Xin Wei, Yun Ki J, Ricci Francesca, Zahurak Marianna, Qiu Wanglong, Su Gloria H, Yeo Charles J, Hruban Ralph H, Kern Scott E, Iacobuzio-Donahue Christine A
Department of Pathology, The University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Clin Cancer Res. 2004 Dec 15;10(24):8516-20. doi: 10.1158/1078-0432.CCR-04-0885.
MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P < 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P < 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis.
MKK4（丝裂原活化蛋白激酶4/应激活化蛋白激酶激酶1）是丝裂原活化蛋白激酶家族的成员，最初被鉴定为一种通过直接磷酸化c-Jun氨基末端激酶参与应激激活蛋白激酶途径的激酶。在一部分胰腺癌中观察到MKK4基因失活，这表明应激激活蛋白激酶途径失调与胰腺癌发生有关。我们通过免疫组织化学标记评估了60例手术切除的原发性浸润性胰腺腺癌（24例已知MKK4基因状态）以及14种不同组织芯片中Mkk4蛋白的表达模式，这些组织芯片代表了26例死于转移性胰腺癌患者的原发性癌和所有大体转移灶。在手术切除的癌组织中，60例中有52例（86.7%）发现Mkk4蛋白呈局灶性或弥漫性阳性免疫标记。在8例Mkk4免疫标记阴性的癌组织中，3例存在MKK4基因的纯合缺失或基因内突变，而52例Mkk4免疫标记阳性的病例中无一例出现这种情况（P<0.01）。Mkk4免疫标记缺失显示出存活时间缩短的趋势，Mkk4阳性癌组织的死亡风险是Mkk4阴性癌组织的一半（P = 0.09）。我们还评估了尸检标本中不可切除的原发性和转移性癌组织的Mkk4免疫标记模式，结果表明88.8%的不可切除原发性癌组织中Mkk4免疫标记完整，而远处转移灶中这一比例为63.3%（P<0.001）。我们的数据表明，胰腺癌中Mkk4蛋白表达缺失可能比仅由基因失活率所显示的更为常见，并且MKK4缺失可能促进疾病进展。MKK4基因状态与免疫标记模式的相关性验证了在常规组织学切片中评估MKK4状态的这种方法，并可能提供有关患者预后的有用信息。
