Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.
Virchows Arch. 2021 Aug;479(2):277-284. doi: 10.1007/s00428-021-03062-0. Epub 2021 Feb 27.
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide with high morbidity and mortality rates. The discovery of small molecule anticancer reagents has significantly affected cancer therapy. However, the anticancer effects of these therapies are not sufficient to completely cure CRC. PDZ-binding kinase (PBK) was initially identified as a mitotic kinase for mitogen-activated protein kinase and is involved in cytokinesis and spermatogenesis. Aberrant expression of PBK has been reported to be closely associated with malignant phenotypes of many cancers and/or patient survival. However, the expression of PBK and its association to patient survival in CRC have not been fully elucidated. In the present study, 269 primary CRCs were evaluated immunohistochemically for PBK expression to assess its ability as a prognostic factor. CRC tumor cells variably expressed PBK (range, 0-100%; median, 32%) in the nucleus and cytoplasm. Univariate analyses identified a significant inverse correlation between PBK expression and pT stage (P<0.0001). Furthermore, patients carrying CRC with higher PBK expression showed significantly favorable survival (P=0.0094). Multivariate Cox proportional hazards regression analysis revealed high PBK expression (HR, 0.52; P=0.015) as one of the potential favorable factors for CRC patients. PBK expression showed significant correlation to Ki-67 labeling indices (ρ=0.488, P<0.0001). In vitro, the PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells with PBK expression through downregulation of P-ERK and induction of apoptosis. These results suggest that PBK-targeting therapeutics may be useful for the treatment of PBK-expressing CRC patients.
结直肠癌（CRC）是全球最常见的胃肠道癌症之一，发病率和死亡率都很高。小分子抗癌试剂的发现极大地影响了癌症治疗。然而，这些疗法的抗癌效果不足以完全治愈 CRC。PDZ 结合激酶（PBK）最初被鉴定为丝裂原激活蛋白激酶的有丝分裂激酶，参与细胞分裂和精子发生。已经报道 PBK 的异常表达与许多癌症的恶性表型和/或患者生存密切相关。然而，CRC 中 PBK 的表达及其与患者生存的关系尚未完全阐明。在本研究中，通过免疫组织化学评估了 269 例原发性 CRC 中 PBK 的表达，以评估其作为预后因素的能力。CRC 肿瘤细胞在核和细胞质中表达 PBK（范围 0-100%；中位数 32%）。单因素分析确定 PBK 表达与 pT 分期之间存在显著负相关（P<0.0001）。此外，携带高 PBK 表达的 CRC 患者的生存显著改善（P=0.0094）。多因素 Cox 比例风险回归分析显示，高 PBK 表达（HR，0.52；P=0.015）是 CRC 患者潜在的有利因素之一。PBK 表达与 Ki-67 标记指数呈显著相关（ρ=0.488，P<0.0001）。在体外，PBK 抑制剂 OTS514 通过下调 P-ERK 和诱导细胞凋亡来抑制具有 PBK 表达的 CRC 细胞的细胞增殖。这些结果表明，针对 PBK 的治疗方法可能对治疗表达 PBK 的 CRC 患者有用。
