Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma.
Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma.
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PBK/TOPK的过度表达与胃癌的肿瘤恶性潜能和不良预后有关。
DOI：
10.1038/bjc.2016.394
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发表时间：
2017-01-17
影响因子：
8.8
通讯作者：
Otsuji E
中科院分区：
文献类型：
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作者：
Ohashi T;Komatsu S;Ichikawa D;Miyamae M;Okajima W;Imamura T;Kiuchi J;Kosuga T;Konishi H;Shiozaki A;Fujiwara H;Okamoto K;Tsuda H;Otsuji E
PDZ结合激酶/T-LAK细胞来源的蛋白激酶（PBK/TOPK）是一种丝氨酸-苏氨酸激酶，通过抑制p53和PTEN的反式激活活性在多种类型的癌症中过表达。我们测试了PBK/TOPK是否通过其在胃癌（GC）中的激活/过表达作为促癌基因。我们分析了5个GC细胞系和144个原发性肿瘤，这些肿瘤在2001年至2003年期间在我院进行了根治性切除。PBK/TOPK蛋白的过表达在GC细胞系中频繁检测到（5个细胞系中的4个，80.0%），在GC的原发性肿瘤样品中检测到（144个病例中的24个，16.6%），并且与静脉浸润、肿瘤深度和复发率显著相关。PDZ结合激酶/T-LAK细胞源性蛋白激酶过表达肿瘤的生存率低于非表达肿瘤（P=0.0009，对数秩检验）。多因素分析显示PDZ结合激酶/T-LAK细胞源性蛋白激酶阳性与预后不良独立相关（P<0.0001，危险比6.40（2.71-14.49））。在PBK/TOPK过表达的GC细胞中，PBK/TOPK的敲低以TP 53突变依赖的方式通过p53激活抑制细胞增殖，并以TP 53突变非依赖的方式通过PTEN上调抑制细胞迁移/侵袭。这些发现表明，PBK/TOPK通过其过表达在肿瘤恶性潜能中起着至关重要的作用，并突出了其作为GC的预后因子和潜在治疗靶点的有用性。
PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) is a serine–threonine kinase and overexpressed in various types of cancer by inhibiting the transactivation activities of p53 and PTEN. We tested whether PBK/TOPK acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). We analysed five GC cell lines and 144 primary tumours, which were curatively resected in our hospital between 2001 and 2003. Overexpression of the PBK/TOPK protein was frequently detected in GC cell lines (4 out of 5 lines, 80.0%) was detected in primary tumour samples of GC (24 out of 144 cases, 16.6%) and was significantly correlated with venous invasion, tumour depth and recurrence rate. PDZ-binding kinase/T-LAK cell-originated protein kinase-overexpressing tumours had a worse survival rate than those with non-expressing tumours (P=0.0009, log-rank test). PDZ-binding kinase/T-LAK cell-originated protein kinase positivity was independently associated with a worse outcome in multivariate analysis (P<0.0001, hazard ratio 6.40 (2.71–14.49)). In PBK/TOPK-overexpressing GC cells, knockdown of PBK/TOPK inhibited the cell proliferation through the p53 activation in a TP53 mutation-dependent manner and inhibited the migration/invasion through the PTEN upregulation in a TP53 mutation-independent manner. These findings suggest PBK/TOPK plays a crucial role in tumour malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.