Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Research Article

Identification of the Roles of Coagulation-related Signature and its Key Factor RABIF in Hepatoma Cell Malignancy

Author(s): Yanying Chen, Yin Li and Bingyi Zhou*

Volume 19, Issue 5, 2024

Published on: 26 September, 2023

Page: [695 - 710] Pages: 16

DOI: 10.2174/1574892819666230829151148

Price: $65

Abstract

Background: Hepatoma is a high morbidity and mortality cancer, and coagulation is a potential oncogenic mechanism for hepatoma development.

Objective: In this study, we aimed to reveal the role of coagulation in hepatoma.

Methods: We applied the LASSO to construct a coagulation-related risk score (CRS) and a clinical nomogram with independent validation. The heterogeneity of various aspects, including functional enrichment, SNV, CN, immunocyte infiltration, immune pathways, immune checkpoint, and genomic instability indexes, was evaluated. Besides, the prognostic value of the CRS genes was tested. We selected the critical risky gene related to coagulation from the LASSO coefficients, for which we applied transwell and clone formation assays to confirm its roles in hepatoma cell migration and clone formation ability, respectively.

Results: The CRS and the nomogram predicted patients’ survival with good accuracy in both two datasets. The high-CRS group was associated with higher cell cycle, DNA repair, TP53 mutation rates, amplification, and lower deletion rates at chromosome 1. For immunocyte infiltration, we noticed increased Treg infiltration and globally upregulated immune checkpoints and genomic instability indexes. Additionally, every single CRS gene affected the patient’s survival. Finally, we observed that RABIF was the riskiest gene in the CRS. Its knockdown suppressed hepatoma cell migration and clone formation capability, which could be rescued by RABIF overexpression.

Conclusion: We built a robust CRS with great potential as a prognosis and immunotherapeutic indicator. Importantly, we identified RABIF as an oncogene, promoting hepatoma cell migration and clone formation, revealing underlying pathological mechanisms, and providing novel therapeutic targets for hepatoma treatment.

[1]
Villanueva A. Hepatocellular carcinoma. N Engl J Med 2019; 380(15): 1450-62.
[http://dx.doi.org/10.1056/NEJMra1713263] [PMID: 30970190]
[2]
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391(10127): 1301-14.
[http://dx.doi.org/10.1016/S0140-6736(18)30010-2] [PMID: 29307467]
[3]
Zhou H, Song T. Conversion therapy and maintenance therapy for primary hepatocellular carcinoma. Biosci Trends 2021; 15(3): 155-60.
[http://dx.doi.org/10.5582/bst.2021.01091] [PMID: 34039818]
[4]
Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol 2022; 19(3): 151-72.
[http://dx.doi.org/10.1038/s41571-021-00573-2] [PMID: 34764464]
[5]
Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: Biological and clinical aspects. J Thromb Haemost 2013; 11(2): 223-33.
[http://dx.doi.org/10.1111/jth.12075] [PMID: 23279708]
[6]
Jia Q, Xue T, Zhang Q, et al. CCN3 is a therapeutic target relating enhanced stemness and coagulation in hepatocellular carcinoma. Sci Rep 2017; 7(1): 13846.
[http://dx.doi.org/10.1038/s41598-017-14087-4] [PMID: 29061995]
[7]
Tibshirani R. The lasso method for variable selection in the Cox model. Stat Med 1997; 16(4): 385-95.
[http://dx.doi.org/10.1002/(SICI)1097-0258(19970228)16:4<385::AID-SIM380>3.0.CO;2-3] [PMID: 9044528]
[8]
Charoentong P, Finotello F, Angelova M, et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep 2017; 18(1): 248-62.
[http://dx.doi.org/10.1016/j.celrep.2016.12.019] [PMID: 28052254]
[9]
Chen DS, Mellman I. Oncology meets immunology: The cancer-immunity cycle. Immunity 2013; 39(1): 1-10.
[http://dx.doi.org/10.1016/j.immuni.2013.07.012] [PMID: 23890059]
[10]
Schubert M, Klinger B, Klünemann M, et al. Perturbation-response genes reveal signaling footprints in cancer gene expression. Nat Commun 2018; 9(1): 20.
[http://dx.doi.org/10.1038/s41467-017-02391-6] [PMID: 29295995]
[11]
Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 2015; 12(5): 453-7.
[http://dx.doi.org/10.1038/nmeth.3337] [PMID: 25822800]
[12]
Becht E, Giraldo NA, Lacroix L, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol 2016; 17(1): 218.
[http://dx.doi.org/10.1186/s13059-016-1070-5] [PMID: 27765066]
[13]
Li B, Severson E, Pignon JC, et al. Comprehensive analyses of tumor immunity: Implications for cancer immunotherapy. Genome Biol 2016; 17(1): 174.
[http://dx.doi.org/10.1186/s13059-016-1028-7] [PMID: 27549193]
[14]
Aran D, Hu Z, Butte AJ. xCell: Digitally portraying the tissue cellular heterogeneity landscape. Genome Biol 2017; 18(1): 220.
[http://dx.doi.org/10.1186/s13059-017-1349-1] [PMID: 29141660]
[15]
Racle J, de Jonge K, Baumgaertner P, Speiser DE, Gfeller D. Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. eLife 2017; 6: e26476.
[http://dx.doi.org/10.7554/eLife.26476] [PMID: 29130882]
[16]
Finotello F, Mayer C, Plattner C, et al. Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data. Genome Med 2019; 11(1): 34.
[http://dx.doi.org/10.1186/s13073-019-0638-6] [PMID: 31126321]
[17]
Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018; 48(4): 812-830.e14.
[http://dx.doi.org/10.1016/j.immuni.2018.03.023] [PMID: 29628290]
[18]
Liang X, Wang Z, Dai Z, Zhang H, Cheng Q, Liu Z. Promoting prognostic model application: A review based on gliomas. J Oncol 2021; 2021: 1-14.
[http://dx.doi.org/10.1155/2021/7840007] [PMID: 34394352]
[19]
Sauzeau V, Beignet J, Vergoten G, Bailly C. Overexpressed or hyperactivated Rac1 as a target to treat hepatocellular carcinoma. Pharmacol Res 2022; 179: 106220.
[http://dx.doi.org/10.1016/j.phrs.2022.106220] [PMID: 35405309]
[20]
Li LM, Chen C, Ran RX, et al. Loss of TARBP2 drives the progression of hepatocellular carcinoma via miR-145-SERPINE1 axis. Front Oncol 2021; 11: 620912.
[http://dx.doi.org/10.3389/fonc.2021.620912] [PMID: 34249676]
[21]
Dong Y, Wu Z, He M, et al. ADAM9 mediates the interleukin-6-induced Epithelial–Mesenchymal transition and metastasis through ROS production in hepatoma cells. Cancer Lett 2018; 421: 1-14.
[http://dx.doi.org/10.1016/j.canlet.2018.02.010] [PMID: 29432845]
[22]
Liu H, Lan T, Li H, et al. Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR. Theranostics 2021; 11(3): 1396-411.
[http://dx.doi.org/10.7150/thno.53227] [PMID: 33391541]
[23]
OuYang HY, Xu J, Luo J, et al. MEP1A contributes to tumor progression and predicts poor clinical outcome in human hepatocellular carcinoma. Hepatology 2016; 63(4): 1227-39.
[http://dx.doi.org/10.1002/hep.28397] [PMID: 26660154]
[24]
Pawlinski R, Mackman N. Use of mouse models to study the role of tissue factor in tumor biology. Semin Thromb Hemost 2008; 34(2): 182-6.
[http://dx.doi.org/10.1055/s-2008-1079258] [PMID: 18645923]
[25]
Mueller BM, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis. J Clin Invest 1998; 101(7): 1372-8.
[http://dx.doi.org/10.1172/JCI930] [PMID: 9525979]
[26]
Versteeg HH, Arnold Spek C, Richel DJ, Peppelenbosch MP. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene 2004; 23(2): 410-7.
[http://dx.doi.org/10.1038/sj.onc.1207066] [PMID: 14724569]
[27]
Ruf W, Graf C. Coagulation signaling and cancer immunotherapy. Thromb Res 2020; 191 (Suppl. 1): S106-11.
[http://dx.doi.org/10.1016/S0049-3848(20)30406-0] [PMID: 32736766]
[28]
Xu D, Wu J, Dong L, et al. Serpinc1 acts as a tumor suppressor in hepatocellular carcinoma through inducing apoptosis and blocking macrophage polarization in an ubiquitin-proteasome manner. Front Oncol 2021; 11: 738607.
[http://dx.doi.org/10.3389/fonc.2021.738607] [PMID: 34881176]
[29]
Langhans B, Nischalke HD, Krämer B, et al. Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma. Cancer Immunol Immunother 2019; 68(12): 2055-66.
[http://dx.doi.org/10.1007/s00262-019-02427-4] [PMID: 31724091]
[30]
Kuang X, Li J. Chromosome instability and aneuploidy as context-dependent activators or inhibitors of antitumor immunity. Front Immunol 2022; 13: 895961.
[http://dx.doi.org/10.3389/fimmu.2022.895961] [PMID: 36003402]
[31]
Zhou Z, Ding Z, Yuan J, et al. Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients. J Hematol Oncol 2022; 15(1): 62.
[http://dx.doi.org/10.1186/s13045-022-01283-7] [PMID: 35585646]

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