YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation.
YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation.
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DOI：
10.1093/procel/pwac011
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发表时间：
2023-04-13
期刊：
影响因子：
21.1
通讯作者：
Cao, Cong
中科院分区：
文献类型：
--
作者：
Liu, Fang;Chen, Gang;Zhou, Li-Na;Wang, Yin;Zhang, Zhi-qing;Qin, Xihu;Cao, Cong
识别新的胶质瘤驱动信号分子并探索相应的分子靶向治疗对于更好、更有效地治疗胶质瘤至关重要。YME1L （YME1 Like 1 ATPase）是atp酶AAA家族的主要成员，位于线粒体内膜（Anand et al., 2014; MacVicar et al., 2019; Ohba et al., 2020）。YME1L对于维持线粒体形态、功能和可塑性至关重要（Anand等人，2014；MacVicar等人，2019；Ohba等人，2020）。YME1L在线粒体内膜内组装成寡聚物（Anand et al., 2014; MacVicar et al., 2019; Ohba et al., 2020）。此外，YME1L可以降解线粒体蛋白，包括脂质转移蛋白、IM易位蛋白和动力蛋白样GTPase optic atrophy 1 (OPA1)（Anand等，2014；MacVicar等，2019；Ohba等，2020）。YME1L耗损加速了依赖oma1的长型OPA1裂解，导致短型OPA1积累，增加了线粒体裂变和线粒体断裂（Wai et al., 2015）。YME1L控制呼吸链亚基的积累，是凋亡抵抗、嵴形态发生和细胞增殖所必需的（Stiburek et al., 2012）。ymel介导的线粒体重塑是胰腺导管腺癌细胞生长所必需的（MacVicar等，2019）。相反，YME1L沉默或敲除会破坏线粒体功能，抑制PDAC细胞生长（MacVicar等，2019）。然而，YME1L在胶质瘤中的表达及其潜在功能尚未被研究。Gαi蛋白，或鸟嘌呤核苷酸结合蛋白G (i)亚基α，有三个亚基，Gαi1， Gαi2和Gαi3 （Fan et al., 2011）。本小组已经确定了Gαi蛋白在多受体酪氨酸激酶（RTKs）转导信号中的重要作用（Cao等，2009；Zhang等，2015；Liu等，2018；Marshal等，2018；Sun等，2018；Bai等，2021；Wang等，2021）。与配体激活的RTKs相关的Gαi蛋白，是下游致癌信号转导所必需的，包括磷脂酰肌醇-3激酶(PI3K)- akt -哺乳动物雷帕霉素靶点（mTOR）和细胞外信号调节激酶(Erk)-丝裂原活化蛋白激酶（MAPK）级联（Cao等，2009；Zhang等，2015；Liu等，2018；Marshall等，2018；Sun等，2018；Bai等，2021；Wang等，2021）。g - αi过表达对于胶质瘤和其他癌症的进展也是必不可少的（Liu et al., 2018; Lv et al., 2021; Wang et al., 2021）。在本研究中，我们将证明YME1L过表达通过促进g - αi1表达和Akt激活在胶质瘤中发挥促瘤活性。首先，首先参考癌症基因组图谱（TCGA）数据库检索人类胶质瘤中的YME1L RNA测序数据。如图所示，在人类胶质瘤组织（“Tumor”，n= 166）中，YME1L mRNA转录本的数量显著高于正常脑组织（“normal”，n= 1157）（P< 0.001，图1A）。在正常脑组织中，从基因型组织表达（GTEx）数据库中检索了1152个组织，从TCGA数据库（肿瘤周围正常脑组织）中检索了5个组织（图2）。1)。基于临床特征的亚组分析显示，人胶质瘤组织中YME1L mRNA的高表达与IDH（异柠檬酸脱氢酶）突变相关（P< 0.001，图1B）。与患者的年龄（图1C）和性别（图1D）无关。为了证实生物信息学观察的意义，我们检测了YME1L在局部人类胶质瘤组织（“T”）和周围脑组织中的表达。
Identifying novel glioma-driven signaling molecules and exploring the corresponding molecularly targeted therapies are essential for better and efficient glioma therapy. YME1L (YME1 Like 1 ATPase), a primary member of the AAA family of ATPase, is located at the inner mitochondrial membrane (Anand et al., 2014; MacVicar et al., 2019; Ohba et al., 2020). YME1L is essential for maintaining mitochondrial morphology, function, and plasticity (Anand et al., 2014; MacVicar et al., 2019; Ohba et al., 2020). YME1L assembles into a homo-oligomeric complex within the inner mitochondrial membrane (Anand et al., 2014; MacVicar e t al., 2019; Ohba et al., 2020). Moreover, YME1L can degrade mitochondrial proteins, including lipid-transferring proteins, IM translocation proteins, and the dynamin-like GTPase optic atrophy 1 (OPA1)(Anand et al., 2014; MacVicar et al., 2019; Ohba et al., 2020). YME1L depletion accelerated OMA1-dependent long-form OPA1 cleavage, resulting in short-form OPA1 accumulation, increased mitochondrial fission, and mitochondrial fragmentations (Wai e t al., 2015). YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation (Stiburek et al., 2012). YME1L-mediated mitochondrial reshaping is required for the growth of pancreatic ductal adenocarcinoma cells (MacVicar et al., 2019). Conversely, YME1L silencing or knockout disrupted mitochondrial functions and inhibited PDAC cell growth (MacVicar et al., 2019). Nevertheless, the expression and potential functions of YME1L in human glioma have not been studied. Gαi proteins, or guanine nucleotide-binding protein G (i) subunit alpha, have three subunits, Gαi1, Gαi2, and Gαi3 (Fan et al., 2011). Our group has identified an essential role of Gαi proteins in transducing signals by multiple receptor tyrosine kinases (RTKs)(Cao et al., 2009; Zhang et al., 2015; Liu et al., 2018; Marshal l et al., 2018; Sun et al., 2018; Bai et al., 2021; Wang et al., 2021). Gαi proteins associated with ligand-activated RTKs, required for the transduction of downstream oncogenic signalings, including phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (Erk)-mitogen-activated protein kinase (MAPK) cascades (Cao e t al., 2009; Zhang et al., 2015; Liu et al., 2018; Marshall et al., 2018; Sun et al., 2018; Bai et al., 2021; Wang et al., 2021). Gαi overexpression is also essential for the progression of glioma and other cancers (Liu et al., 2018; Lv et al., 2021; Wang et al., 2021). In this study, we will show that YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation. First, The Cancer Genome Atlas (TCGA) database was first consulted to retrieve YME1L RNA sequencing data in human glioma. As shown, in the human glioma tissues (“Tumor,” n= 166), the number of YME1L mRNA transcripts is significantly higher than that in the normal brain tissues (“Normal,” n= 1,157)(P< 0.001, Fig. 1A). Of the normal brain tissues, 1,152 of them were retrieved from the Genotype-Tissue Expression (GTEx) database and five tissues were from TCGA database (tumor-surrounding normal brain tissues)(Fig. 1A). The subgroup analyses based on clinical characteristics showed that high YME1L mRNA expression in human glioma tissues was correlated with IDH (isocitrate dehydrogenase) mutation (P< 0.001, Fig. 1B). It was not correlated with age (Fig. 1C) and sex (Fig. 1D) of the patients. To confirm the significance of the bioinformatics observations, we tested YME1L expression in local human glioma tissues (“T”) and surrounding …
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DOI：
10.1016/j.bbamcr.2011.01.012
发表时间：
2011-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Fan H;Li P;Zingarelli B;Borg K;Halushka PV;Birnbaumer L;Cook JA
通讯作者：
Cook JA
G α i1 和 G α i3 介导 VEGF 诱导的 VEGFR2 内吞作用、信号传导和血管生成
影响因子：
12.4
作者：
Sun J;Huang W;Yang SF;Zhang XP;Yu Q;Zhang ZQ;Yao J;Li KR;Jiang Q;Cao C
通讯作者：
Cao C
影响因子：
56.9
作者：
Wai, Timothy;Garcia-Prieto, Jaime;Langer, Thomas
通讯作者：
Langer, Thomas
影响因子：
6.5
作者：
Zhang, Yi-ming;Zhang, Zhi-qing;Cao, Cong
通讯作者：
Cao, Cong
白介素 4 诱导的信号传导、巨噬细胞 M2 极化和过敏性哮喘反应中 G α i1 和 G α i3 的需要
影响因子：
12.4
作者：
Bai JY;Li Y;Xue GH;Li KR;Zheng YF;Zhang ZQ;Jiang Q;Liu YY;Zhou XZ;Cao C
通讯作者：
Cao C