A low amino acid environment promotes cell macropinocytosis through the YY1-FGD6 axis in Ras-mutant pancreatic ductal adenocarcinoma
A low amino acid environment promotes cell macropinocytosis through the YY1-FGD6 axis in Ras-mutant pancreatic ductal adenocarcinoma
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低氨基酸环境通过 Ras 突变型胰腺导管腺癌中的 YY1-FGD6 轴促进细胞巨胞饮作用
DOI：
10.1038/s41388-021-02159-9
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发表时间：
2022-01
期刊：
影响因子：
8
通讯作者：
Huizhen Nie
中科院分区：
文献类型：
--
作者：
Yifan Zhang;Qing Li;Pei-Qi Huang;Tong Su;Shu-Heng Jiang;Yue Sun;Li-peng Hu;Xueli Zhang;Xiao-mei Yang;Jun Li;Hong Pan;Lei Zhu;Lin-Li Yao;Dongxue Li;Yan-zhi Gai;Yong-Wei Sun;Zhi-Gang Zhang;De-Jun Liu;Yanli Zhang;Huizhen Nie
胰腺导管腺癌（PDAC）是一种死亡率高、KRAS突变率最高的癌症，据报道，PDAC通过巨胞饮作用使蛋白质内化，以适应肿瘤微环境中的低氨基酸水平。在这里，我们的目的是确定一个关键的调节巨胞饮的肿瘤细胞在PDAC中的低氨基酸环境中的生存。FYVE、RhoGEF和含PH结构域的蛋白6（FGD 6）被鉴定为巨胞饮的关键调节剂。FGD 6在体外和体内均促进PDAC细胞增殖、巨胞饮和肿瘤生长。PDAC细胞系中的巨胞饮水平随着FGD 6敲低而降低。此外，FGD 6通过参与trans-Golgi网络和增强生长因子受体，特别是TGF-β受体的膜定位来促进巨胞饮。TGF-β增强PDAC细胞中的巨胞饮作用。此外，由低氨基酸肿瘤环境诱导的雅普核转位通过与YY 1共激活启动FGD 6表达。基于TCGA和GEO数据集的临床数据分析显示，PDAC组织中FGD 6表达上调，并且FGD 6高表达与PDAC患者的不良预后相关。在KrasG 12 D/+/Trp 53 R172 H/−/Pdx 1-Cre（KPC）小鼠的肿瘤组织中，FGD 6表达在PDAC发展期间增加。我们的研究结果揭示了一个以前不受重视的机制，大胞饮在PDAC。靶向FGD 6和生长因子膜定位的策略可能被开发用于治疗PDAC。
Pancreatic ductal adenocarcinoma (PDAC), cancer with a high mortality rate and the highest rate ofKRASmutation, reportedly internalizes proteins via macropinocytosis to adapt to low amino acid levels in the tumor microenvironment. Here, we aimed to identify a key regulator of macropinocytosis for the survival of tumor cells in a low amino acid environment in PDAC. FYVE, RhoGEF, and PH domain-containing protein 6 (FGD6) were identified as key regulators of macropinocytosis. FGD6 promoted PDAC cell proliferation, macropinocytosis, and tumor growth both in vitro and in vivo. The macropinocytosis level was decreased with FGD6 knockdown in PDAC cell lines. Moreover, FGD6 promoted macropinocytosis by participating in thetrans-Golgi network and enhancing the membrane localization of growth factor receptors, especially the TGF-beta receptor. TGF-beta enhanced macropinocytosis in PDAC cells. Additionally, YAP nuclear translocation induced by a low amino acid tumor environment initiated FGD6 expression by coactivation with YY1. Clinical data analysis based on TCGA and GEO datasets showed that FGD6 expression was upregulated in PDAC tissue, and high FGD6 expression was correlated with poor prognosis in patients with PDAC. In tumor tissue from KrasG12D/+/Trp53R172H/−/Pdx1-Cre (KPC) mice, FGD6 expression escalated during PDAC development. Our results uncover a previously unappreciated mechanism of macropinocytosis in PDAC. Strategies to target FGD6 and growth factors membrane localization might be developed for the treatment of PDAC.
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影响因子：
2
作者：
R. Dmochowski
通讯作者：
R. Dmochowski
DOI：
10.1016/j.respe.2020.09.004
发表时间：
2020-10-10
期刊：
Revue D'Epidemiologie et De Sante Publique
影响因子：
--
作者：
La rédaction
通讯作者：
La rédaction
影响因子：
9.3
作者：
通讯作者：
--
影响因子：
5.9
作者：
Craighead FL
通讯作者：
Craighead FL