Keywords
Autophagy
Long non-coding RNA
Prognostic risk
HAGLR
Submitted : 2023-02-04
Accepted : 2023-02-19
Published : 2023-03-06
Abstract
Background: Long non-coding RNAs (lncRNAs) play a vital role in autophagy modulation and tumor progression. However, the key lncRNAs and their functions in gastric cancer (GC) remain largely unknown. Methods: A bioinformatic analysis of GC patients’ gene expression profiling data from the Cancer Genome Atlas database was performed to identify autophagy-related lncRNAs that are associated with predictive risk. Through Cox regression and Lasso regression analyses, the autophagy-related lncRNAs that are associated with prognosis were identified, and a novel prognostic model for GC was established. The model was then used to evaluate the clinical features and predictive risk of individuals with GC. By using two datasets, GSE 62254 (n = 300) and GSE 15459 (n = 192), from Gene Expression Omnibus, its effectiveness was verified. Gene set enrichment analysis according to hallmark and Kyoto Encyclopedia of Genes and Genomes were used to determine the possible biological roles of these lncRNAs. Furthermore, the HOXD antisense growth-associated long non-coding RNA (HAGLR) mechanism in GC was discovered through in vitro and in vivo experiments. Results: Six lncRNAs associated with autophagy in GC were identified, and a new prognostic risk model based on these lncRNAs was established. The six-lncRNA signature was significantly associated with adverse clinicopathological features and found to be an independent GC prognostic factor. The model was proven to be effective and robust by GSE62254 and GSE15459. According to gene set enrichment analysis, the six lncRNAs appeared to be tightly linked to autophagy-related and cancer-related mechanisms. HAGLR was also found to promote tumor growth by enhancing autophagy signaling in GC. Conclusion: A novel prognostic model integrating HAGLR that can effectively evaluate and predict the prognostic risk of GC patients was established. The results indicated that HAGLR promotes gastric cancer progression by enhancing autophagy and is anticipated to be a potential new target for the treatment of gastric cancer.
References
Sung H, Ferlay J, Siegel RL, et al., 2021, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers In 185 Countries. CA Cancer J Clin, 71(3): 209–249.
Sexton RE, Al Hallak MN, Diab M, et al., 2020, Gastric Cancer: A Comprehensive Review of Current and Future Treatment Strategies. Cancer Metastasis Rev, 39(4): 1179–1203.
Iyer MK, Niknafs YS, Malik R, et al., 2015, The Landscape of Long Noncoding RNAs in the Human Transcriptome. Nat Genet, 47(3): 199–208.
Schmitt AM, Chang HY, 2016, Long Noncoding RNAs in Cancer Pathways. Cancer Cell, 29(4): 452–463.
Janku F, McConkey DJ, Hong DS, et al., 2011, Autophagy as a Target for Anticancer Therapy. Nat Rev Clin Oncol, 8(9): 528–539.
Xu J-L, Yuan L, Tang Y-C, et al., 2020, The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?. Front Cell Dev Biol, 8: 621428.
Islam Khan MZ, Tam SY, Law HKW, 2018, Autophagy-Modulating Long Non-Coding RNAs (LncRNAs) and Their Molecular Events in Cancer. Front Genet, 9: 750.
Barangi S, Hayes AW, Reiter R, et al., 2019, The Therapeutic Role of Long Non-Coding RNAs in Human Diseases: A Focus on the Recent Insights into Autophagy. Pharmacol Res, 142: 22–29.
Li C, Zhao W, Pan X, et al., 2020, LncRNA KTN1-AS1 Promotes the Progression of Non-Small Cell Lung Cancer Via Sponging of Mir-130a-5p and Activation of PDPK1. Oncogene, 39(39): 6157–6171.
Lu M, Qin X, Zhou Y, et al., 2020, LncRNA HOTAIR Suppresses Cell Apoptosis, Autophagy and Induces Cell Proliferation in Cholangiocarcinoma by Modulating the miR-204-5p/HMGB1 Axis. Biomed Pharmacother, 130: 110566.
Wang B, Xu L, Zhang J, et al., 2020, LncRNA NORAD Accelerates the Progression and Doxorubicin Resistance of Neuroblastoma Through Up-Regulating HDAC8 Via Sponging miR-144-3p. Biomed Pharmacother, 129: 110268.
Yang L, Wang H, Shen Q, et al., 2017, Long Non-Coding RNAs Involved in Autophagy Regulation. Cell Death Dis, 8(10): e3073.
Jiang A, Liu N, Bai S, et al., 2021, Identification and Validation of an Autophagy-Related Long Non-Coding RNA Signature as a Prognostic Biomarker for Patients with Lung Adenocarcinoma. J Thorac Dis, 13(2): 720–734.
Humpton TJ, Alagesan B, DeNicola GM, et al., 2019, Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer. Cancer Discov, 9(9): 1268–1287.
Ghafouri-Fard S, Shoorei H, Mohaqiq M, et al., 2021, Exploring the Role of Non-Coding RNAs in Autophagy. Autophagy, 2021: 1–22.
Huang F, Chen W, Peng J, et al., 2018, LncRNA PVT1 Triggers Cyto-Protective Autophagy and Promotes Pancreatic Ductal Adenocarcinoma Development Via the miR-20a-5p/ULK1 Axis. Mol Cancer, 17(1): 98.
Cheng L, Han T, Zhang Z, et al., 2021, Identification and Validation of Six Autophagy-Related Long Non-Coding RNAs as Prognostic Signature in Colorectal Cancer. Int J Med Sci, 18(1): 88–98.
Wang X, Dai C, Ye M, et al., 2021, Prognostic Value of an Autophagy-Related Long-Noncoding-RNA Signature for Endometrial Cancer. Aging (Albany NY), 13(4): 5104–5119.
Pang K, Ran M-J, Zou F-W, et al., 2018, Long Non-Coding RNA LINC00857 Promotes Gastric Cancer Cell Proliferation and Predicts Poor Patient Survival. Oncol Lett, 16(2): 2119–2124.
Li J, Xu Q, Wang W, et al., 2019, MIR100HG: A Credible Prognostic Biomarker and an Oncogenic LncRNA in Gastric Cancer. Biosci Rep, 39(4): BSR20190171.
Zhang N, Zeng X, Sun C, et al., 2019, LncRNA LINC00963 Promotes Tumorigenesis and Radioresistance in Breast Cancer by Sponging miR-324-3p and Inducing ACK1 Expression. Mol Ther Nucleic Acids, 18: 871–881.
Yu M, Yu S, Gong W, et al., 2019, Knockdown of Linc01023 Restrains Glioma Proliferation, Migration and Invasion by Regulating IGF-1R/AKT Pathway. J Cancer, 10(13): 2961–2968.
Ren J, Zhang F-J, Wang J-H, et al., 2021, LINC01315 Promotes the Aggressive Phenotypes of Papillary Thyroid Cancer Cells by Sponging miR-497-5p. Kaohsiung J Med Sci, 37(6): 459–467.
Liang R, Zhang J, Zhang RM, et al., 2021, LINC01315 Silencing Inhibits the Aggressive Phenotypes of Colorectal Carcinoma by Sponging miR-205-3p. Biochem Biophys Res Commun, 534: 1033–1039.
Sun W, Nie W, Wang Z, et al., 2020, Lnc HAGLR Promotes Colon Cancer Progression Through Sponging miR-185-5p and Activating CDK4 and CDK6 In Vitro and In Vivo. Onco Targets Ther, 13: 5913–5925.
Suzuki HI, Kiyono K, Miyazono K, 2010, Regulation of Autophagy by Transforming Growth Factor-Beta (TGF-Beta) Signaling. Autophagy, 6(5): 645–647.
Jin L, Luo C, Wu X, et al., 2021, LncRNA-HAGLR Motivates Triple Negative Breast Cancer Progression by Regulation of WNT2 Via Sponging miR-335-3p. Aging (Albany NY), 13(15): 19306–19316.