Identification of a novel therapeutic candidate, NRK, in primary cancer‑associated fibroblasts of lung adenocarcinoma microenvironment
Identification of a novel therapeutic candidate, NRK, in primary cancer‑associated fibroblasts of lung adenocarcinoma microenvironment
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在肺腺癌微环境的原发癌相关成纤维细胞中鉴定新的候选治疗药物 NRK
DOI：
10.1007/s00432-020-03489-z
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发表时间：
2021
影响因子：
3.6
通讯作者：
Jie Yang
中科院分区：
文献类型：
--
作者：
Tongtong Wei;Jinjing Song;Kai Liang;Li Li;Xiaoxiang Mo;Zhiguang Huang;Gang Chen;Naiquan Mao;Jie Yang
目的 肺腺癌 (LUAD) 约占肺癌患者的一半。癌症相关成纤维细胞（CAF）是肿瘤微环境（TME）的主要组成部分。靶向 CAF 是一种有前途的癌症治疗策略。然而，CAF 在 LUAD 中的治疗靶点仍不清楚...方法分别从接受手术的 LUAD 患者的肿瘤和癌旁组织中分离出 7 个 CAF 和 9 个正常成纤维细胞 (NF)。进行 RNA-seq 和生物信息学分析，以确定与 NF 相比，CAF 中的差异表达基因 (DEG) 及其功能。从RNA-seq、我们之前报道的lncRNA微阵列和公共数据集（E-MTAB-6149、E-MTAB-6653）中获得十个重叠的DEG，并通过RT-qPCR进行验证...Nik相关激酶（NRK）通过RT-qPCR、免疫荧光（IF）、Western Blot（WB）体外和癌细胞系百科全书（CCLE）数据库进一步验证。在Kaplan-Meier绘图仪上进行生存分析...结果共鉴定出1799个DEG，包括650个上调DEG和1149个下调DEG。上调和下调的 DEG 主要富集于细胞外基质 (ECM) 功能和糖酵解/糖异生途径。有趣的是，NRK 是上调最显着的重叠 DEG，以前很少与 CAF 相关。 NRK主要在CAF中表达，但在NF、正常肺支气管上皮细胞系BEAS-2B、LUAD细胞系A549和H1299以及包括LUAD在内的大多数191肺癌细胞系中弱表达。此外，NRK 升高预示着 LUAD 患者的生存率较差......结论在此，我们首先报告 NRK 在 LUAD 相关 CAF 中显着升高，并且可能作为癌症联合治疗的有希望的治疗靶点。此外，调节 ECM 和糖酵解/糖异生途径可能是改变 LUAD 中 CAF 功能的有效方法。
Purpose Lung adenocarcinoma (LUAD) accounts for approximately half of patients in lung cancer. Cancer-associated fibroblasts (CAFs) are the major component in the tumor microenvironment (TME). Targeting CAFs is a promising therapeutic strategy for cancer treatment. However, therapeutic targets of CAFs in LUAD remains largely unclear...Methods Seven CAFs and nine normal fibroblasts (NFs) were isolated from tumor and paratumor tissues of LUAD patients undergoing surgery, respectively. RNA-seq and bioinformatics analysis were performed to identify the differentially expressed genes (DEGs) and their functions in CAFs compared with NFs. DEGs of ten overlaying were obtained from RNA-seq, our previously reported lncRNA microarray and public datasets (E-MTAB-6149, E-MTAB-6653) and validated by RT-qPCR...Nik-related kinase (NRK) was further validated by RT-qPCR, immunofluorescence (IF), Western Blot (WB) in vitro, and in Cancer Cell Line Encyclopedia (CCLE) database. Survival analysis was performed on Kaplan–Meier plotter...Results A total of 1799 DEGs were identified, including 650 upregulated DEGs and 1149 downregulated DEGs. The upregulated and downregulated DEGs were mostly enriched in extracellular matrix (ECM) functions and in glycolysis/ gluconeogenesis pathways. Interestingly, NRK was the most significantly upregulated overlaying DEGs which was rarely associated with CAFs before. NRK was predominantly expressed in CAFs, but weakly expressed in NFs, normal lung bronchial epithelial cell line BEAS-2B, LUAD cell lines A549 and H1299, as well as in the majority of 191 lung cancer cell lines including LUAD. Moreover, elevated NRK predicted poor survival in LUAD patients...Conclusion Here, we first report that NRK is significantly elevated in LUAD-associated CAFs and may function as a promising therapeutic target for cancer combination treatment. Besides, modulation of ECM and glycolysis/gluconeogenesis pathways may be an efficient approach to alter CAFs functionality in LUAD.