Rhophilin-2 Upregulates Glutamine Synthetase by Stabilizing c-Myc Protein and Confers Resistance to Glutamine Deprivation in Lung Cancer.
Rhophilin-2 Upregulates Glutamine Synthetase by Stabilizing c-Myc Protein and Confers Resistance to Glutamine Deprivation in Lung Cancer.
复制标题
Rhophilin-2 通过稳定 c-Myc 蛋白上调谷氨酰胺合成酶并赋予肺癌对谷氨酰胺剥夺的抵抗力
DOI：
10.3389/fonc.2020.571384
复制
发表时间：
2020
影响因子：
4.7
通讯作者：
He J
中科院分区：
文献类型：
--
作者：
Xiao D;He J;Guo Z;He H;Yang S;Huang L;Pan H;He J
RHPN2是Rho结合蛋白家族中的一员，调节肌动蛋白的细胞骨架和囊泡运输，并促进肿瘤的间质转化。我们发现RHPN2在肺腺癌(LUAD)中发生了显著的突变。然而，RHPN2在肺癌中的作用尚不完全清楚。本研究采用定量逆转录聚合酶链式反应(qRT-PCR)方法检测125例LUAD患者中RHPN2的表达，并探讨其表达与临床特征的关系。采用CCK-8法、体外Transwell法、克隆形成法和小鼠移植瘤模型检测RHPN2对肺癌细胞增殖和侵袭能力的影响。用RhoA下拉实验和Western blotting分析RNPN_2在肺癌发生中的作用。RHPN2在LUAD的肿瘤中高表达，且高水平与LUAD患者的预后不良有关。RHPN2是肺癌细胞增殖和侵袭所必需的。有趣的是，RHPN2的过表达增强了肺癌细胞对谷氨酰胺耗竭的抵抗力。机制研究表明，RHPN2的异位过表达通过磷酸化Ser62促进了c-Myc蛋白的稳定性，并增加了c-Myc靶向谷氨酰胺合成酶(GS)。对临床标本中GS表达的分析表明，GS在肿瘤细胞中表达上调。Kaplan-Meier分析显示，高水平的GS与LUAD患者的总体生存时间显著相关。综上所述，本研究提示RHPN2可能通过调节c-Myc的稳定性及其靶基因GS在肺腺癌中的表达而参与肺癌的发生。
RHPN2, a member of rhophilin family of rho-binding proteins, regulates actin cytoskeleton and vesicular trafficking, and promotes mesenchymal transformation in cancer. We have found that RHPN2 was significantly mutated in lung adenocarcinoma (LUAD). However, the role of RHPN2 in lung cancer is not fully understood. In the present study, we investigated the expression of RHPN2 in 125 patients with LUAD by qRT-PCR and correlated its expression with clinical characteristics. The effects of RHPN2 on the proliferation and invasion of lung cancer cells were determined by CCK-8 and in vitro transwell assays, clonogenic assay, and xenograft mouse model. The RhoA pull down assay and Western blotting were performed to elucidate the mechanism of RNPN2 in tumorigenesis of lung cancer. RHPN2 was overexpressed in tumors from LUAD, and high levels of RHPN2 were associated with poor prognosis of LUAD patients. RHPN2 was required for proliferation and invasion of lung cancer cells. Intriguingly, overexpression of RHPN2 conferred the resistance to glutamine depletion in lung cancer cells. Mechanistic studies revealed that ectopic overexpression of RHPN2 promoted the stability of c-Myc protein via phosphorylation at Ser62 and increased c-Myc target glutamine synthetase (GS). Analysis of GS expression in clinical sample showed that the expression of GS was elevated in tumor cells. Kaplan-Meier analysis revealed that high levels of GS were significantly associated with worse overall survival time of the patients with LUAD. Taken together, this study suggested that RHPN2 was involved in tumorigenesis of lung cancer via modulating c-Myc stability and the expression of its target GS in lung adenocarcinoma, which links RHPN2 and glutamine metabolism.
登录
查看更多内容
影响因子：
30.8
作者：
Palomero, Teresa;Couronne, Lucile;Khiabanian, Hossein;Kim, Mi-Yeon;Ambesi-Impiombato, Alberto;Perez-Garcia, Arianne;Carpenter, Zachary;Abate, Francesco;Allegretta, Maddalena;Haydu, J. Erika;Jiang, Xiaoyu;Lossos, Izidore S.;Nicolas, Concha;Balbin, Milagros;Bastard, Christian;Bhagat, Govind;Piris, Miguel A.;Campo, Elias;Bernard, Olivier A.;Rabadan, Raul;Ferrando, Adolfo A.
通讯作者：
Ferrando, Adolfo A.
影响因子：
50.3
作者：
Cortes JR;Ambesi-Impiombato A;Couronné L;Quinn SA;Kim CS;da Silva Almeida AC;West Z;Belver L;Martin MS;Scourzic L;Bhagat G;Bernard OA;Ferrando AA;Palomero T
通讯作者：
Palomero T
影响因子：
21.3
作者：
Cox AG;Hwang KL;Brown KK;Evason K;Beltz S;Tsomides A;O'Connor K;Galli GG;Yimlamai D;Chhangawala S;Yuan M;Lien EC;Wucherpfennig J;Nissim S;Minami A;Cohen DE;Camargo FD;Asara JM;Houvras Y;Stainier DYR;Goessling W
通讯作者：
Goessling W
影响因子：
8
作者：
Cadoret, A;Ovejero, C;Perret, C
通讯作者：
Perret, C
影响因子：
4.2
作者：
Medina, MA
通讯作者：
Medina, MA