| Title | Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma |
| Authors | Liu, Tongyan Han, Chencheng Fang, Panqi Ma, Zhifei Wang, Xiaoxiao Chen, Hao Wang, Siwei Meng, Fanchen Wang, Cheng Zhang, Erbao Dong, Guozhang Zhu, Hongyu Yin, Wenda Wang, Jie Zuo, Xianglin Qiu, Mantang Wang, Jinke Qian, Xu Shen, Hongbing Xu, Lin Hu, Zhibin Yin, Rong |
| Affiliation | Jiangsu Canc Hosp, Jiangsu Key Lab Mol & Translat Canc Res, Dept Thorac Surg, Nanjing 21009, Peoples R China Nanjing Med Univ, Affiliated Canc Hosp, Nanjing 21009, Peoples R China Nanjing Med Univ, Jiangsu Inst Canc Res, Nanjing 21009, Peoples R China Nanjing Med Univ, Dept Sci & Technol, Jiangsu Canc Hosp, Nanjing 21009, Peoples R China Jiangsu Inst Canc Res, Nanjing 21009, Peoples R China Nanjing Univ Chinese Med, Jiangsu Prov Hosp Chinese Med, Dept GCP Res Ctr, Affiliated Hosp, Nanjing 210029, Peoples R China Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Nanjing 211116, Peoples R China Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Int Joint Res Ctr Environm & Human Hlth, Nanjing 211116, Peoples R China Nanjing Med Univ, Dept Bioinformat, Nanjing 211166, Peoples R China Biobank Lung Canc, Jiangsu Biobank Clin Resources, Nanjing 21009, Peoples R China Peking Univ, Dept Thorac Surg, Peoples Hosp, Beijing 100044, Peoples R China Southeast Univ, State Key Lab Bioelect, Nanjing 210018, Peoples R China |
| Keywords | LONG NONCODING RNAS METABOLISM |
| Issue Date | 8-Oct-2022 |
| Publisher | JOURNAL OF HEMATOLOGY & ONCOLOGY |
| Abstract | Background Besides featured glucose consumption, recent studies reveal that cancer cells might prefer "addicting" specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear. Methods Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved. Results We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-kappa B, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD. Conclusion Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD. |
| URI | http://hdl.handle.net/20.500.11897/655682 |
| DOI | 10.1186/s13045-022-01359-4 |
| Indexed | SCI(E) |
| Appears in Collections: | 人民医院 |
