RACK1 overexpression associates with pancreatic ductal adenocarcinoma growth and poor prognosis
RACK1 overexpression associates with pancreatic ductal adenocarcinoma growth and poor prognosis
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RACK1过度表达与胰腺导管腺癌生长和不良预后相关
DOI：
10.1016/j.yexmp.2016.08.001
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发表时间：
2016-10-01
影响因子：
3.6
通讯作者：
Wan, Chunhua
中科院分区：
文献类型：
--
作者：
Li, Xiaohong;Xiao, Ying;Wan, Chunhua
目的：活化蛋白激酶C受体（RACK1）是一种参与多种细胞内信号通路的支架蛋白。先前的研究表明，RACK1与多种癌症类型的进展有关，包括肝细胞癌和胃癌。然而，RACK1在人胰腺导管腺癌（PDAC）中的作用尚不清楚。方法：采用Western blot分析8对新鲜PDAC组织中RACK1的表达，并对179块石蜡包埋切片进行免疫组化。然后采用Fisher精确检验分析RACK1表达与临床病理特征的相关性。采用饥饿再饲喂法评价细胞周期。Western blot、CCK8、流式细胞术和菌落形成分析表明，RACK1在PDAC的发展中发挥了重要作用。Annexin-V/PI凋亡实验和western blot显示RACK1参与调控PDAC细胞凋亡。结果：RACK1在PDAC组织和细胞系中高表达，与多种临床病理因素显著相关。单因素和多因素分析表明，RACK1高表达是影响PDAC患者生存的独立预后因素。体外血清饥饿-再喂养实验表明，RACK1在增殖的PDAC细胞中表达上调，并与S期细胞比例上调，且与Cyclin D1表达相关。RACK1的过表达促进了PDAC细胞的增殖和细胞周期的进展，而RACK1的下调则导致PDAC细胞的生长障碍、G1/S细胞周期阻滞和凋亡。沉默RACK1可降低bcl-2表达，增加cleaved caspase3表达水平，诱导PDAC细胞凋亡。结论：我们的研究结果表明RACK1可能在PDAC的肿瘤发生中发挥重要作用，并可能成为PDAC治疗的潜在治疗靶点。(C) 2016 Elsevier Inc.版权所有。
Objectives: The receptor for activated protein kinase C (RACK1) is a scaffold protein involved in multiple intracellular signal pathways. Previous studies have shown that RACK1 is associated with the progression of multiple cancer types, including hepatocellular carcinoma and gastric cancer. However, the role of RACK1 in human pancreatic ductal adenocarcinoma (PDAC) remains unclear.Methods: In this study, the expression of RACK1 was evaluated by Western blot analysis in 8 paired fresh PDAC tissues and immunohistochemistry on 179 paraffin-embedded slices. Then, we used Fisher exact test to analyze the correlation between RACK1 expression and clinicopathological characteristics. Starvation and re-feeding assay was used to assess cell cycle. Western blot, CCK8, flow cytometry assays, and colony formation analyses demonstrated that RACK1 played an essential role in PDAC development. Annexin-V/PI apoptotic assay and western blot showed that RACK1 was involved in regulating the apoptosis of PDAC cells.Results: RACK1 was highly expressed in PDAC tissues and cell lines and was significantly associated with multiple clinicopathological factors. Univariate and multivariate analyses showed that high RACK1 expression was identified to be an independent prognostic factor for PDAC patients' survival. In vitro, serum starvation-refeeding-experiment suggested that RACK1 was upregulated in proliferating PDAC cells, together with the percentage of cells at the S phase, and was correlated with the expression of Cyclin D1. Moreover, Overexpression of RACK1 facilitated the proliferation and cell cycle progression of PDAC cells, while downregulation of RACK1 induced growth impairment, G1/S cell cycle arrest and apoptosis in PDAC cells. Silencing RACK1 decreased bcl-2 expression, increased cleaved caspase3 expression level and induced the apoptosis of PDAC cells.Conclusions: Our results suggest that RACK1 could play an important role in the tumorigenesis of PDAC and serve as a potential therapeutical target in PDAC treatment. (C) 2016 Elsevier Inc. All rights reserved.