Dasen Boris, Vlajnic Tatjana, Mengus Chantal, Ruiz Christian, Bubendorf Lukas, Spagnoli Giulio, Wyler Stephen, Erne Paul, Resink Thérèse J, Philippova Maria
Department of Biomedicine, Laboratory for Signal Transduction University Hospital Basel Switzerland.
Institute of Pathology, University Hospital Basel Switzerland.
J Pathol Clin Res. 2016 Nov 26;3(1):44-57. doi: 10.1002/cjp2.61. eCollection 2017 Jan.
Prostate cancer represents the second leading cause of cancer-related death in men. T-cadherin (CDH13) is an atypical GPI-anchored member of the cadherin family of adhesion molecules. Its gene was reported to be downregulated in a small series of prostate tumours. T-cadherin protein expression/localisation in prostate tissue has never been investigated. The purpose of our study was to analyse CDH13 gene and protein levels in large sets of healthy and cancer prostate tissue specimens and evaluate CDH13 effects on the sensitivity of prostate cancer cells to chemotherapy. Analysis of CDH13 gene expression in the TCGA RNAseq dataset for prostate adenocarcinoma ( = 550) and in tissue samples ( = 101) by qPCR revealed weak positive correlation with the Gleason score in cancer and no difference between benign and malignant specimens. Immunohistochemical analysis of tissue sections ( = 12) and microarrays ( = 128 specimens) demonstrated the presence of CDH13 on the apical surface and at intercellular contacts of cytokeratin 8-positive luminal cells and cells double-positive for cytokeratin 8 and basal marker p63. T-cadherin protein expression was markedly upregulated in cancer as compared to benign prostate hyperplasia, the increase being more prominent in organ-confined than in advanced hormone-resistant tumours, and correlated negatively with the Gleason pattern. T-cadherin protein level correlated strongly with cytokeratin 8 and with an abnormal diffuse/membrane localisation pattern of p63. Ectopic expression of CDH13 in metastatic prostate cancer cell line DU145 reduced cell growth in the presence of doxorubicin. We conclude that CDH13 protein, but not its gene expression, is strongly upregulated in early prostate cancer, correlates with changes in luminal/basal differentiation and p63 localisation, and promotes sensitivity of cancer cells to doxorubicin. These data identify CDH13 as a novel molecule relevant for prostate cancer progression and response to therapy.
前列腺癌是男性癌症相关死亡的第二大主要原因。T-钙黏蛋白（CDH13）是黏附分子钙黏蛋白家族的一个非典型糖基磷脂酰肌醇锚定成员。据报道，其基因在一小部分前列腺肿瘤中表达下调。T-钙黏蛋白蛋白在前列腺组织中的表达/定位从未被研究过。我们研究的目的是分析大量健康和癌性前列腺组织标本中的CDH13基因和蛋白水平，并评估CDH13对前列腺癌细胞化疗敏感性的影响。通过qPCR分析前列腺腺癌的TCGA RNAseq数据集（n = 550）和组织样本（n = 101）中的CDH13基因表达，发现其与癌症中的Gleason评分呈弱正相关，良性和恶性标本之间无差异。对组织切片（n = 12）和微阵列（n = 128个标本）进行免疫组织化学分析，结果显示CDH13存在于细胞角蛋白8阳性的管腔细胞以及细胞角蛋白8和基底标志物p63双阳性细胞的顶端表面和细胞间连接处。与良性前列腺增生相比，T-钙黏蛋白蛋白表达在癌症中明显上调，在器官局限性肿瘤中比在晚期激素抵抗性肿瘤中增加更为显著，且与Gleason分级呈负相关。T-钙黏蛋白蛋白水平与细胞角蛋白8以及p6(3)异常的弥漫性/膜定位模式密切相关。在转移性前列腺癌细胞系DU145中异位表达CDH13可降低阿霉素存在时的细胞生长。我们得出结论，CDH13蛋白而非其基因表达在早期前列腺癌中强烈上调，与管腔/基底分化和p63定位的变化相关，并促进癌细胞对阿霉素的敏感性。这些数据表明CDH13是一种与前列腺癌进展和治疗反应相关的新分子。
