Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling.
Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling.
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Derlin-1 过表达导致肌层浸润性膀胱癌预后不良，并通过 PI3K/AKT 和 ERK/MMP 信号传导导致化疗耐药和侵袭
DOI：
10.18632/oncotarget.15001
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发表时间：
2017-03-07
期刊：
影响因子：
--
通讯作者：
Wang E
中科院分区：
文献类型：
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作者：
Dong Q;Fu L;Zhao Y;Tan S;Wang E
已发现 Derlin-1 在多种人类癌症中过度表达。然而，其在膀胱癌中的临床意义和生物学作用仍有待探索。在这里，我们发现 Derlin-1 在 38.6% (58/150) 的癌症样本中表达上调。肌层浸润性膀胱癌 (MIBC) 中 Derlin-1 过表达率高于非肌层浸润性膀胱癌 (NMIBC) (p=0.0079)。 Derlin-1 是患者预后不良的预测因素。 Derlin-1 缺失会受到抑制，而其过表达则会促进细胞侵袭和集落形成。此外，Derlin-1 过表达会诱导顺铂耐药，而其缺失则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 信号传导消除了 Derlin-1 对 Bcl-2 和顺铂耐药性的影响。免疫沉淀表明 Derlin-1 与 PI3K 的 p110α 亚基相互作用。此外，我们发现 Derlin-1 缺失下调，其过表达上调细胞 MMP-2/9 表达和 ERK 磷酸化。 ERK 抑制剂可以阻断 Derlin-1 介导的 MMP-2/9 上调。总之，我们的研究表明，Derlin-1 在膀胱癌中过度表达，并通过 ERK/MMP 和 PI3K/AKT/Bcl-2 信号通路促进恶性表型。
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.