Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma.
Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma.
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发表时间：
2002-11
期刊：
影响因子：
11.2
通讯作者：
S. Yamada;J. Hickson;Yancey Hrobowski;Donald J. Vander Griend;David Benson;A. Montag;T. Karrison
中科院分区：
文献类型：
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作者：
S. Yamada;J. Hickson;Yancey Hrobowski;Donald J. Vander Griend;David Benson;A. Montag;T. Karrison
尽管化疗有所改进，人们认识到积极的手术细胞减少是有益的，但大多数被诊断为卵巢癌的患者将死于转移性疾病。与卵巢癌转移能力的获得有关的分子变化知之甚少。我们假设转移抑制基因失活或下调在卵巢癌的进展中起作用。丝裂原活化蛋白激酶4(MKK4)是应激激活蛋白激酶信号转导通路中的一员，近年来被发现是一种肿瘤转移抑制基因。采用免疫组织化学方法检测临床卵巢癌转移过程中MKK4异常表达的可能性。检测MKK4在正常卵巢组织和转移卵巢组织中的表达。正常卵巢上皮细胞MKK4高表达，而转移性卵巢上皮细胞MKK4表达显著降低。这些结果支持MKK4基因异常在临床疾病发生发展中的作用。采用功能性方法来测试MKK4抑制转移性定植的能力，转移性定植是指播散性癌细胞在体内的次级部位寄居和生长的过程。选择SKOV3ip.1人卵巢癌细胞株进行这些研究是因为它缺乏内源性MKK4的表达，但保留了MKK4信号级联的上游和下游成分。在这些细胞中异位表达MKK4，当注射到雌性SCID小鼠体内时，可以抑制近90%的明显转移植入的数量。此外，MKK4的表达使动物的寿命延长了70%。综上所述，这些数据支持MKK4在抑制卵巢癌转移定植中的作用。
Despite improvements in chemotherapy and the recognition that aggressive surgical cytoreduction is beneficial, the majority of patients diagnosed with ovarian cancer will die as a result of metastatic disease. The molecular changes associated with acquisition of metastatic ability in ovarian cancer are poorly understood. We hypothesize that metastasis suppressor gene inactivation or down-regulation plays a role in ovarian cancer progression. Mitogen-activated protein kinase kinase 4 (MKK4), a member of the stress-activated protein kinase signaling cascade, has been identified recently as a metastasis-suppressor gene. An immunohistochemical approach was taken to test the possibility that MKK4 dysregulation occurs during the development of clinical ovarian cancer metastases. MKK4 expression was evaluated in normal and metastatic ovarian tissues. Normal ovarian epithelial cells showed high intensity staining for MKK4, whereas metastatic tissues showed a statistically significant decrease in expression. These results support a role for MKK4 dysregulation in the development of clinical disease. A functional approach was taken to test the ability of MKK4 to suppress metastatic colonization, the process whereby disseminated cancer cells lodge and grow at a secondary site in vivo. The SKOV3ip.1 human ovarian cancer cell line was chosen for these studies because it lacks endogenous MKK4 expression but retains both upstream and downstream components of the signaling cascade of MKK4. Ectopic expression of MKK4 in these cells, when injected into female SCID mice, suppressed the number of overt metastatic implants by nearly 90%. Furthermore, MKK4 expression increased the life span of the animals by 70%. Taken together, these data support a role for MKK4 in the suppression of metastatic colonization in ovarian cancer.