Application of midkine to diagnosis and treatment of tumors and growth of blood stem cells.

用酶联免疫测定法对血清中期因子水平进行了大规模调查，发现80%以上的癌症患者血清中期因子水平高于正常人。中期因子水平可作为肿瘤标志物。进一步证实了截短型中期因子mRNA的肿瘤特异性，所有有淋巴结转移的病例均有中期因子mRNAs的截短，因此，截短型中期因子mRNA可作为结肠癌手术前微小转移的标志物。在14例食管癌中有8例表达Midkine，而在正常组织中无表达。Midkine基因上游2.3kb5区域含有启动子序列，可使下游基因在食管癌细胞中表达。将胸苷激酶基因插入启动子下方，并将其导入癌细胞，使其对更昔洛韦的敏感性增加。因此，提出了一种利用MK启动子进行肿瘤治疗的策略。中期因子在骨折部位有表达。中期因子基因的导入和过表达诱导前软骨细胞分化。中期因子可用于骨折的治疗。中期因子缺陷小鼠对顺铂的肾毒性更敏感。中期因子可能有助于降低抗癌药物的毒性。中期因子促进巨噬细胞和中性粒细胞的迁移。在中期因子缺陷小鼠，球囊损伤模型未见巨噬细胞迁移和新生内膜形成。这一发现表明中期因子促进了炎症细胞的迁移，并参与了病理状态的形成。

Large scale survey of serum midkine levels determined by enzyme-linked immunoassay revealed that in more than 80% cases of cancer patients, the serum midkine levels increased as compared to that of normal human subjects. Midkine levels may be used as a tumor marker. Tumor specificity of truncated midkine mRNA was further confirmed, and all cases of lymph node metastasis had truncated midkine mRNA.Thus, the truncated mRNA can be a marker to detect minor metastasis upon surgical operation by using PCR.We also found that midkine mRNA expression was increased in adenoma before development of colon carcinoma. Midkine was expressed in 8 cases among 14 cases of esophageal carcinoma, but not in the normal tissues. The 2.3 kb 5 upstream region of midkine gene contains a promoter sequence, which enabled expression of downstream genes in esophageal carcinoma cells. Thymidine kinase gene was placed under the promoter and transfected to the carcinoma cells, resulting in increased sensitivity to ganciclovir. Thus, a strategy of cancer therapy was proposed using the MK promoter. Midkine was expressed at the site of bone fracture. Introduction of midkine cDNA and overexpression induced differentiation of prechondrocytes. Midkine may be applied to cure of bone fracture. Midkine deficient mice were more susceptible to renal toxicity of cisplatin. Midkine may be useful in reducing toxicity of anti-cancer drugs. Midkine promoted migration of macrophages as well as neutrophils. In midkine deficient mice, macrophage migration and neointima formation did not occur upon balloon injury model. This finding implicated that midkine promoted migration of inflammatory cells and contributed to formation of pathological status.