Development and validation of a two glycolysis-related LncRNAs prognostic signature for glioma and in vitro analyses

Springer Science and Business Media LLC - Tập 18 - Trang 1-15 - 2023
Xiaoping Xu1, Shijun Zhou1, Yuchuan Tao1, Zhenglan Zhong2, Yongxiang Shao1, Yong Yi1
1Department of Neurosurgery, The Second People’s Hospital of Yibin, Yibin, China
2Department of Health Examination, The Second People’s Hospital of Yibin, Yibin, China

Tóm tắt

Mounting evidence suggests that there is a complex regulatory relationship between long non-coding RNAs (lncRNAs) and the glycolytic process during glioma development. This study aimed to investigate the prognostic role of glycolysis-related lncRNAs in glioma and their impact on the tumor microenvironment. This study utilized glioma transcriptome data from public databases to construct, evaluate, and validate a prognostic signature based on differentially expressed (DE)-glycolysis-associated lncRNAs through consensus clustering, DE-lncRNA analysis, Cox regression analysis, and receiver operating characteristic (ROC) curves. The clusterProfiler package was applied to reveal the potential functions of the risk score-related differentially expressed genes (DEGs). ESTIMATE and Gene Set Enrichment Analysis (GSEA) were utilized to evaluate the relationship between prognostic signature and the immune landscape of gliomas. Furthermore, the sensitivity of patients to immune checkpoint inhibitor (ICI) treatment based on the prognostic feature was predicted with the assistance of the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Finally, qRT-PCR was used to verify the difference in the expression of the lncRNAs in glioma cells and normal cell. By consensus clustering based on glycolytic gene expression profiles, glioma patients were divided into two clusters with significantly different overall survival (OS), from which 2 DE-lncRNAs, AL390755.1 and FLJ16779, were obtained. Subsequently, Cox regression analysis demonstrated that all of these lncRNAs were associated with OS in glioma patients and constructed a prognostic signature with a robust prognostic predictive efficacy. Functional enrichment analysis revealed that DEGs associated with risk scores were involved in immune responses, neurons, neurotransmitters, synapses and other terms. Immune landscape analysis suggested an extreme enrichment of immune cells in the high-risk group. Moreover, patients in the low-risk group were likely to benefit more from ICI treatment. qRT-PCR results showed that the expression of AL390755.1 and FLJ16779 was significantly different in glioma and normal cells. We constructed a novel prognostic signature for glioma patients based on glycolysis-related lncRNAs. Besides, this project had provided a theoretical basis for the exploration of new ICI therapeutic targets for glioma patients.

Tài liệu tham khảo

Almquist DR, Ahn DH, Bekaii-Saab TS. The role of immune checkpoint inhibitors in colorectal adenocarcinoma. BioDrugs. 2020;34(3):349–62. https://doi.org/10.1007/s40259-020-00420-3.

Bai Y, Lin H, Chen J, Wu Y, Yu S. Identification of prognostic glycolysis-related lncRNA signature in tumor immune microenvironment of hepatocellular carcinoma. Front Mol Biosci. 2021;8:645084. https://doi.org/10.3389/fmolb.2021.645084.

Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27(5):977-987 e974. https://doi.org/10.1016/j.cmet.2018.02.024.

Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. 2011;59(8):1169–80. https://doi.org/10.1002/glia.21136.

Fan L, Huang C, Li J, Gao T, Lin Z, Yao T. Long noncoding RNA urothelial cancer associated 1 regulates radioresistance via the hexokinase 2/glycolytic pathway in cervical cancer. Int J Mol Med. 2018;42(4):2247–59. https://doi.org/10.3892/ijmm.2018.3778.

Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013;12:152. https://doi.org/10.1186/1476-4598-12-152.

He Z, Wang C, Xue H, Zhao R, Li G. Identification of a metabolism-related risk signature associated with clinical prognosis in glioblastoma using integrated bioinformatic analysis. Front Oncol. 2020;10:1631. https://doi.org/10.3389/fonc.2020.01631.

Huang P, Zhu S, Liang X, Zhang Q, Luo X, Liu C, et al. Regulatory mechanisms of LncRNAs in cancer glycolysis: facts and perspectives. Cancer Manag Res. 2021;13:5317–36. https://doi.org/10.2147/CMAR.S314502.

Innao V, Allegra AG, Musolino C, Allegra A. New frontiers about the role of human microbiota in immunotherapy: the immune checkpoint inhibitors and CAR T-cell therapy era. Int J Mol Sci. 2020;21(23):8902. https://doi.org/10.3390/ijms21238902.

Jiang Y, Chen J, Ling J, Zhu X, Jiang P, Tang X, et al. Construction of a glycolysis-related long noncoding RNA signature for predicting survival in endometrial cancer. J Cancer. 2021;12(5):1431–44. https://doi.org/10.7150/jca.50413.

Kesarwani P, Kant S, Prabhu A, Chinnaiyan P. The interplay between metabolic remodeling and immune regulation in glioblastoma. Neuro Oncol. 2017;19(10):1308–15. https://doi.org/10.1093/neuonc/nox079.

Liu Y, He D, Xiao M, Zhu Y, Zhou J, Cao K. Long noncoding RNA LINC00518 induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1alpha negative feedback loop in melanoma. Cell Death Dis. 2021;12(3):245. https://doi.org/10.1038/s41419-021-03523-z.

Madden MZ, Rathmell JC. The complex integration of T-cell metabolism and immunotherapy. Cancer Discov. 2021. https://doi.org/10.1158/2159-8290.CD-20-0569.

Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro Oncol. 2020;22(12):iv1–96. https://doi.org/10.1093/neuonc/noaa200.

Park C, Na KJ, Choi H, Ock CY, Ha S, Kim M, et al. Tumor immune profiles noninvasively estimated by FDG PET with deep learning correlate with immunotherapy response in lung adenocarcinoma. Theranostics. 2020;10(23):10838–48. https://doi.org/10.7150/thno.50283.

Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011;10(9):671–84. https://doi.org/10.1038/nrd3504.

Velpula KK, Bhasin A, Asuthkar S, Tsung AJ. Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect. Cancer Res. 2013;73(24):7277–89. https://doi.org/10.1158/0008-5472.CAN-13-1868.

Wang Y, Zhang H, Wang J. Discovery of a novel three-long non-coding RNA signature for predicting the prognosis of patients with gastric cancer. J Gastrointest Oncol. 2020;11(4):760–9. https://doi.org/10.21037/jgo-20-140.

Wang Y, Zhou W, Ma S, Guan X, Zhang D, Peng J, et al. Identification of a glycolysis-related LncRNA signature to predict survival in diffuse glioma patients. Front Oncol. 2020;10:597877. https://doi.org/10.3389/fonc.2020.597877.

Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021;591(7851):645–51. https://doi.org/10.1038/s41586-020-03045-2.

Wu C, Cai X, Yan J, Deng A, Cao Y, Zhu X. Identification of novel glycolysis-related gene signatures associated with prognosis of patients with clear cell renal cell carcinoma based on TCGA. Front Genet. 2020;11:589663. https://doi.org/10.3389/fgene.2020.589663.

Xiao ZD, Zhuang L, Gan B. Long non-coding RNAs in cancer metabolism. BioEssays. 2016;38(10):991–6. https://doi.org/10.1002/bies.201600110.

Xu Z, Zhang D, Zhang Z, Luo W, Shi R, Yao J, et al. MicroRNA-505, suppressed by oncogenic long Non-coding RNA LINC01448, acts as a novel suppressor of glycolysis and tumor progression through inhibiting HK2 expression in pancreatic cancer. Front Cell Dev Biol. 2020;8:625056. https://doi.org/10.3389/fcell.2020.625056.

Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature. 2021;591(7851):652–8. https://doi.org/10.1038/s41586-021-03326-4.

Zhang C, Wang M, Ji F, Peng Y, Wang B, Zhao J, et al. A novel glucose metabolism-related gene signature for overall survival prediction in patients with glioblastoma. Biomed Res Int. 2021;2021:8872977. https://doi.org/10.1155/2021/8872977.

Zhang Z, Fang E, Rong Y, Han H, Gong Q, Xiao Y, et al. Hypoxia-induced lncRNA CASC9 enhances glycolysis and the epithelial–mesenchymal transition of pancreatic cancer by a positive feedback loop with AKT/HIF-1alpha signaling. Am J Cancer Res. 2021;11(1):123–37.

Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med. 2019;25(3):462–9. https://doi.org/10.1038/s41591-019-0349-y.