Dong Qianze, Fu Lin, Zhao Yue, Tan Shutao, Wang Enhua
Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China.
Oncotarget. 2017 Mar 7;8(10):17059-17069. doi: 10.18632/oncotarget.15001.
Derlin-1 has been found to be overexpressed in several human cancers. However, its clinical significance and biological roles in bladder cancer remain unexplored. Here, we found that Derlin-1 was upregulated in 38.6% (58/150) cases of cancer samples. The rate of Derlin-1 overexpression was higher in muscle invasive bladder cancer (MIBC) than non-muscle invasive bladder cancer (NMIBC) (p=0.0079). Derlin-1 was a predicting factor for poor patient prognosis. Derlin-1 depletion inhibited while its overexpression facilitated cell invasion and colony formation. In addition, Derlin-1 overexpression induced cisplatin resistance while its depletion sensitized cancer cells to cisplatin. Further analysis demonstrated that Derlin-1 activated AKT phosphorylation and upregulated Bcl-2 expression. Blockage of AKT signaling by LY294005 abolished the effects of Derlin-1 on Bcl-2 and cisplatin resistance. Immunoprecipitation indicated Derlin-1 interacted with p110α subunit of PI3K. In addition, we showed that Derlin-1 depletion downregulated and its overexpression upregulated cell MMP-2/9 expression and ERK phosphorylation. Derlin-1 mediated upregulation of MMP-2/9 could be blocked by ERK inhibitor. In conclusion, our study demonstrated that Derlin-1 is overexpressed in bladder cancer and promotes malignant phenotype through ERK/MMP and PI3K/AKT/Bcl-2 signaling pathway.
已发现Derlin-1在几种人类癌症中过表达。然而，其在膀胱癌中的临床意义和生物学作用仍未得到探索。在此，我们发现Derlin-1在38.6%（58/150）的癌症样本中上调。Derlin-1过表达率在肌肉浸润性膀胱癌（MIBC）中高于非肌肉浸润性膀胱癌（NMIBC）（p = 0.0079）。Derlin-1是患者预后不良的预测因素。Derlin-1的缺失抑制而其过表达促进细胞侵袭和集落形成。此外，Derlin-1的过表达诱导顺铂耐药，而其缺失使癌细胞对顺铂敏感。进一步分析表明，Derlin-1激活AKT磷酸化并上调Bcl-2表达。LY294005阻断AKT信号通路消除了Derlin-1对Bcl-2和顺铂耐药的影响。免疫沉淀表明Derlin-1与PI3K的p110α亚基相互作用。此外，我们表明Derlin-1的缺失下调而其过表达上调细胞MMP-2/9表达和ERK磷酸化。ERK抑制剂可阻断Derlin-1介导的MMP-2/9上调。总之，我们的研究表明Derlin-1在膀胱癌中过表达，并通过ERK/MMP和PI3K/AKT/Bcl-2信号通路促进恶性表型。
