Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, China; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, China.
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
Biochem Biophys Res Commun. 2018 May 15;499(3):433-440. doi: 10.1016/j.bbrc.2018.03.152. Epub 2018 Mar 31.
Kelch-like family member 21 (KLHL21) is involved in cell mitosis and motility. Nevertheless, the clinical significance and biological function of KLHL21 in cholangiocarcinoma (CCA) are elusive. This is the first study to describe a pivotal role for KLHL21 in the progression of CCA. The expression of KLHL21 was elevated in CCA tissues compared with paired normal bile duct tissues. In addition, immunohistochemical and statistical analyses demonstrated that the expression of KLHL21 correlated inversely with tumor histological grade (p < 0.05) and the overall survival of patients (p < 0.01). In CCA cells, we found that the inhibition of KLHL21 significantly reduced proliferation, migration and invasion. Further results indicated that inhibition of KLHL21 triggered G0/G1 cell cycle arrest, leading to the increased expression of P21 and P27 and decreased expression of Cyclin E1, which eventually resulted in proliferation suppression in CCA cells. Furthermore, KLHL21 knockdown alleviated the activation of the Erk signaling pathway via decreasing the expression of phospho-Erk1/2. Our data demonstrated that KLHL21 plays an essential role in the tumorigenesis and progression of CCA, implying that it might serve as a potential therapeutic target for CCA treatment.
Kelch 样家族成员 21（KLHL21）参与细胞有丝分裂和运动。然而，KLHL21 在胆管癌（CCA）中的临床意义和生物学功能尚不清楚。这是首次描述 KLHL21 在 CCA 进展中的关键作用的研究。与配对的正常胆管组织相比，CCA 组织中 KLHL21 的表达升高。此外，免疫组织化学和统计学分析表明，KLHL21 的表达与肿瘤组织学分级呈负相关（p<0.05），与患者的总生存率呈负相关（p<0.01）。在 CCA 细胞中，我们发现抑制 KLHL21 显著降低了增殖、迁移和侵袭。进一步的结果表明，抑制 KLHL21 触发了 G0/G1 细胞周期停滞，导致 P21 和 P27 的表达增加，Cyclin E1 的表达减少，最终导致 CCA 细胞增殖受到抑制。此外，KLHL21 敲低通过降低磷酸化 Erk1/2 的表达来减轻 Erk 信号通路的激活。我们的数据表明，KLHL21 在 CCA 的发生和发展中起着重要作用，表明它可能成为 CCA 治疗的潜在治疗靶点。
