The sodium/myo-inositol co-transporter SLC5A3 promotes non-small cell lung cancer cell growth.
The sodium/myo-inositol co-transporter SLC5A3 promotes non-small cell lung cancer cell growth.
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DOI：
10.1038/s41419-022-05017-y
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发表时间：
2022-06-27
影响因子：
9
通讯作者：
Xu, Chun
中科院分区：
文献类型：
--
作者：
Cui, Zihan;Mu, Chuanyong;Wu, Zhichao;Pan, Shu;Cheng, Zewen;Zhang, Zhi-qing;Zhao, Jun;Xu, Chun
寻找新的非小细胞肺癌（NSCLC）分子信号靶点具有重要意义。本研究探讨了钠/肌醇共转运体SLC5A3在非小细胞肺癌中的表达、功能和可能的潜在机制。Cancer Genome Atlas （TCGA）数据库和局部NSCLC组织结果显示，SLC5A3在NSCLC组织（包括患者源性原发NSCLC细胞）中的表达显著高于正常肺组织和肺上皮细胞。在原发性非小细胞肺癌细胞和永生化系中，使用小发夹RNA （shRNA）和CRSIRP/Cas9方法，SLC5A3缺失明显阻碍细胞增殖和迁移，同时引发细胞周期阻滞和凋亡。相反，SLC5A3异位过表达进一步增强了原发性NSCLC细胞的增殖和迁移。SLC5A3沉默或敲除（KO）在很大程度上抑制了细胞内肌醇含量和Akt-mTOR的激活，但在原发性NSCLC细胞中，SLC5A3过表达后增强了细胞内肌醇含量和Akt-mTOR的激活。值得注意的是，SLC5A3 ko诱导的抗nsclc细胞活性可以通过外源性添加肌醇或组成型活性Akt构建体得到很大程度的改善。通过采用患者源性异种移植物（PDX）模型，我们发现瘤内注射SLC5A3 shRNA腺相关病毒（AAV）在很大程度上抑制了裸鼠皮下非小细胞肺癌异种移植物的生长。在SLC5A3 shRNA病毒注射的非小细胞肺癌异种移植组织中检测到SLC5A3沉默、肌醇消耗、Akt-mTOR失活和细胞凋亡诱导。总之，升高的SLC5A3可能通过维持肌醇含量和促进Akt-mTOR激活来促进NSCLC细胞生长。
Identification of novel molecular signaling targets for non-small cell lung cancer (NSCLC) is important. The present study examined expression, functions and possible underlying mechanisms of the sodium/myo-inositol co-transporter SLC5A3 in NSCLC. The Cancer Genome Atlas (TCGA) database and local NSCLC tissue results demonstrated that SLC5A3 expression in NSCLC tissues (including patient-derived primary NSCLC cells) was significantly higher than that in normal lung tissues and lung epithelial cells. In primary NSCLC cells and immortalized lines, SLC5A3 depletion, using small hairpin RNA (shRNA) and CRSIRP/Cas9 methods, robustly impeded cell proliferation and migration, simultaneously provoking cell cycle arrest and apoptosis. Conversely, ectopic overexpression of SLC5A3 further enhanced proliferation and migration in primary NSCLC cells. The intracellular myo-inositol contents and Akt-mTOR activation were largely inhibited by SLC5A3 silencing or knockout (KO), but were augmented following SLC5A3 overexpression in primary NSCLC cells. Significantly, SLC5A3 KO-induced anti-NSCLC cell activity was largely ameliorated by exogenously adding myo-inositol or by a constitutively-active Akt construct. By employing the patient-derived xenograft (PDX) model, we found that the growth of subcutaneous NSCLC xenografts in nude mice was largely inhibited by intratumoral injection SLC5A3 shRNA adeno-associated virus (AAV). SLC5A3 silencing, myo-inositol depletion, Akt-mTOR inactivation and apoptosis induction were detected in SLC5A3 shRNA virus-injected NSCLC xenograft tissues. Together, elevated SLC5A3 promotes NSCLC cell growth possibly by maintaining myo-inositol contents and promoting Akt-mTOR activation.
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