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

通过酶联免疫分析法测定的血清midkine水平的大规模调查显示，在80%以上的癌症患者中，血清midkine水平比正常人高。Midkine水平可作为肿瘤标志物。进一步证实了截断的midkine mRNA的肿瘤特异性，所有淋巴结转移病例均有截断的midkine mRNA。因此，截断的mRNA可以作为PCR检测手术后轻微转移的标志。我们还发现，midkine mRNA在结肠癌发生前在腺瘤中表达增加。14例食管癌中有8例表达Midkine，正常组织中无表达。midkine基因上游2.3 kb的5个区域包含一个启动子序列，使下游基因能够在食管癌细胞中表达。将胸苷激酶基因置于启动子下，转染到癌细胞中，使其对更昔洛韦的敏感性增加。因此，提出了一种利用MK启动子治疗癌症的策略。Midkine在骨折部位表达。引入midkine cDNA及过表达诱导软骨前细胞分化。Midkine可用于骨折的治疗。Midkine缺陷小鼠对顺铂的肾毒性更敏感。Midkine可能有助于降低抗癌药物的毒性。Midkine促进巨噬细胞和中性粒细胞的迁移。在midkine缺陷小鼠中，球囊损伤模型未发生巨噬细胞迁移和新生内膜形成。这一发现提示midkine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.