均显著低于MRP-1/ cd9阳性肿瘤患者（P=0.0005和P=0.0380）。Cox回归分析也显示MRP-1/CD9状态是影响预后的重要因素（p=0.0016）。在胰腺癌中，17例MRP-1/CD9基因表达降低的肿瘤患者的总生存率显著低于18例MRP-1/CD9阳性肿瘤患者（p=0.0015）。在使用Cox比例风险模型的多变量分析中，MRP-1/CD9状态被发现是生存的唯一重要预后因素。而对于结肠癌患者，由于观察时间较短，没有发现明显的差异。我们的数据表明，恶性肿瘤的低MRP-1/CD9表达可能与预后不良有关。另一方面，对肺癌的序列分析显示，MRP-1/CD9在密码子143和163处存在热点，均由A变为g，前者氨基酸由LYS变为ARG，后者由ASN变为ASP。然而，这些突变体MRP-1/CD9 DNA转染对其功能没有影响。由于异常启动子而不是突变导致的下调可能是癌症进展中更常见的机制。少

项目成果

Higashiyama M., et. al.: "Reduced motility related protein-1(MRP-1/CD9)gene expression as a factor of poor prognosis in non-small cell lung cancer." Cancer Research. 55. 6040-6044 (1995)

东山M.等。

Higashiyama, M.Taki, T.Ieki, Y.Adachi, M.Huang, C.Koh, T.Kodama, K.Doi, O.Miyake, M.: "Reduced Motility Related Protein-1 (MRP-1/CD9) Gene Expression as a Factor of Poor Prognosis in Non-Small Cell Lung Cancer" Cancer Res.55. 6040-6044 (1995)

Higashiyama，M.Taki，T.Ieki，Y.Adachi，M.Huang，C.Koh，T.Kodama，K.Doi，O.Miyake，M.：“减少运动相关蛋白-1（MRP-1/CD9）

Adachi M: "Reduced integrin α3 expression as a factor of poor prognosis of patients with adenocarcinoma of the lung." J.Clinic.Oncol.(3月掲載予定). (1998)

Adachi M：“整合素 α3 表达减少是肺腺癌患者预后不良的一个因素。”（计划于 3 月出版）。

Miyake M. , et. al.: "Motility related protein-1(MRP-1/CD9)expression : Inverse correlation with metastases in breast cancer." Cancer Research. 55. 4127-4137 (1995)

三宅M.，等。

Huang, C.Taki, T.Adachi, M.Yagita, M.Sawada, S.Takabayashi, A.Inufusa, H.Yoshie, O.Miyake, M: "MRP-1/CD9 and KAI1/CD82 expression in normal and various cancer tissues." Int.J.Oncol.11. 1045-1051 (1997)

Huang, C.Taki, T.Adachi, M.Yagita, M.Sawada, S.Takabayashi, A.Inufusa, H.Yoshie, O.Miyake, M：“MRP-1/CD9 和 KAI1/CD82 在正常和