Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis.
Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis.
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Akt 激酶 LANCL2 是 EGFR 突变型肺腺癌肿瘤发生的关键驱动因素
DOI：
10.1038/s41419-021-03439-8
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发表时间：
2021-02-10
影响因子：
9
通讯作者：
Han B
中科院分区：
文献类型：
--
作者：
Lou Y;Xu J;Zhang Y;Zhang W;Zhang X;Gu P;Zhong H;Wang H;Lu J;Han B
表皮生长因子受体（Epidermal growth factor receptor，EGFR）是肺腺癌（lung adenocarcinoma，LUAD）的关键癌基因。EGFR酪氨酸激酶抑制剂耐药是EGFR突变LUAD患者的主要障碍。我们的基因芯片阵列，定量聚合酶链反应验证和基于shRNA的高含量筛选确定了Akt激酶羊毛硫氨酸合成酶C样蛋白2（LANCL 2）作为EGFR突变LUAD细胞系PC 9中的促增殖基因。因此，我们研究了LANCL 2是否在EGFR突变型LUAD中促进细胞增殖和耐药性方面发挥作用。使用Cancer Genome Atlas肺腺癌数据集的计算机临床相关性分析揭示了LANCL 2和EGFR表达之间的正相关性，以及LANCL 2功能获得性与LUAD患者生存率之间的负相关性。EGFR突变型LUAD细胞系PC 9和HCC 827显示出比非EGFR突变型细胞系A549更高的LANCL 2表达。此外，在PC 9细胞中，吉非替尼+培美曲塞联合治疗后LANCL 2下调。在体外，LANCL 2敲低降低了PC 9、HCC 827和A549细胞的增殖并增强了细胞凋亡，在体内抑制了小鼠PC 9异种移植肿瘤的生长。值得注意的是，LANCL 2过表达挽救了这些作用，并促进了PC 9和HCC 827细胞中的吉非替尼+培美曲塞耐药性。LANCL 2敲低细胞中差异表达基因的途径分析和免疫共沉淀以及质谱分析揭示了几种癌症信号传导途径的富集。此外，细丝蛋白A和谷胱甘肽S-转移酶Mu 3被鉴定为LANCL 2的两个新的蛋白质相互作用物。总之，LANCL 2促进EGFR突变LUAD细胞的致瘤性增殖，抑制细胞凋亡，并促进吉非替尼+培美曲塞耐药。基于LANCL 2、EGFR和下游Akt信号之间的正相关性，LANCL 2可能是EGFR突变型LUAD的有希望的新治疗靶点。
Epidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD). Resistance to EGFR tyrosine kinase inhibitors is a major obstacle for EGFR-mutant LUAD patients. Our gene chip array, quantitative polymerase chain reaction validation, and shRNA-based high-content screening identified the Akt kinase lanthionine synthetase C-like protein 2 (LANCL2) as a pro-proliferative gene in the EGFR-mutant LUAD cell line PC9. Therefore, we investigated whether LANCL2 plays a role in promoting cell proliferation and drug resistance in EGFR-mutant LUAD. In silico clinical correlation analysis using the Cancer Genome Atlas Lung Adenocarcinoma dataset revealed a positive correlation between LANCL2 and EGFR expression and an inverse relationship between LANCL2 gain-of-function and survival in LUAD patients. The EGFR-mutant LUAD cell lines PC9 and HCC827 displayed higher LANCL2 expression than the non-EGFR-mutant cell line A549. In addition, LANCL2 was downregulated following gefitinib+pemetrexed combination therapy in PC9 cells. LANCL2 knockdown reduced proliferation and enhanced apoptosis in PC9, HCC827, and A549 cells in vitro and suppressed murine PC9 xenograft tumor growth in vivo. Notably, LANCL2 overexpression rescued these effects and promoted gefitinib + pemetrexed resistance in PC9 and HCC827 cells. Pathway analysis and co-immunoprecipitation followed by mass spectrometry of differentially-expressed genes in LANCL2 knockdown cells revealed enrichment of several cancer signaling pathways. In addition, Filamin A and glutathione S-transferase Mu 3 were identified as two novel protein interactors of LANCL2. In conclusion, LANCL2 promotes tumorigenic proliferation, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on the positive association between LANCL2, EGFR, and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.
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DOI：
10.1016/j.apsb.2015.07.001
发表时间：
2015-09
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Huang L;Fu L
通讯作者：
Fu L
影响因子：
--
作者：
Checa-Rojas A;Delgadillo-Silva LF;Velasco-Herrera MDC;Andrade-Domínguez A;Gil J;Santillán O;Lozano L;Toledo-Leyva A;Ramírez-Torres A;Talamas-Rohana P;Encarnación-Guevara S
通讯作者：
Encarnación-Guevara S
影响因子：
7.3
作者：
Franke, Thomas F.
通讯作者：
Franke, Thomas F.
影响因子：
--
作者：
Feng, Xu;Dong, Chun-Qiang;Zheng, Bao-Shi
通讯作者：
Zheng, Bao-Shi
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J