Generic placeholder image

Current Bioinformatics

Editor-in-Chief

ISSN (Print): 1574-8936
ISSN (Online): 2212-392X

Research Article

A Simple and Practical microRNA-based Nomogram to Predict Metastatic HCC

Author(s): Yong Zhu, Yusheng Jie, Yuankai Wu, Wenting Tang, Jing Cao, Zhongzhen Su, Zhenjian Zhuo*, Jiao Gong* and Yutian Chong*

Volume 17, Issue 6, 2022

Published on: 23 August, 2022

Page: [521 - 530] Pages: 10

DOI: 10.2174/1574893617666220428103832

Price: $65

Abstract

Background: Despite unprecedented scientific progress that has been achieved over the years, there is no established microRNA-based model for predicting hepatocellular carcinoma (HCC) metastasis. To this end, we aimed to develop a simple model based on the expression of miRNAs to identify patients at high risk of metastatic HCC.

Methods: HCC datasets with metastasis data were acquired from the Gene Expression Omnibus (GEO) database, and samples were randomly divided into training (n=169) and validation (n=72) groups. Based on the expression of miRNAs in the training group, we developed a predictive nomogram for metastatic HCC. We evaluated its performance using the area under the receiver operating characteristic curve (AUC), calibration curve, decision curve and clinical impact curve analysis.

Results: By applying the absolute shrinkage and selection operator regression (LASSO) and multivariate logistic regression, it has been found that the expressions of miR-30c, miR-185, and miR-323 were independent predictors of metastatic HCC. These miRNAs were used to construct a nomogram that yielded good performance in predicting metastasis in training (AUC 0.869 [95% CI 813-0.925], sensitivity 92.7%, specificity 57.8%) and validation groups (0.821 [CI 0.720-0.923], sensitivity 94.7%, specificity 60%). The calibration curve showed a good agreement between actual and predicted outcomes. Decision curve analysis showed a high clinical net benefit of nomogram predictions for our patients. Moreover, higher total scores of our nomogram were associated with dead patients. In addition, functional enrichment analysis showed that the predicted target genes of these 3 miRNAs correlated with tumor metastasis-associated terms, such as filopodium, and identified their related hub genes.

Conclusions: Our easy-to-use nomogram could assist in identifying HCC patients at high risk of metastasis, which provides valuable information for clinical treatment.

Keywords: HCC metastasis, nomogram, miRNA signature, bioinformatic analysis, gene expression omnibus (GEO), LASSO.

Graphical Abstract

[1]
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16(10): 589-604.
[http://dx.doi.org/10.1038/s41575-019-0186-y] [PMID: 31439937]
[2]
Villanueva A, Hernandez-Gea V, Llovet JM. Medical therapies for hepatocellular carcinoma: A critical view of the evidence. Nat Rev Gastroenterol Hepatol 2013; 10(1): 34-42.
[http://dx.doi.org/10.1038/nrgastro.2012.199] [PMID: 23147664]
[3]
Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: Patterns, treatments, and prognosis. Ann Surg 2015; 261(5): 947-55.
[http://dx.doi.org/10.1097/SLA.0000000000000710] [PMID: 25010665]
[4]
Budhu A, Jia HL, Forgues M, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 2008; 47(3): 897-907.
[http://dx.doi.org/10.1002/hep.22160] [PMID: 18176954]
[5]
Asano N, Matsuzaki J, Ichikawa M, et al. A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes. Nat Commun 2019; 10(1): 1299.
[http://dx.doi.org/10.1038/s41467-019-09143-8] [PMID: 30898996]
[6]
Callegari E, Gramantieri L, Domenicali M, D’Abundo L, Sabbioni S, Negrini M. MicroRNAs in liver cancer: A model for investigating pathogenesis and novel therapeutic approaches. Cell Death Differ 2015; 22(1): 46-57.
[http://dx.doi.org/10.1038/cdd.2014.136] [PMID: 25190143]
[7]
Xu X, Tao Y, Shan L, et al. The role of micrornas in hepatocellular carcinoma. J Cancer 2018; 9(19): 3557-69.
[http://dx.doi.org/10.7150/jca.26350] [PMID: 30310513]
[8]
Song BN, Chu IS. A gene expression signature of FOXM1 predicts the prognosis of hepatocellular carcinoma. Exp Mol Med 2018; 50(1)e418
[http://dx.doi.org/10.1038/emm.2017.159] [PMID: 29303511]
[9]
Yuan S, Wang J, Yang Y, et al. The prediction of clinical outcome in hepatocellular carcinoma based on a six-gene metastasis signature. Clin Cancer Res 2017; 23(1): 289-97.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0395] [PMID: 27449498]
[10]
Budhu A, Forgues M, Ye QH, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006; 10(2): 99-111.
[http://dx.doi.org/10.1016/j.ccr.2006.06.016] [PMID: 16904609]
[11]
Yi B, Tang C, Tao Y, Zhao Z. Definition of a novel vascular invasion-associated multi-gene signature for predicting survival in patients with hepatocellular carcinoma. Oncol Lett 2020; 19(1): 147-58.
[PMID: 31897125]
[12]
Li B, Feng W, Luo O, et al. Development and validation of a three-gene prognostic signature for patients with hepatocellular carcinoma. Sci Rep 2017; 7(1): 5517.
[http://dx.doi.org/10.1038/s41598-017-04811-5] [PMID: 28717245]
[13]
Yuan K, Xie K, Lan T, Xu L, Wu H. TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin. Cell Death Differ 2019; 1-14.
[PMID: 31570854]
[14]
Liu G-M, Zeng H-D, Zhang C-Y, Xu J-W. Identification of a six-gene signature predicting overall survival for hepatocellular carcinoma. Cancer Cell Int 2019; 19(1): 138.
[http://dx.doi.org/10.1186/s12935-019-0858-2] [PMID: 31139015]
[15]
Yang Y, Xu Z, Song D. Missing value imputation for microRNA expression data by using a GO-based similarity measure. BMC Bioinformatics 2016; 17(S1)(Suppl. 1): 10.
[http://dx.doi.org/10.1186/s12859-015-0853-0] [PMID: 26818962]
[16]
Nagy Á, Lánczky A, Menyhárt O, Győrffy B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep 2018; 8(1): 9227.
[http://dx.doi.org/10.1038/s41598-018-27521-y] [PMID: 29907753]
[17]
Ru Y, Kechris KJ, Tabakoff B, et al. The multiMiR R package and database: Integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res 2014; 42(17)e133
[http://dx.doi.org/10.1093/nar/gku631] [PMID: 25063298]
[18]
Gong J, Li R, Chen Y, et al. HCC subtypes based on the activity changes of immunologic and hallmark gene sets in tumor and nontumor tissues. Brief Bioinform 2021; 22(5)bbaa427
[http://dx.doi.org/10.1093/bib/bbaa427] [PMID: 33515024]
[19]
Muthukrishnan R, Rohini R. LASSO: A feature selection technique in predictive modeling for machine learning. 2016 Ieee International Conference on Advances in Computer Applications (Icaca). 18-20.
[http://dx.doi.org/10.1109/ICACA.2016.7887916]
[20]
Gong J, Ou J, Qiu X, et al. a tool to early predict severe corona virus disease 2019 (COVID-19): A multicenter study using the risk nomogram in Wuhan and Guangdong, China. Clinical Infectious Diseases 2020.
[21]
Liu Y, Li L, Liu Z, Yuan Q, Lu X. Plasma miR-323 as a biomarker for screening papillary thyroid cancer from healthy controls. Front Med (Lausanne) 2020; 7(122): 122.
[http://dx.doi.org/10.3389/fmed.2020.00122] [PMID: 32478079]
[22]
Fan JM, Zheng ZR, Zeng YM, Chen XY. MiR-323-3p Targeting Transmembrane Protein with EGF-Like and 2 Follistatin Domain (TMEFF2) inhibits human lung cancer A549 cell apoptosis by regulation of AKT and ERK signaling pathways. Med Sci Monit 2020; 26e919454.
[http://dx.doi.org/10.12659/MSM.919454] [PMID: 32009129]
[23]
Wang C, Liu P, Wu H, et al. MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct sup-pression of SMAD2 and SMAD3. Oncotarget 2016; 7(12): 14912-24.
[http://dx.doi.org/10.18632/oncotarget.7482] [PMID: 26908446]
[24]
Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 2006; 125(6): 1111-24.
[http://dx.doi.org/10.1016/j.cell.2006.04.031] [PMID: 16777601]
[25]
Shivdasani RA. MicroRNAs: Regulators of gene expression and cell differentiation. Blood 2006; 108(12): 3646-53.
[http://dx.doi.org/10.1182/blood-2006-01-030015] [PMID: 16882713]
[26]
Ye J, Xu M, Tian X, Cai S, Zeng S. Research advances in the detection of miRNA. J Pharm Anal 2019; 9(4): 217-26.
[http://dx.doi.org/10.1016/j.jpha.2019.05.004] [PMID: 31452959]
[27]
Jacquemet G, Hamidi H, Ivaska J. Filopodia in cell adhesion, 3D migration and cancer cell invasion. Curr Opin Cell Biol 2015; 36: 23-31.
[http://dx.doi.org/10.1016/j.ceb.2015.06.007] [PMID: 26186729]
[28]
Beri P, Popravko A, Yeoman B, et al. Cell adhesiveness serves as a biophysical marker for metastatic potential. Cancer Res 2020; 80(4): 901-11.
[http://dx.doi.org/10.1158/0008-5472.CAN-19-1794] [PMID: 31857292]
[29]
Jiang W, Liang Y-L, Liu Y, et al. MeCP2 inhibits proliferation and migration of breast cancer via suppression of epithelial-mesenchymal transition. J Cell Mol Med 2020; 24(14): 7959-67.
[http://dx.doi.org/10.1111/jcmm.15428] [PMID: 32510753]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy