Growth factor progranulin promotes tumorigenesis of cervical cancer via PI3K/Akt/mTOR signaling pathway.
Growth factor progranulin promotes tumorigenesis of cervical cancer via PI3K/Akt/mTOR signaling pathway.
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生长因子颗粒体蛋白前体通过PI3K/Akt/mTOR信号通路促进宫颈癌发生
DOI：
10.18632/oncotarget.11126
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发表时间：
2016-09-06
期刊：
影响因子：
--
通讯作者：
Tang W
中科院分区：
文献类型：
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作者：
Feng T;Zheng L;Liu F;Xu X;Mao S;Wang X;Liu J;Lu Y;Zhao W;Yu X;Tang W
颗粒体蛋白前体 (PGRN) 是一种自分泌生长因子，在包括宫颈癌在内的多种肿瘤中具有致瘤作用。在这项研究中，我们研究了哺乳动物雷帕霉素靶点 (mTOR) 信号对 PGRN 诱导的反应，以及 PGRN 刺激的 PI3K/Akt/mTOR 信号通路在宫颈癌转化和进展中的贡献。在这里，我们发现了宫颈癌组织中 PGRN 和磷酸化 mTOR 之间的紧密联系。 PGRN促进人宫颈粘膜上皮细胞和宫颈癌细胞中mTOR的磷酸化并激活mTOR信号传导，而PGRN刺激的mTOR信号传导需要TNFR2。用雷帕霉素抑制 mTOR 信号传导可减少 PGRN 刺激的蛋白质合成、体外宫颈细胞的转化和增殖，以及体内肿瘤的形成和生长。因此，我们的研究结果表明 mTOR 信号传导有助于 PGRN 刺激的宫颈癌发生，从而更新了 PGRN 的信号转导途径。抑制 PGRN/PI3K/Akt/mTOR 信号传导可能是宫颈癌治疗的目标。
Progranulin (PGRN) is an autocrine growth factor with tumorigenic roles in various tumors including cervical cancer. In this study, we investigated mammalian target of rapamycin (mTOR) signaling in response to PGRN induction and the contribution of the PGRN-stimulated PI3K/Akt/mTOR signaling pathway in the transformation and progression of cervical cancer. Here we identified a strong linkage between PGRN and phosphorylated-mTOR in cervical cancer tissues. PGRN promoted the phosphorylation of mTOR and activated mTOR signaling in human cervical mucosa epithelial cells and cervical cancer cells, and TNFR2 was needed for PGRN-stimulated mTOR signaling. Inhibition of mTOR signaling with rapamycin decreased PGRN-stimulated protein synthesis, transformation and proliferation of cervical cells in vitro, and tumor formation and growth in vivo. Thus, our findings update the signal transduction pathways of PGRN by suggesting that mTOR signaling contributes to PGRN-stimulated carcinogenesis of cervical cancer. Inhibition of PGRN/PI3K/Akt/mTOR signaling may be targeted in treatment of cervical cancer.