Lotan T L, Lyon M, Huo D, Taxy J B, Brendler C, Foster B A, Stadler W, Rinker-Schaeffer C W
Department of Pathology, University of Chicago, Chicago, IL, USA.
J Pathol. 2007 Aug;212(4):386-94. doi: 10.1002/path.2194.
Identification of the signalling cascades that are differentially activated during prostatic tumourigenesis is a crucial step in the search for future molecular targets in this disease. The stress-activated protein kinase (SAPK) signalling cascade culminates in the phosphorylation of the JNK and p38 mitogen-activated protein kinases (MAPKs). Recently, the upstream activators of these proteins, the MAPK kinases (MKKs), have been implicated as inhibitors of tumour progression in a variety of clinical and experimental tumour models. This study evaluates MKK4, MKK6 and MKK7 expression during prostate cancer progression in humans and in the transgenic adenocarcinoma of a mouse prostate (TRAMP) model of prostate tumourigenesis. Benign prostate, prostatic intraepithelial neoplasia (PIN) lesions and tumour tissues were collected from 37 TRAMP mice. Additionally, six tissue microarrays were constructed with tumours from a matched group of 102 men who underwent radical prostatectomy. Tissues from 20 patients with extensive high-grade prostatic intraepithelial neoplasia (HGPIN) were also analysed. For all samples, immunohistochemical staining for MKK4, MKK6 and MKK7 was scored in normal and neoplastic glands. Staining intensities of MKK4, MKK6 and MKK7 were significantly increased in HGPIN and prostate cancer compared to surrounding normal glands in both the TRAMP and human samples (p < 0.0001 for all markers). Increased levels of MKK4 or MKK7 correlated with higher pathological stage at prostatectomy (p = 0.01 and p = 0.04). Using multivariate analysis, there was no association between protein levels and time to biochemical recurrence in the human samples. The up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression in both TRAMP and human tissues highlights an important role for the SAPK signalling cascade in prostatic neoplasia. The finding that higher MKK4 and MKK7 expression is associated with higher-stage prostatic tumours underscores the dynamic regulation of these proteins during prostatic tumourigenesis.
识别在前列腺肿瘤发生过程中差异激活的信号级联反应，是寻找该疾病未来分子靶点的关键步骤。应激激活蛋白激酶（SAPK）信号级联反应最终导致JNK和p38丝裂原活化蛋白激酶（MAPK）的磷酸化。最近，这些蛋白的上游激活剂，即MAPK激酶（MKK），在多种临床和实验肿瘤模型中被认为是肿瘤进展的抑制剂。本研究评估了MKK4、MKK6和MKK7在人类前列腺癌进展过程以及前列腺肿瘤发生的转基因小鼠前列腺腺癌（TRAMP）模型中的表达。从37只TRAMP小鼠收集了良性前列腺、前列腺上皮内瘤变（PIN）病变和肿瘤组织。此外，用来自102名接受根治性前列腺切除术的匹配男性组的肿瘤构建了六个组织微阵列。还分析了20例广泛高级别前列腺上皮内瘤变（HGPIN）患者的组织。对于所有样本，在正常和肿瘤腺体中对MKK4、MKK6和MKK7进行免疫组织化学染色评分。在TRAMP和人类样本中，与周围正常腺体相比，HGPIN和前列腺癌中MKK4、MKK6和MKK7的染色强度均显著增加（所有标志物p < 0.0001）。MKK4或MKK7水平升高与前列腺切除时更高的病理分期相关（p = 0.01和p = 0.04）。使用多变量分析，在人类样本中蛋白水平与生化复发时间之间无关联。在TRAMP和人类组织中前列腺癌进展过程中MKK4、MKK6和MKK7的上调突出了SAPK信号级联反应在前列腺肿瘤形成中的重要作用。更高的MKK4和MKK7表达与更高分期的前列腺肿瘤相关这一发现强调了这些蛋白在前列腺肿瘤发生过程中的动态调节。
