Development of Predictive Signature and Dynamic Nomogram for m7G Methylation-Related LncRNAs in Hepatocellular Carcinoma

Abstract

Abstract: Objective The purpose of this study was to explore the prognostic value of m7G methylation-related long non-coding RNAs (lncRNAs) in hepatocellular carcinoma and develop a dynamic nomogram based on the Cancer Genome Atlas (TCGA) database. Methods The Cancer Genome Atlas (TCGA) database was used to retrieve clinical and transcriptomic data. Univariate Cox regression analysis and multivariate Cox regression analysis were used to screen m7G methylation-related lncRNAs, and finally to construct predictive signature and dynamic nomogram. Results Four m7G methylation-related lncRNAs (AL031985.3, AL365203.2, AC009403.1 and AC015908.3) determined by univariate and multivariate COX regression analysis were used to establish the predictive signature and validated the validity of the model. After assessing level of immune cell infiltration, immune function, and immune checkpoints, significant differences were found between the high-risk and low-risk groups. Finally, a validated online version of the dynamic nomogram was developed. Conclusion The prognosis model and dynamic nomogram of liver cancer based on m7G methylation-related lncRNAs can more accurately predict the prognosis of liver cancer patients, and provide greater convenience for clinical diagnosis and treatment.

Key words: hepatocellular carcinoma, m7G, lncRNAs, predictive signature, dynamic nomogram

摘要： 目的基于癌症基因组图谱（TCGA）数据库探究m7G甲基化相关的长非编码RNAs（lncRNAs）在肝癌中的预后价值并开发动态列线图。方法应用TCGA数据库来检索临床和转录组数据。采用单因素Cox回归分析和多因素Cox回归分析筛选预后相关的m7G甲基化相关lncRNAs,最后构建预后模型和动态列线图。结果通过单因素和多因素Cox回归分析,得到4个m7G甲基化相关的lncRNAs（AL031985.3、AL365203.2、AC009403.1和AC015908.3）。构建了预后模型并验证了该模型的有效性。在评估了免疫细胞浸润水平、免疫功能、免疫检查点后,发现高风险组和低风险组之间存在显著差异。最后开发了有效的在线版动态列线图。结论基于m7G甲基化相关的lncRNAs的肝癌预后模型和动态列线图可以更准确预测肝癌患者的预后,并为临床的诊治提供了更大的方便性。

关键词: 肝细胞癌, m7G, lncRNAs, 预后模型, 列线图

CLC Number:

R735.7

PENG Ke-nan, NING Jing-yuan, SUN Ke-ran, FAN Xiao-qing, ZONG Yan-hong, TANG Zhi-peng, TIE Yan-qing. Development of Predictive Signature and Dynamic Nomogram for m7G Methylation-Related LncRNAs in Hepatocellular Carcinoma[J]. Journal of Chengde Medical University, 2023, 40(5): 366-371.

彭克楠, 宁静源, 孙克然, 范小晴, 宗彦红, 唐志鹏, 帖彦清. 肝癌中m7G甲基化相关lncRNAs预后模型和动态列线图的开发[J]. 承德医学院学报, 2023, 40(5): 366-371.

References

[1] Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA: a cancer journal for clinicians, 2021, 71(3): 209-249.
[2] Chew V, Lai L, Pan L, et al.Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses[J]. Proceedings of the National Academy of Sciences, 2017, 114(29): E5900-E5909.
[3] El-Khoueiry AB, Sangro B, Yau T, et al.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. The Lancet, 2017, 389(10088): 2492-2502.
[4] Zhu AX, Finn RS, Edeline J, et al.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial[J]. The Lancet Oncology, 2018, 19(7): 940-952.
[5] Merrick WC, Pavitt GD.Protein Synthesis Initiation in Eukaryotic Cells[J]. Cold Spring Harbor Perspectives in Biology, 2018, 10(12): a033092.
[6] Raggi C, Invernizzi P.Methylation and liver cancer[J]. Clinics and Research in Hepatology and Gastroenterology, 2013, 37(6): 564-571.
[7] Ramanatnan A, Robb GB, CHAN SH. mRNA capping: biological functions and applications[J]. Nucleic Acids Research, 2016, 44(16): 7511-7526.
[8] Wood S, Willbanks A, Cheng JX.The Role of RNA Modifications and RNA-modifying Proteins in Cancer Therapy and Drug Resistance[J]. Current Cancer Drug Targets, 2021, 21(4): 326-352.
[9] He Z,Yang D,Fan X, et al.The Roles and Mechanisms of lncRNAs in Liver Fibrosis[J]. International Journal of Molecular Sciences, 2020, 21(4): E1482.
[10] Peng L, Chen Y, Ou Q, et al.LncRNA MIAT correlates with immune infiltrates and drug reactions in hepatocellular carcinoma[J]. International Immunopharmacology, 2020, 89(Pt A): 107071.
[11] Huang Z, Zhou JK, Peng Y, et al.The role of long noncoding RNAs in hepatocellular carcinoma[J]. Molecular Cancer, 2020, 19(1): 77.
[12] Sheng JQ, Wang MR, Fang D, et al.LncRNA NBR2 inhibits tumorigenesis by regulating autophagy in hepatocellular carcinoma[J]. Biomed Pharmacother, 2021, 133: 111023.
[13] Tian X, Wu Y, Yang Y, et al.Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating Wnt/β-catenin signaling[J]. Molecular Oncology, 2020, 14(2): 462-483.
[14] Alestrom P, Akusjarvi G, Perricaudet M, et al.The gene for polypeptide IX of adenovirus type 2 and its unspliced messenger RNA[J]. Cell, 1980, 19(3): 671-681.
[15] Sim HW, Knox J.Hepatocellular carcinoma in the era of immunotherapy[J]. Current Problems in Cancer, 2018, 42(1): 40-48.
[16] Llovet JM, Kelley RK, Villanueva A, et al.Hepatocellular carcinoma[J]. Nature Reviews. Disease Primers, 2021, 7(1): 6.
[17] Zhao M, Feng J, Tang L.Competing endogenous RNAs in lung cancer[J]. Cancer Biology & Medicine, 2021, 18(1): 1-20.
[18] Su K, Wang N, Shao Q, et al.The role of a ceRNA regulatory network based on lncRNA MALAT1 site in cancer progression[J]. Biomed Pharmacother, 2021, 137: 111389.
[19] Zhang J, Jin H, Liu H, et al.MiRNA-99a directly regulates AGO₂ through translational repression in hepatocellular carcinoma[J]. Oncogenesis, 2014, 3(4): e97-e97.
[20] Cheng N, Li Y, Han ZG.Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma[J]. Hepatology (Baltimore, Md.), 2013, 57(5): 1906-1918.
[21] Loomba R, Friedman SL, Shulman GI.Mechanisms and disease consequences of nonalcoholic fatty liver disease[J]. Cell, 2021, 184(10): 2537-2564.
[22] Devalaraja S, To TKJ, Folkert IW, et al. Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression[J]. Cell, 2020, 180(6): 1098-1114.e16.
[23] Weber R, Fleming V, Hu X, et al.Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors[J]. Frontiers in Immunology, 2018, 9: 1310.
[24] Ye Y, Xu Y, Lai Y, et al.Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization[J]. Journal of Cellular Biochemistry, 2018, 119(3): 2951-2963.
[25] Donisi C, Puzzoni M, Ziranu P, et al.Immune Checkpoint Inhibitors in the Treatment of HCC[J]. Frontiers in Oncology, 2020, 10: 601240.