PTEN lipid phosphatase inactivation links the hippo and PI3K/Akt pathways to induce gastric tumorigenesis.
PTEN lipid phosphatase inactivation links the hippo and PI3K/Akt pathways to induce gastric tumorigenesis.
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PTEN 脂质磷酸酶失活将 hippo 和 PI3K/Akt 通路联系起来，诱导胃肿瘤发生
DOI：
10.1186/s13046-018-0795-2
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发表时间：
2018-08-22
期刊：
影响因子：
--
通讯作者：
Lu N
中科院分区：
文献类型：
--
作者：
Xu W;Yang Z;Xie C;Zhu Y;Shu X;Zhang Z;Li N;Chai N;Zhang S;Wu K;Nie Y;Lu N
研究背景PTEN是一种重要的肿瘤抑制基因，其编码的蛋白兼具蛋白磷酸酶和脂磷酸酶的活性。然而，蛋白质磷酸酶活性的替代效应尚不清楚。PI3K/Akt是PTEN最常见的负调控通路。HIPPO和PI3K/Akt信号通路在调节细胞增殖和凋亡中起共同作用。因此，PTEN脂质磷酸酶失活在胃癌发生发展中的作用以及HIPPO和PI3K/Akt信号转导通路在PTEN脂质磷酸酶失活介导的胃癌发生发展中的作用还有待进一步研究。建立了稳定表达野生型或显性负性突变体PTEN的细胞系。采用四甲基偶氮唑蓝(MTT)法、BrdU比色法、集落形成法、Transwell法和高含量分析法检测稳定细胞的体外增殖和迁移情况，并观察裸鼠移植瘤生长的差异。免疫印迹法检测河马和Akt信号通路中关键分子表达的变化。采用核浆分离、免疫荧光和免疫共沉淀法检测稳定细胞系中河马蛋白的表达。结果PTEN脂磷酸酶失活在体外可显著促进胃癌细胞的增殖和迁移，促进体内肿瘤生长。胃癌组织的免疫组织化学分析显示，磷酸化的PTEN与核YAP的表达显著相关，两者都被确定为胃癌的独立预后因素。机制上，PTEN脂磷酸酶失活可阻断MOB1-LATS1/2相互作用，降低YAP的磷酸化，最终促进YAP的核转位，从而增强YAP-TEAD的协同作用，从而诱导细胞增殖和迁移。此外，PTEN脂磷酸酶失活促进了PI3K/Akt通路的激活，YAP-tead驱动的转录中断以剂量依赖的方式降低了Akt的激活。结论PTEN脂磷酸酶失活共同促进了HIPPO和PI3K/Akt通路，促进了胃癌的发生和发展。
BackgroundPhosphatase and tensin homolog (PTEN) is an important tumor suppressor gene, and its encoded protein has activities of both a protein phosphatase and a lipid phosphatase. However, the substitution effect of protein phosphatase activity remains unclear. PI3K/Akt is the most common pathway negatively regulated by PTEN. The Hippo and PI3K/Akt pathways have a joint effect in regulating cell proliferation and apoptosis. Therefore, how PTEN lipid phosphatase inactivation contributes to the occurrence and development of gastric cancer and the potential role of the Hippo and PI3K/Akt pathways in PTEN lipid phosphatase inactivation mediated gastric tumorigenesis remain to be explored.MethodsImmunohistochemical staining was performed to detect the expression of p-PTEN and YAP in a gastric cancer tissue microarray. Stable cell lines expressing a wild-type or dominant-negative mutant PTEN were established. The proliferation and migration of stable cells were detected by MTT, BrdU, and colony-formation, transwell assay and high content analysis in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the Hippo and Akt signaling pathways were detected by western blot. Nuclear-cytoplasm separation, immunofluorescence and coimmunoprecipitation analyses were conducted to explore the dysregulation of Hippo in the stable cell lines.ResultsPTEN lipid phosphatase inactivation strongly promoted the proliferation and migration of gastric cancer cells in vitro and tumor growth in vivo. A immunohistochemical analysis of gastric cancer tissues revealed a significant correlation between phosphorylated PTEN and nuclear YAP expression, and both were determined to be independent prognostic factors for gastric cancer. Mechanistically, PTEN lipid phosphatase inactivation abolished the MOB1-LATS1/2 interaction, decreased YAP phosphorylation and finally promoted YAP nuclear translocation, which enhanced the synergistic effect of YAP-TEAD, thus inducing cell proliferation and migration. Moreover, PTEN lipid phosphatase inactivation promoted the PI3K/Akt pathway, and disruption of YAP-TEAD-driven transcription decreased the activation of Akt in a dose-dependent manner.ConclusionsTaken together, our findings indicate that PTEN lipid phosphatase inactivation links the Hippo and PI3K/Akt pathways to promote gastric tumorigenesis and cancer development.
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影响因子：
24.5
作者：
Deng N;Goh LK;Wang H;Das K;Tao J;Tan IB;Zhang S;Lee M;Wu J;Lim KH;Lei Z;Goh G;Lim QY;Tan AL;Sin Poh DY;Riahi S;Bell S;Shi MM;Linnartz R;Zhu F;Yeoh KG;Toh HC;Yong WP;Cheong HC;Rha SY;Boussioutas A;Grabsch H;Rozen S;Tan P
通讯作者：
Tan P
影响因子：
64.8
作者：
通讯作者：
--
YAP 1 过度表达导致人膀胱尿路上皮癌的进展特征和不良预后
影响因子：
3.8
作者：
Liu JY;Li YH;Lin HX;Liao YJ;Mai SJ;Liu ZW;Zhang ZL;Jiang LJ;Zhang JX;Kung HF;Zeng YX;Zhou FJ;Xie D
通讯作者：
Xie D
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5
作者：
Kang, YH;Lee, HS;Kim, WH
通讯作者：
Kim, WH