Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, Liaoning, China.
Am J Pathol. 2013 Mar;182(3):954-64. doi: 10.1016/j.ajpath.2012.11.019. Epub 2013 Jan 7.
Previous studies indicated a role of Derlin-1 in human cancers; however, its expression pattern in non-small cell lung cancer (NSCLC) and the molecular mechanism of Derlin-1 on cancer progression have not been characterized. In the present study, Derlin-1 expression was examined in lung cancer cell lines and human tissues. Derlin-1 overexpression correlated with pTNM stage, lymph node metastasis, and poor overall survival. siRNA knockdown of Derlin-1 impaired anchorage-dependent and anchorage-independent cell growth and invasion in A549 and H1299 cell lines, and its overexpression promoted proliferation and invasion in HBE and LTE cell lines. Derlin-1 depletion decreased matrix metalloproteinase (MMP)-2/9 at both protein and mRNA levels, with decreased MAP kinase/extracellular signal-regulated kinase (ERK)/ERK phosphorylation. Derlin-1 overexpression up-regulated MMP-2/9 expression and ERK phosphorylation, which could be reversed by MAP kinase/ERK kinase inhibitor, PD98059. The effect of Derlin-1 on MMP-2/9 up-regulation was abolished in ERK1/2 siRNA-treated cells. Further analysis showed that Derlin-1 overexpression induced EGFR phosphorylation. EGFR inhibitor blocked Derlin-1-mediated up-regulation of EGFR and ERK phosphorylation. MMP-2/9 and p-ERK up-regulation by Derlin-1 was partly blocked in EGFR-depleted cells with siRNA treatment. Immunoprecipitation confirmed the association between Derlin-1 and EGFR. In summary, our results showed that Derlin-1 is overexpressed in NSCLC and promotes invasion by EGFR-ERK-mediated up-regulation of MMP-2 and MMP-9. Derlin-1 may serve as a therapeutic target for NSCLC.
先前的研究表明 Derlin-1 在人类癌症中发挥作用；然而，其在非小细胞肺癌（NSCLC）中的表达模式以及 Derlin-1 对癌症进展的分子机制尚未得到阐明。在本研究中，检测了 Derlin-1 在肺癌细胞系和人体组织中的表达。Derlin-1 的过表达与 pTNM 分期、淋巴结转移和总体生存不良相关。Derlin-1 的 siRNA 敲低可削弱 A549 和 H1299 细胞系中的锚定依赖性和非锚定依赖性细胞生长和侵袭，而过表达则可促进 HBE 和 LTE 细胞系的增殖和侵袭。Derlin-1 的耗竭可降低基质金属蛋白酶（MMP）-2/9 的蛋白和 mRNA 水平，同时降低丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）/ERK 磷酸化。Derlin-1 的过表达可上调 MMP-2/9 的表达和 ERK 磷酸化，而 MAP 激酶/ERK 激酶抑制剂 PD98059 可逆转这一作用。在 ERK1/2 siRNA 处理的细胞中，Derlin-1 对 MMP-2/9 上调的作用被消除。进一步分析表明，Derlin-1 过表达可诱导 EGFR 磷酸化。EGFR 抑制剂可阻断 Derlin-1 介导的 EGFR 和 ERK 磷酸化的上调。用 siRNA 处理可部分阻断 Derlin-1 耗竭细胞中 MMP-2/9 和 p-ERK 的上调。免疫沉淀证实了 Derlin-1 与 EGFR 之间的关联。总之，我们的结果表明 Derlin-1 在 NSCLC 中过表达，并通过 EGFR-ERK 介导的 MMP-2 和 MMP-9 上调促进侵袭。Derlin-1 可能成为 NSCLC 的治疗靶点。
