Golgi phosphoprotein 3 induces autophagy and epithelial-mesenchymal transition to promote metastasis in colon cancer.
Golgi phosphoprotein 3 induces autophagy and epithelial-mesenchymal transition to promote metastasis in colon cancer.
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高尔基体磷蛋白3诱导自噬和上皮-间质转化促进结肠癌转移
DOI：
10.1038/s41420-022-00864-2
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发表时间：
2022-02-21
影响因子：
7
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Gong LY;Tu T;Zhu J;Hu AP;Song JW;Huang JQ;Yang Y;Zhu Z;Chen Y
本研究旨在探讨高尔基体磷蛋白3（Golgi phosphoprotein 3，GOLPH 3）是否以及如何通过调节自噬和上皮-间质转化（epithelial-mesenchymal transition，EMT）促进结肠癌转移。使用蛋白质印迹、免疫组织化学、transwell、伤口愈合和斑马鱼测定分析GOLPH 3在结肠癌转移中的作用。通过RNA测序（RNA-seq）分析、mRFP-GFP-LC 3报告基因测定及其相关标志物评估自噬和EMT。结肠癌临床和病理分期与预后不良之间存在显著相关性。GOLPH 3在体外和体内均促进结肠癌转移。GOLPH 3过表达和对照细胞模型的RNA-seq分析显示，GOLPH 3增强EMT和自噬。此外，检查GOLPH 3过表达，沉默，和控制细胞系中的自噬，上皮和间充质标志物显示，GOLPH 3促进EMT和自噬。当自噬被抑制时，GOLPH 3促进的转移和EMT在体外和体内被抵消。使用RNA-seq，PI 3 K/Akt信号传导被鉴定为GOLPH 3作用的关键下游通路。从机制上讲，我们证明GOLPH 3通过抑制蛋白激酶B（Akt）在Ser 473的磷酸化来刺激自噬并诱导EMT。总之，GOLPH 3诱导自噬和EMT，促进结肠癌的转移。除此之外，与传统观点相反，我们发现GOLPH 3抑制Akt在Ser 473的磷酸化。
In this study, we aimed to investigate whether and how Golgi phosphoprotein 3 (GOLPH3) facilitates colon cancer metastasis via the regulation of autophagy and epithelial–mesenchymal transition (EMT). The role GOLPH3 plays in colon cancer metastasis was analyzed using western blotting, immunohistochemistry, transwell, wound-healing, and zebrafish assays. Autophagy and EMT were assessed via RNA-sequencing (RNA-seq) analysis, mRFP-GFP-LC3 reporter assays, and their related markers. Significant associations were found between colon cancer clinical and pathological stages and poor prognosis. GOLPH3 facilitates colon cancer metastasis, both in vitro and in vivo. RNA-seq analysis of GOLPH3-overexpressing and control cell models revealed that GOLPH3 enhances EMT and autophagy. Moreover, examination of autophagic, epithelial, and mesenchymal markers in GOLPH3-overexpressing, -silenced, and control cell lines revealed that GOLPH3 promotes EMT and autophagy. When autophagy was inhibited, GOLPH3-promoted metastasis and EMT were counteracted in vitro and in vivo. Using RNA-seq, PI3K/Akt signaling was identified as the key downstream pathway on which GOLPH3 acts. Mechanistically, we demonstrated that GOLPH3 stimulates autophagy and induces EMT via the suppression of the phosphorylation of protein kinase B (Akt) at Ser473. In summary, GOLPH3 induces autophagy and EMT, promoting metastasis in colon cancer. Beyond this, and in contrast to conventional perspectives, we discovered that GOLPH3 represses the phosphorylation of Akt at Ser473.
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影响因子：
4
作者：
Brown M;Strudwick N;Suwara M;Sutcliffe LK;Mihai AD;Ali AA;Watson JN;Schröder M
通讯作者：
Schröder M
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
3.3
作者：
Lin, Yi-Chia;Lin, Ji-Fan;Hwang, Thomas I-Sheng
通讯作者：
Hwang, Thomas I-Sheng
影响因子：
3
作者：
Mehnert, Janice M.;Kaveney, Amanda D.;Stein, Mark N.
通讯作者：
Stein, Mark N.
影响因子：
2.9
作者：
Gassmann, Max;Grenacher, Beat;Vogel, Johannes
通讯作者：
Vogel, Johannes