Department of Pulmonary Medicine, Affiliated Shandong Provincial Hospital, Shandong University, Shandong, P.R. China.
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
Int J Oncol. 2017 Jul;51(1):91-103. doi: 10.3892/ijo.2017.4021. Epub 2017 May 26.
Malignant pleural mesothelioma (MPM) is an aggressive cancer for which more effective treatments are needed. In this study, strong to moderate staining of MET and ERK5 was detected in 67.1 and 48% of the analyzed 73 human mesothelioma tumors, and significant correlation of MET and ERK5 expression was identified (P<0.05). We evaluated the doublecortin-like kinase 1 (DCLK1) expression in human mesothelioma tumors. Our results showed that 50.7% of the immunohistochemistry analyzed human mesothelioma tumors have strong to moderate staining of DCLK1, and its expression is significantly correlated with MET or ERK5 expression (P<0.05). Also, the upregulation of DCLK1 is correlated with poor prognosis in MPM patients (P=0.0235). To investigate whether DCLK1 is downstream of MET/ERK5 signaling in human mesothelioma, the effect of DCLK1 expression was analyzed after treatments with either the MET inhibitor XL184 or the ERK5 inhibitor XMD8-92 in human mesothelioma cell lines. Our results showed that the MET inhibitor XL184 reduced the expression of phospho‑ERK5 and DCLK1 expression in human mesothelioma cell lines. In addition, the ERK5 inhibitor XMD8-92 reduced the expression of phospho-ERK5 and DCLK1 expression in human mesothelioma cell lines. Furthermore, XML184 and XMD8-92 treatment impaired invasion and tumor sphere formation ability of H290 mesothelioma cells. These results suggest that DCLK1 is regulated by MET/ERK5 signaling in human mesothelioma, and the MET/ERK5/DCLK1 signaling cascade could be further developed into a promising therapeutic target against mesothelioma.
恶性胸膜间皮瘤（MPM）是一种侵袭性癌症，需要更有效的治疗方法。在这项研究中，在分析的 73 个人胸膜间皮瘤肿瘤中，MET 和 ERK5 的强至中度染色分别检测到 67.1%和 48%，并且鉴定到 MET 和 ERK5 表达的显著相关性（P<0.05）。我们评估了人类间皮瘤肿瘤中的双皮质激酶 1（DCLK1）表达。我们的结果表明，50.7%的免疫组织化学分析的人类间皮瘤肿瘤具有强至中度的 DCLK1 染色，并且其表达与 MET 或 ERK5 表达显著相关（P<0.05）。此外，DCLK1 的上调与 MPM 患者的不良预后相关（P=0.0235）。为了研究 DCLK1 是否是人类间皮瘤中 MET/ERK5 信号的下游，在人类间皮瘤细胞系中用 MET 抑制剂 XL184 或 ERK5 抑制剂 XMD8-92 处理后分析 DCLK1 表达的变化。我们的结果表明，MET 抑制剂 XL184 降低了人类间皮瘤细胞系中磷酸化 ERK5 和 DCLK1 的表达。此外，ERK5 抑制剂 XMD8-92 降低了人类间皮瘤细胞系中磷酸化 ERK5 和 DCLK1 的表达。此外，XL184 和 XMD8-92 处理损害了 H290 间皮瘤细胞的侵袭和肿瘤球体形成能力。这些结果表明，DCLK1 受人类间皮瘤中 MET/ERK5 信号的调节，并且 MET/ERK5/DCLK1 信号级联可能进一步开发成为针对间皮瘤的有前途的治疗靶标。
Zotero 插件
