Identification of Prognostic Glycolysis-Related lncRNA Signature in Tumor Immune Microenvironment of Hepatocellular Carcinoma

Frontiers in Molecular Biosciences - Tập 8
Yang Bai1, Haiping Lin, Jiaqi Chen2, Yulian Wu1, Shi’an Yu
1Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
2The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China

Tóm tắt

Purpose: The purpose of this study was to construct a novel risk scoring model with prognostic value that could elucidate tumor immune microenvironment of hepatocellular carcinoma (HCC).Samples and methods: Data were obtained through The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox analysis were carried out to screen for glycolysis-related long noncoding RNAs (lncRNAs) that could provide prognostic value. Finally, we established a risk score model to describe the characteristics of the model and verify its prediction accuracy. The receiver operating characteristic (ROC) curves of 1, 3, and 5 years of overall survival (OS) were depicted with risk score and some clinical features. ESTIMATE algorithm, single-sample gene set enrichment analysis (ssGSEA), and CIBERSORT analysis were employed to reveal the characteristics of tumor immune microenvironment in HCC. The nomogram was drawn by screening indicators with high prognostic accuracy. The correlation of risk signature with immune infiltration and immune checkpoint blockade (ICB) therapy was analyzed. After enrichment of related genes, active behaviors and pathways in high-risk groups were identified and lncRNAs related to poor prognosis were validated in vitro. Finally, the impact of MIR4435-2HG upon ICB treatment was uncovered.Results: After screening through multiple steps, four glycolysis-related lncRNAs were obtained. The risk score constructed with the four lncRNAs was found to significantly correlate with prognosis of samples. From the ROC curve of samples with 1, 3, and 5 years of OS, two indicators were identified with high prognostic accuracy and were used to draw a nomogram. Besides, the risk score significantly correlated with immune score, immune-related signature, infiltrating immune cells (i.e. B cells, etc.), and ICB key molecules (i.e. CTLA4,etc.). Gene enrichment analysis indicated that multiple biological behaviors and pathways were active in the high-risk group. In vitro validation results showed that MIR4435-2HG was highly expressed in the two cell lines, which had a significant impact on the OS of samples. Finally, we corroborated that MIR4435-2HG had intimate relationship with ICB therapy in hepatocellular carcinoma.Conclusion: We elucidated the crucial role of risk signature in immune cell infiltration and immunotherapy, which might contribute to clinical strategies and clinical outcome prediction of HCC.

Từ khóa


Tài liệu tham khảo

Anderson, 2018, The emerging role and targetability of the TCA cycle in cancer metabolism, Protein Cell, 9, 216, 10.1007/s13238-017-0451-1

Anwanwan, 2020, Challenges in liver cancer and possible treatment approaches, Biochim. Biophys. Acta (Bba) - Rev. Cancer, 1873, 188314, 10.1016/j.bbcan.2019.188314

Banks, 2013, Oncogene-induced cellular senescence elicits an anti-Warburg effect, Proteomics, 13, 2542, 10.1002/pmic.201300335

Bejani, 2020, Theory of adaptive SVD regularization for deep neural networks, Neural Networks, 128, 33, 10.1016/j.neunet.2020.04.021

Boon, 2016, Long noncoding RNAs, J. Am. Coll. Cardiol., 67, 1214, 10.1016/j.jacc.2015.12.051

Carpenter, 2018, Cytokines and long noncoding RNAs, Cold Spring Harbor Perspect. Biol., 10, 10.1101/cshperspect.a028589

Chan, 2019, Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic, Ann. Oncol., 30, 44, 10.1093/annonc/mdy495

Chen, 2018, High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis, Hepatology, 67, 1823, 10.1002/hep.29663

Cheng, 2019, Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies, Am. J. Cancer Res., 9, 1536

Dawes, 2019, Injury-specific variables improve risk adjustment and hospital quality assessment in severe traumatic brain injury, J. Trauma Acute Care Surg., 87, 386, 10.1097/ta.0000000000002297

Denaro, 2019, Long noncoding RNA s as regulators of cancer immunity, Mol. Oncol., 13, 61, 10.1002/1878-0261.12413

DiStefano, 2017, Long noncoding RNAs in the initiation, progression, and metastasis of hepatocellular carcinoma, Non-coding RNA Res., 2, 129, 10.1016/j.ncrna.2017.11.001

Dufour, 2013, Intermediate hepatocellular carcinoma: current treatments and future perspectives, Ann. Oncol., ii24, 10.1093/annonc/mdt054

Fang, 2019, LncRNA GAS5 enhanced the killing effect of NK cell on liver cancer through regulating miR-544/RUNX3, Innate Immun., 25, 99, 10.1177/1753425919827632

Ganapathy-Kanniappan, 2018, Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype, Crit. Rev. Biochem. Mol. Biol., 53, 667, 10.1080/10409238.2018.1556578

Goodman, 2017, PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas, Nat. Rev. Clin. Oncol., 14, 203, 10.1038/nrclinonc.2016.168

Hsu, 2015, Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs, Oncol. Rep., 34, 1620, 10.3892/or.2015.4092

Hu, 2019, A new substage classification strategy for Barcelona clinic liver cancer stage B patients with hepatocellular carcinoma, J. Gastroenterol. Hepatol., 34, 1984, 10.1111/jgh.14673

Huang, 2016, Identification of differentially expressed long non-coding RNAs in polarized macrophages, Scientific Rep., 6, 19705, 10.1038/srep19705

2018, Invalidcitation, 29

Ji, 2018, Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC, Cel Death andDis., 9, 478, 10.1038/s41419-018-0528-7

Kim, 2017, Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas, Clin. Cancer Res., 23, 124, 10.1158/1078-0432.ccr-15-1535

Kong, 2019, The lncRNA MIR4435-2HG is upregulated in hepatocellular carcinoma and promotes cancer cell proliferation by upregulating miRNA-487a, Cell andMol. Biol. Lett., 24, 26, 10.1186/s11658-019-0148-y

Kopp, 2018, Functional classification and experimental dissection of long noncoding RNAs, Cell, 172, 393, 10.1016/j.cell.2018.01.011

Lei, 2020, Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy, Cancer Lett., 470, 126, 10.1016/j.canlet.2019.11.009

Liang, 2019, 2,3′4,4′,5-Pentachlorobiphenyl induces hepatocellular carcinoma cell proliferation through pyruvate kinase M2-dependent glycolysis, Toxicol. Lett., 313, 108, 10.1016/j.toxlet.2019.06.006

Liberzon, 2015, The molecular signatures database hallmark gene set collection, Cel Syst., 1, 417, 10.1016/j.cels.2015.12.004

Lin, 2014, Transcriptional regulation of STAT3 by SPTBN1 and SMAD3 in HCC through cAMP-response element-binding proteins ATF3 and CREB2, Carcinogenesis, 35, 2393, 10.1093/carcin/bgu163

Liu, 2020, Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma, Gut, 69, 365, 10.1136/gutjnl-2018-317257

Llovet, 2018, Molecular therapies and precision medicine for hepatocellular carcinoma, Nat. Rev. Clin. Oncol., 15, 599, 10.1038/s41571-018-0073-4

Lu, 2015, The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism, Cancer Lett., 356, 156, 10.1016/j.canlet.2014.04.001

Mayakonda, 2018, Maftools: efficient and comprehensive analysis of somatic variants in cancer, Genome Res., 28, 1747, 10.1101/gr.239244.118

Miao, 2019, A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation, PLoS Genet., 15, e1008144, 10.1371/journal.pgen.1008144

Mushtaq, 2018, Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers, J. Immunother. Cancer, 6, 65, 10.1186/s40425-018-0376-0

Ng, 2020, Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma, J. Immunother. Cancer, 8, 10.1136/jitc-2020-000987

Nishino, 2017, Monitoring immune-checkpoint blockade: response evaluation and biomarker development, Nat. Rev. Clin. Oncol., 14, 655, 10.1038/nrclinonc.2017.88

Pascale, 2020, The Warburg effect 97 Years after its discovery, Cancers, 12, 2819, 10.3390/cancers12102819

Peng, 2020, LncRNA MIAT correlates with immune infiltrates and drug reactions in hepatocellular carcinoma, Int. immunopharmacology, 89, 107071, 10.1016/j.intimp.2020.107071

Pitt, 2016, Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors, Immunity, 44, 1255, 10.1016/j.immuni.2016.06.001

Riera Leal, 2020, 17β-estradiol-induced mitochondrial dysfunction and Warburg effect in cervical cancer cells allow cell survival under metabolic stress, Int. J. Oncol., 56, 33, 10.3892/ijo.2019.4912

Rizvi, 2015, Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Science, 348, 124, 10.1126/science.aaa1348

Ruan, 2016, Over-expression of cathepsin B in hepatocellular carcinomas predicts poor prognosis of HCC patients, Mol. Cancer, 15, 17, 10.1186/s12943-016-0503-9

Salik, 2020, Targeting immune checkpoints in hematological malignancies, J. Hematol. andOncol., 13, 111, 10.1186/s13045-020-00947-6

Schmitt, 2016, Long noncoding RNAs in cancer pathways, Cancer cell, 29, 452, 10.1016/j.ccell.2016.03.010

Shen, 2019, Down‐regulation of long noncodingRNA PVT1 inhibits esophageal carcinoma cell migration and invasion and promotes cell apoptosis via microRNA‐145‐mediated inhibition ofFSCN1, Mol. Oncol., 13, 2554, 10.1002/1878-0261.12555

Siegel, 2020, Cancer statistics, 2020, CA A. Cancer J. Clin., 70, 7, 10.3322/caac.21590

Snyder, 2014, Genetic basis for clinical response to CTLA-4 blockade in melanoma, N. Engl. J. Med., 371, 2189, 10.1056/nejmoa1406498

Sun, 2018, Metabolic reprogramming for cancer cells and their microenvironment: beyond the Warburg Effect, Biochim. Biophys. Acta (Bba) - Rev. Cancer, 1870, 51, 10.1016/j.bbcan.2018.06.005

Terabe, 2019, Chondroprotective effects of 4-methylumbelliferone and hyaluronan synthase-2 overexpression involve changes in chondrocyte energy metabolism, J. Biol. Chem., 294, 17799, 10.1074/jbc.ra119.009556

Vidyasagar, 2015, Identifying predictive features in drug response using machine learning: opportunities and challenges, Annu. Rev. Pharmacol. Toxicol., 55, 15, 10.1146/annurev-pharmtox-010814-124502

Wei, 2019, The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma, Mol. Cancer, 18, 147, 10.1186/s12943-019-1086-z

Yuan, 2016, Long noncoding RNA, the methylation of genomic elements and their emerging crosstalk in hepatocellular carcinoma, Cancer Lett., 379, 239, 10.1016/j.canlet.2015.08.008

Ždralević, 2018, Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism, J. Biol. Chem., 293, 15947, 10.1074/jbc.RA118.004180

Zhai, 2018, Ido1 in cancer: a Gemini of immune checkpoints, Cell Mol Immunol, 15, 447, 10.1038/cmi.2017.143

Zhang, 2016, Expression and clinical significance of the novel long noncoding RNA znf674-AS1 in human hepatocellular carcinoma, Biomed. Research International, 2016, 3608914, 10.1155/2016/3608914

Zhang, 2019, Landscape and dynamics of single immune cells in hepatocellular carcinoma, Cell, 179, 829, 10.1016/j.cell.2019.10.003

Thông tin
Thông tin xuất bản

Frontiers in Molecular Biosciences

Tập 8

Thông tin tác giả