Gastrokine 1 induces senescence through p16/Rb pathway activation in gastric cancer cells
Gastrokine 1 induces senescence through p16/Rb pathway activation in gastric cancer cells
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DOI：
10.1136/gut.2010.230623
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发表时间：
2012-01-01
期刊：
影响因子：
24.5
通讯作者：
Lu, Youyong
中科院分区：
文献类型：
--
作者：
Xing, Rui;Li, Wenmei;Lu, Youyong
背景和目的 Gastrokine 1 (GKN1) 是一种胃特异性蛋白质，通常在胃粘膜中表达，但在原发性肿瘤和细胞系中不表达。基于这一证据，推测 GKN1 可能在胃癌的发展中发挥作用；然而，其功能和分子机制尚不清楚。结合多种方法开展系统研究，明确GKN1在胃癌细胞中的分子机制。方法采用蛋白质组学、Western blotting和免疫组化技术检测GKN1的表达水平。采用蛋白质印迹法结合免疫荧光来监测该蛋白的分泌过程。随后，我们对GKN1的功能和分子机制进行了体外和体内研究。结果表明，GKN1是一种自分泌/旁分泌蛋白，可抑制由于p16/Rb和p21(waf)通路激活导致的衰老引起的细胞生长。此外，GKN1治疗后，胃癌细胞和异种移植裸鼠模型中Ras/Raf/MEK/ERK信号持续激活。结论这些结果为GKN1诱导胃癌细胞衰老提供了全面的分子证据，并表明GKN1可能是胃癌治疗的潜在新靶点。
Background and aims Gastrokine 1 (GKN1) is a stomach-specific protein that is normally expressed in gastric mucosa but not in primary tumours and cell lines. Based on this evidence, it was presumed that GKN1 might play a role in gastric cancer development; however, its function and molecular mechanism are not clear. A systematic study was initiated that combined multiple approaches to define the molecular mechanism of GKN1 in gastric cancer cells.Method Proteomics, western blotting and immunohistochemistry were used to measure the expression level of GKN1. Western blotting combined with immunofluorescence was used to monitor the secretory process of this protein. Subsequently, the function and molecular mechanism of GKN1 was explored in vitro and in vivo.Results It was shown that GKN1 is an autocrine/paracrine protein and inhibits cell growth due to senescence, which resulted from activation of p16/Rb and p21(waf) pathways. Furthermore, sustained activation of Ras/Raf/MEK/ERK signalling was characterised in gastric cancer cells and a xenograft nude mouse model following GKN1 treatment.Conclusion These results provide comprehensive molecular evidence of GKN1 in inducing senescence of gastric cancer cells, and indicate that GKN1 might be a potential novel target for gastric cancer therapeutics.