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Analysis of structure of MRP-1/CD9 mutation and regulation of metastasis of cancer by means of MRP-1/CD9 control

MRP-1/CD9突变结构分析及MRP-1/CD9调控癌症转移

基本信息

批准号：
06454405
负责人：
MIYAKE Masayuki
金额：
$ 4.1万
依托单位：
Tazuke Kofukai Medical Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454405/
关键词：
MRP-1 CD9 lung cancer breast cancer metastasis prognosis recurrence RT-PCR

项目摘要

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 white cell differentiation antigen. Transfection of MRP-1/CD9 cDNA into cultured non-hematopoietic cells suppresses cell motility. The extent of suppression is directly 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 investigated MRP-1/CD9 expression in 143 invasive ductal carcinomas of the breast. Of 97 patients with MRP-1/CD9-positive tumors, only 36 (37.1%) had lymph node involvement. By contrast, 21/39 (53.8%) patients whose tumors had reduced MRP-1/CD9 immunoreactivity, and 5/7 patients whose primary carcinomas were not stained by the anti-MRP-1/CD9 MAb had lym … More ph node metastases. The comparison of protein expression by 62 primary tumors and their respective metastatic lymph nodes revealed that in almost 50% of the cases the latter had lower MRP-1/CD9 levels than the former. Moreover, reverse transcriptase polymerase chain reaction (RT-PCR)-based analysis disclosed that MRP-1/CD9 gene expression in the metastatic lymph nodes of 17/32 patients was strikingly lower than in the primary invasive ductal carcinomas. Gene overexpression was not observed in any of the samples studied. Our data suggest that low MRP-1/CD9 expression may be associated with the metastatic potential of certain human tumors. In consideration of these findings, we have now applied RT-PCR to determine MRP-1/CD9 gene expression in lung cancer. We analyzed tumor tissues of 109 patients ; 49 tumors were stage I,15, stage II and 45, stage III.We found that 67 patients had MRP-1/CD9 -positive tumors, and that gene expression was reduced in the tumors of the remaining 42 individuals. The overall rate of survival was strikingly higher among patients with positive tumors than in those whose tumors had reduced gene expression (62.3% vs.34.9% ; p<0.001). This also pertained to patients with adenocarcinomas of the lung (55.4% vs.26.0% ; p<0.001). Multivariate analysis with the Cox regression model indicated that MRP-1/CD9 positivity correlated better with overall survival rate than other variables, except lymph node status. Our data suggest that low MRP-1/CD9 expression by tumors of the lung may be associated with poor prognosis. It is conceivable that testing for MRP-1/CD9 may identify node-negative lung cancer patients and patients with adenocarcinomas who are at high risk for early disease recurrence. 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. 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的序列与白细胞分化抗原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，我们研究了143例乳腺浸润性导管癌中MRP-1/CD9的表达。在97例MRP-1/ cd9阳性肿瘤患者中，只有36例（37.1%）有淋巴结受累。相比之下，肿瘤MRP-1/CD9免疫反应性降低的患者中有21/39(53.8%)，原发癌未被抗MRP-1/CD9单抗染色的患者中有5/7发生淋巴瘤。62例原发肿瘤及其各自的转移性淋巴结的蛋白表达比较显示，在近50%的病例中，后者的MRP-1/CD9水平低于前者。此外，基于逆转录聚合酶链反应（RT-PCR）的分析显示，17/32例患者转移性淋巴结中的MRP-1/CD9基因表达明显低于原发性浸润性导管癌。在研究的任何样本中均未观察到基因过度表达。我们的数据表明，低MRP-1/CD9表达可能与某些人类肿瘤的转移潜力有关。考虑到这些发现，我们现在应用RT-PCR检测MRP-1/CD9基因在肺癌中的表达。我们分析了109例患者的肿瘤组织；I期49例，II期15例，III期45例。我们发现67例患者有MRP-1/CD9阳性肿瘤，其余42例患者肿瘤中MRP-1/CD9基因表达降低。肿瘤阳性患者的总体生存率明显高于肿瘤基因表达降低的患者（62.3% vs.34.9%; p<0.001）。肺腺癌患者也是如此（55.4% vs.26.0%; p<0.001）。Cox回归模型的多因素分析表明，除淋巴结状态外，MRP-1/CD9阳性与总生存率的相关性优于其他变量。我们的数据表明，肺肿瘤的低MRP-1/CD9表达可能与预后不良有关。可以想象，检测MRP-1/CD9可能会发现淋巴结阴性肺癌患者和腺癌患者，这些患者是疾病早期复发的高危人群。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。少