Proprotein Convertase Subtilisin/ Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apo

2021-07-09 15:36

《Lung metastasis of gastric cancer》

Title：《Proprotein Convertase Subtilisin/ Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation》（译：《前蛋白转化酶枯草溶菌素 9 通过 HSP70 上调 MAPK 信号通路促进胃癌转移抑制细胞凋亡》）
Abstract：Objective: To examine the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) on gastric cancer (GC) progression and prognosis, and to explore the underlying mechanism. Methods PCSK9 expression levels in human GC tissues were determined by quantitative real-time PCR, western blotting, and immunohistochemical assay. PCSK9 serum levels were detected by enzyme-linked immunosorbent assay. The relationships of PCSK9 and GC progression and survival were analyzed using the Chi-square test, Kaplan-Meier analysis, and Cox proportional hazards model. The effect of PCSK9 on cell invasion, migration, and apoptosis were determined in human GC cell lines and mouse xenograft model separately using PCSK9 knockdown and overexpression strategies. The PCSK9 interacting molecules, screened by co-immunoprecipitation combined with LC-MS/MS, were identified by immunofluorescence localization and western blotting. Additionally, the mitogen-activated protein kinase (MAPK) pathway was assessed by western blotting. Results PCSK9 mRNA and protein levels were significantly elevated in GC tissues compared with the paired normal tissues at our medical center (P < 0.001). Notably, the up-regulation of PCSK9 expression in GC tissues was related to tumor progression and poor survival. GC patients had higher serum levels of PCSK9 than the age-matched healthy controls (P < 0.001); PCSK9 promoted invasive and migratory ability and inhibited apoptosis in GC cells with no apparent affection in cell proliferation. The silencing of PCSK9 reversed these effects, suppressing tumor metastasis in vitro and in vivo . Furthermore, PCSK9 maintained these functions through up-regulating heat shock protein 70 (HSP70), ultimately facilitating the mitogen-activated protein kinase (MAPK) pathway. Conclusion Collectively, our data revealed that high PCSK9 expression levels in GC tissue were correlated with GC progression and poor prognosis and that PCSK9 could promote GC metastasis and suppress apoptosis by facilitating MAPK signaling pathway through HSP70 up-regulation. PCSK9 may represent a novel potential therapeutic target in GC.（译：目的:探讨前蛋白转化酶枯草杆菌蛋白酶/可欣9型（PCSK9）对胃癌（GC）进展及预后的影响，并探讨其作用机制。方法:采用实时定量PCR、蛋白质印迹法和免疫组化法测定人胃癌组织中PCSK9的表达水平。PCSK9 血清水平通过酶联免疫吸附试验检测。使用卡方检验、Kaplan-Meier 分析和 Cox 比例风险模型分析 PCSK9 与 GC 进展和生存的关系。PCSK9 对细胞侵袭、迁移和凋亡的影响分别使用 PCSK9 敲低和过表达策略在人 GC 细胞系和小鼠异种移植模型中确定。通过免疫共沉淀结合 LC-MS/MS 筛选的 PCSK9 相互作用分子，通过免疫荧光定位和蛋白质印迹鉴定。此外，通过蛋白质印迹评估丝裂原活化蛋白激酶 (MAPK) 途径。结果与我们医疗中心的配对正常组织相比，GC组织中PCSK9 mRNA和蛋白质水平显着升高（P<0.001）。值得注意的是，GC 组织中 PCSK9 表达的上调与肿瘤进展和较差的存活率有关。GC 患者的 PCSK9 血清水平高于年龄匹配的健康对照（P < 0.001）；PCSK9促进GC细胞的侵袭和迁移能力并抑制细胞凋亡，对细胞增殖没有明显影响。PCSK9 的沉默逆转了这些效应，在体外和体内抑制了肿瘤转移。此外，PCSK9 通过上调热休克蛋白 70 (HSP70) 来维持这些功能，最终促进丝裂原活化蛋白激酶 (MAPK) 通路。结论总的来说，我们的数据表明，GC 组织中 PCSK9 的高表达水平与 GC 进展和不良预后相关，PCSK9 可以通过 HSP70 上调促进 MAPK 信号通路促进 GC 转移并抑制细胞凋亡。PCSK9 可能代表 GC 中一个新的潜在治疗靶点。我们的数据显示，GC 组织中 PCSK9 的高表达水平与 GC 进展和不良预后相关，并且 PCSK9 可以通过 HSP70 上调促进 MAPK 信号通路促进 GC 转移并抑制细胞凋亡。PCSK9 可能代表 GC 中一个新的潜在治疗靶点。我们的数据显示，GC 组织中 PCSK9 的高表达水平与 GC 进展和不良预后相关，并且 PCSK9 可以通过 HSP70 上调促进 MAPK 信号通路促进 GC 转移并抑制细胞凋亡。PCSK9 可能代表 GC 中一个新的潜在治疗靶点。）
Periodical：Frontiers in Oncology
Impact Factor: 4.848
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Researcher：Shuyu Li
Research unit：Department of Gastroenterology, Shanghai Zhongshan Hospital
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