The analysis of the function of TM4SF and the suppression of the cancer metastasis by its regulation

MRP-1/CD9属于跨膜4超家族（TM4SF），该家族包括至少19个成员，在各种组织中表达。除了MRP-1/CD9外，TM4 SF的另外两个成员KAI1/CD82和ME491/CD63也参与了肿瘤的进展和转移。然而，ME491/CD63 mRNA水平在几乎所有的肺癌、乳腺癌和胰腺癌中都得到了很好的保存，没有检测到降低。相反，ME491/CD63与其他TM4SF成员CD81和MRP-1/CD9相关。此外，CD81和KAI1/CD82通过相互结合以及与整合素alpha3、alpha4、alpha6和beta6结合形成多分子膜复合物。MRP-1/CD9也是如此。因此，TM4SF成员可能在大的多组分复合物中起作用，并作为受体相关离子通道，或可能通过质膜转导信号并调节细胞的激活、发育、增殖和运动。此外，通过检测MRP-1/CD9和KAI1/CD82的表达，可以更准确地预测肺癌、乳腺癌或胰腺癌患者的预后。考虑到恶性肿瘤的进展，KAI1/CD82的降低可能先于MRP-1/CD9的降低。在这些肿瘤的早期，肿瘤抑制基因p53或RB发生突变或缺失，因此KAI1/CD82基因可能处于下降状态。在最后阶段，MRP-1/CD9的水平可能由于启动子的甲基化而降低，因此MRP-1/CD9的正常功能可能丧失。因此，恶性细胞最终获得转移潜能。因此，我们研究了MRP-1/CD9表达通过基因转移阻止BL6转移的可能性。利用复制缺陷腺病毒载体进行MRP-1/CD9 cDNA的体内转染。静脉注射表达MRP-1/CD9的腺病毒载体（rAd-MRP-1/CD9）导致小鼠肺转移数量减少85%，并且用rAd-MRP-1/CD9治疗的小鼠的中位生存时间明显长于用rAd-betagal载体治疗的小鼠。少

MRP-1/CD9 belongs to the transmembrane 4 superfamily (TM4SF), which includes at least 19 members that are expressed on various tissues.Apart from MRP-1/CD9, two other members of the TM4 SF, KAI1/CD82 and ME491/CD63 are noted for their involvement in tumor progression and metastasis.However, the ME491/CD63 mRNA levels in almost all of the lung cancers, breast cancers and pancreas cancers were well preserved and no reductions were detected.In contrast, ME491/CD63 is associated with other TM4SF members, CD81 and MRP-1/CD9.In addition, CD81 and KAI1/CD82 formed multimolecular membrane complexes by associating with each other and with integrin alpha3 alpha4 alpha6 and beta6.This is true of MRP-1/CD9.Therefore, TM4SF members may act in large multicomponent complexes, and serve as receptor-associated ion channels or may act to transduce of signals across the plasma membrane and to regulate cell activation, development, proliferation, and motility.Moreover, we can predict the prognosis of pati … More ents with lung cancers, breast cancers or pancreas cancers more precisely by evaluating the expression of both MRP-1/CD9 and KAI1/CD82.Considering the progression of malignant tumors, the reduction in KAI1/CD82 might precede the reduction in MRP-1/CD9.The tumor suppressor genes, p53 or RB had been mutated or deleted during the early stage of these tumors and thus the KAI1/CD82 gene might be in decline.During the last stage, the levels of MRP-1/CD9 might be diminishing due to methylation of the promoter and therefore the normal functions of MRP-1/CD9 could be lost.Thus, the malignant cells could finally acquire metastatic potential.Therefore, we investigated the possibility of preventing metastasis of BL6 by expression of MRP-1/CD9 through gene transfer.A replication-deficient adenovirus vector was used for the in vivo transfer of MRP-1/CD9 cDNA.Intravenous injection of an adenovirus vector (rAd-MRP-1/CD9) expressing MRP-1/CD9 resulted in a 85% reduction in the number of pulmonary metastases of mice and the median survival time of mice treated with rAd-MRP-1/CD9 was significantly longer than those treated with the rAd-betagal vector. Less