Genomic sequencing and editing revealed the GRM8 signaling pathway as potential therapeutic targets of squamous cell lung cancer
Genomic sequencing and editing revealed the GRM8 signaling pathway as potential therapeutic targets of squamous cell lung cancer
复制标题
基因组测序和编辑揭示了 GRM8 信号通路是鳞状细胞肺癌的潜在治疗靶点。
DOI：
10.1016/j.canlet.2018.10.035
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发表时间：
2019-02-01
期刊：
影响因子：
9.7
通讯作者：
Yang, Yue
中科院分区：
文献类型：
--
作者：
Zhang, Panpan;Kang, Bin;Yang, Yue
该研究旨在探索导致鳞状细胞肺癌（LUSC）的新型遗传畸变。整合全外显子组 (WES)、全基因组 (WGS) 和目标区域 (TS) 测序以及 CRISPR-Cas9 基因组编辑技术，探索和验证来自 LUSC 原发性肿瘤和相应患者来源的异种移植物 (PDX) 的新型靶向候选物。通过生物信息学分析，鉴定出七个具有高频率单核苷酸变异（SNV）和拷贝数变异（CNV）的基因（FGFR2、GRM1、PIK3CG、PIK3CA、ZFHX4、CSMD3、GAMS）和两个仅具有CNV的基因（CLDN1和RIT1）。这些候选物的功能通过 CRISPR-Cas9 系统在原代 PDX 细胞中得到验证。此外，我们重点对代谢型谷氨酸受体8（GRM8）进行了遗传和功能分析，阐明了其转录激活通过抑制CAMP通路和激活MAPK通路来促进LUSC肿瘤细胞的存活。 GRM8、A112G 中鉴定的 SNV 激活下游信号通路并诱导细胞增殖，cAMP 刺激剂和 MEK 抑制剂可以逆转这种情况。总之，GRM8信号通路的组成部分可以作为携带GRM8激活变异体的鳞状细胞肺癌的潜在靶点。
The study sought to explore novel genetic aberration driving squamous cell lung carcinoma (LUSC). The whole exome (WES), whole genome (WGS) and target region (TS) sequencings and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from LUSC primary tumors and corresponding patient-derived xenografts (PDXs). Seven genes (FGFR2, GRM1,PIK3CG, PIK3CA,ZFHX4, CSMD3, GAMS) with high frequencies of both single nucleotide variants (SNVs) and copy number variants (CNVs), and two genes (CLDN1 and RIT1) only with CNVs were identified by bioinformatics analysis. The functions of these candidates were validated through CRISPR-Cas9 system in primary PDX cells. Furthermore, we focused on the genetic and functional analysis of Metabotropic glutamate receptor 8 (GRM8), whose transcriptional activation was elucidated to promote the survival of LUSC tumor cell through inhibiting CAMP pathway and activating MAPK pathway. The SNV identified in GRM8, A112G, activated downstream signaling pathway and induced cell proliferation, which could be reversed by cAMP stimulator and MEK inhibitor. In conclusion, the components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer carrying GRM8 activating variants.