CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer.
CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer.
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CENPH 通过调节结直肠癌中 GOLPH3 依赖性 mTOR 信号通路抑制雷帕霉素敏感性
DOI：
10.7150/jca.19940
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发表时间：
2017
影响因子：
3.9
通讯作者：
Su X
中科院分区：
文献类型：
--
作者：
Wu W;Wu F;Wang Z;Di J;Yang J;Gao P;Jiang B;Su X
背景：着丝粒蛋白 H (CENPH) 被认为是活性着丝粒复合体的基本组成部分，其过度表达与各种实体瘤的不良预后相关。 mTOR 抑制剂雷帕霉素已被证明具有抗肿瘤活性，并能预防肠道肿瘤发生。然而，CENPH 在结直肠癌 (CRC) 中的预后价值以及 CENPH 在雷帕霉素敏感性中的作用仍不清楚。材料和方法：通过 MTT 和/或集落形成测定评估 CENPH 对 CRC 中细胞增殖、克隆形成和细胞对雷帕霉素反应的影响。对于潜在机制，通过免疫共沉淀、GST Pull-down 和 His-tag Pull-down 测定以及激光扫描共聚焦显微镜检测 CENPH 和 GOLPH3 之间的相互作用。 mTOR 信号传导中激酶的状态通过蛋白质印迹确定。最后，使用包含 CENPH 转录本和临床信息的公共 CRC 数据集分析了 CENPH 的临床意义。结果：CENPH 抑制 CRC 恶性表型，降低对雷帕霉素的敏感性，并通过与高尔基体磷蛋白 3 (GOLPH3) 相互作用减弱 mTOR 信号通路中的 mTORC1 和 mTORC2，高尔基体磷蛋白 3 (GOLPH3) 已被确定为潜在的癌基因并调节对雷帕霉素的反应。此外，与正常结直肠组织相比，结直肠癌组织中检测到的 CENPH 水平升高。根据 CRC 肿瘤分期，高水平的 CENPH 表达逐渐降低。 CENPH 高表达的患者具有良好的生存率。结论：我们的结果表明，CENPH 通过调节 GOLPH3 依赖性 mTOR 通路来抑制雷帕霉素敏感性。高 CENPH 表达与 CRC 患者更好的预后相关。综上所述，CENPH 可以作为 CRC 患者雷帕霉素敏感性和治疗靶点的潜在预测因子。
Background: Centromere protein H (CENPH) is known as a fundamental component of the active centromere complex, and its overexpression is correlated with poor prognosis in various solid tumors. mTOR inhibitor rapamycin has been shown to possess antitumor activity, as well as prevent intestinal tumorigenesis. However, the prognostic value of CENPH in colorectal cancer (CRC) and the role of CENPH in rapamycin sensitivity remain unknown. Materials and methods: The effect of CENPH on the cell proliferation, clonogenicity, and cell response to rapamycin in CRC were evaluated by MTT and/or colony formation assays. For the underlying mechanisms, the interaction between CENPH and GOLPH3 were detected by co-immunoprecipitation, GST pull-down, and His-tag pull-down assays, as well as the laser scanning confocal microscopy. The status of kinases in mTOR signaling was determined by Western blot. Finally, the clinical significance of CENPH was analyzed using public CRC datasets with CENPH transcripts and clinical information. Results: CENPH inhibited CRC malignant phenotypes, conferred reduced sensitivity to rapamycin, and attenuated both mTORC1 and mTORC2 in mTOR signaling pathway through the interaction with golgi phosphoprotein 3 (GOLPH3), which has been identified as a potential oncogene and modulates the response to rapamycin. Moreover, elevated levels of CENPH were detected in CRC tissues, compared with normal colorectal tissues. High levels of CENPH expression gradually decreased according to CRC tumor stages. Patients with high CENPH expression had favorable survival. Conclusions: Our results suggest that CENPH inhibits rapamycin sensitivity by regulating GOLPH3 dependent mTOR pathway. High CENPH expression is associated with better prognosis in CRC patients. Taken together, CENPH may serve as a potential predictor for rapamycin sensitivity and therapeutic target for CRC patients.
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