A Strategy based on Bioinformatics and Machine Learning Algorithms Reveals Potential Mechanisms of Shelian Capsule against Hepatocellular Carcinoma


Cite item

Full Text

Abstract

Background:Hepatocellular carcinoma (HCC) is a prevalent and life-threatening form of cancer, with Shelian Capsule (SLC), a traditional Chinese medicine (TCM) formulation, being recommended for clinical treatment. However, the mechanisms underlying its efficacy remain elusive. This study sought to uncover the potential mechanisms of SLC in HCC treatment using bioinformatics methods.

Methods:Bioactive components of SLC were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and HCC-related microarray chip data were sourced from the Gene Expression Omnibus (GEO) database. The selection criteria for components included OB ≧ 30% and DL ≧ 0.18. By integrating the results of differential expression analysis and weighted gene co-expression network analysis (WGCNA), disease-related genes were identified. Therapeutic targets were determined as shared items between candidate targets and disease genes. Protein-protein interaction (PPI) network analysis was conducted for concatenated genes, with core protein clusters identified using the MCODE plugin. Machine learning algorithms were applied to identify signature genes within therapeutic targets. Subsequently, immune cell infiltration analysis, single-cell RNA sequencing (sc-RNA seq) analysis, molecular docking, and ADME analysis were performed for the screened genes.

Result:A total of 153 SLC ingredients and 170 candidate targets were identified, along with 494 HCCrelated disease genes. Overlapping items between disease genes and drug candidates represented therapeutic genes, and PPI network analysis was conducted using concatenated genes. MCODE1 and MCODE2 cluster genes underwent Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Four signature genes (TOP2A, CYP1A2, CYP2B6, and IGFBP3) were identified from 28 therapeutic genes using 3 machine learning algorithms, with ROC curves plotted. Molecular docking validated the interaction modes and binding abilities between signature genes and corresponding compounds, with free binding energy all <-7 kcal/mol. Finally, ADME analysis revealed similarities between certain SLC components and the clinical drugs Sorafenib and Lenvatinib.

Conclusion:In summary, our study revealed that the mechanism underlying the anti-HCC effects of SLC involves interactions at three levels: components (quercetin, beta-sitosterol, kaempferol, baicalein, stigmasterol, and luteolin), pathways (PI3K-Akt signaling pathway, TNF signaling pathway, and IL-17 signaling pathway), and targets (TOP2A, CYP1A2, CYP2B6, and IGFBP3). This study provides preliminary insights into the potential pharmacological mechanisms of SLC in HCC treatment, aiming to support its clinical application and serve as a reference for future laboratory investigations.

About the authors

Xianqiang Zhou

Department of Traditional Chinese Medicine, Shanghai Medical College, Jing’an District Central Hospital Affiliated to Fudan University

Email: info@benthamscience.net

Fang Tan

Department of Neurology,, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine

Email: info@benthamscience.net

Suxian Zhang

Department of Traditional Chinese Medicine, Shanghai Medical College, Jing’an District Central Hospital Affiliated to Fudan University

Email: info@benthamscience.net

An'an Wang

Department of Pulmonary Diseases, Shanghai University of Traditional Chinese Medicine,

Author for correspondence.
Email: info@benthamscience.net

Tiansong Zhang

Department of Traditional Chinese Medicine, Shanghai Medical College, Jing’an District Central Hospital Affiliated to Fudan University,

Author for correspondence.
Email: info@benthamscience.net

References

  1. Wen N, Cai Y, Li F, et al. The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines: 2022 update. Biosci Trends 2022; 16(1): 20-30. doi: 10.5582/bst.2022.01061 PMID: 35197399
  2. Xu J. Trends in liver cancer mortality among adults aged 25 and over in the United States, 2000-2016. NCHS Data Brief 2018; (314): 1-8. PMID: 30044212
  3. Jemal A, Ward EM, Johnson CJ, et al. Annual report to the nation on the status of cancer, 1975-2014, featuring survival. J Natl Cancer Inst 2017; 109(9): djx030. doi: 10.1093/jnci/djx030 PMID: 28376154
  4. 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. doi: 10.1038/s41575-019-0186-y PMID: 31439937
  5. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017; 153(4): 996-1005.e1. doi: 10.1053/j.gastro.2017.06.012 PMID: 28642197
  6. Villanueva A. Hepatocellular carcinoma. N Engl J Med 2019; 380(15): 1450-62. doi: 10.1056/NEJMra1713263 PMID: 30970190
  7. Gusani NJ, Jiang Y, Kimchi ET. Staveley-OʼCarroll KF, Cheng H, Ajani JA. New pharmacological developments in the treatment of hepatocellular cancer. Drugs 2009; 69(18): 2533-40. doi: 10.2165/11530870-000000000-00000 PMID: 19943706
  8. Zhang LY, Zhang JG, Yang X, Cai MH, Zhang CW, Hu ZM. Targeting tumor immunosuppressive microenvironment for the prevention of hepatic cancer: Applications of traditional chinese medicines in targeted delivery. Curr Top Med Chem 2020; 20(30): 2789-800. doi: 10.2174/1568026620666201019111524 PMID: 33076809
  9. Tong WU, Zhiyun Y, Yuying Y, et al. Effect of decoction of Fuzheng Jiedu Xiaoji formula plus chemoembolization on primary liver cancer in patients. J Tradit Chin Med 2022; 42(3): 446-50. doi: 10.19852/j.cnki.jtcm.2022.03.011 PMID: 35610015
  10. Chen TT, Du SL, Wang SJ, Wu L, Yin L. Dahuang Zhechong pills inhibit liver cancer growth in a mouse model by reversing Treg/Th1 balance. Chin J Nat Med 2022; 20(2): 102-10. doi: 10.1016/S1875-5364(22)60160-2 PMID: 35279237
  11. Zhai X, Liu X, Shen F, Fan J, Ling C. Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: A randomized controlled study. Cancer 2018; 124(10): 2161-8. doi: 10.1002/cncr.30915 PMID: 29499082
  12. Soilemezi D, Leydon GM, Yan R, et al. Herbal medicine for acute bronchitis: A qualitative interview study of patients’ and health professionals’ views. Complement Ther Med 2020; 55: 102613. doi: 10.1016/j.ctim.2020.102613 PMID: 33221589
  13. Zhang X, Hu M, Li S, et al. Clinical study on Yanghe decoction in improving neo-adjuvant chemotherapy efficacy and immune function of breast cancer patients. Medicine 2022; 101(10): e29031. doi: 10.1097/MD.0000000000029031 PMID: 35451408
  14. Panahi Y, Saberi-Karimian M, Valizadeh O, et al. Effects of curcuminoids on systemic inflammation and quality of life in patients with colorectal cancer undergoing chemotherapy: A randomized controlled trial. Adv Exp Med Biol 2021; 1328: 1-9. doi: 10.1007/978-3-030-73234-9_1 PMID: 34981467
  15. Liu J, Wang J, Guo Y, Zhang H. The efficacy of psychological care and chinese herbal decoction in postoperative chemotherapy patients with endometrial cancer. J Healthc Eng 2022; 2022: 5700637. doi: 10.1155/2022/5700637
  16. Wei XM, Chen XF, Shu P, et al. Study on efficacy and safety of Huangqi Guizhi Wuwu decoction treatment for oxaliplatin induced peripheral neurotoxicity. Medicine 2020; 99(22): e19923. doi: 10.1097/MD.0000000000019923 PMID: 32481364
  17. Xu R, Wu J, Zhang X, et al. Modified Bu-zhong-yi-qi decoction synergies with 5 fluorouracile to inhibits gastric cancer progress via PD-1/PD- L1-dependent T cell immunization. Pharmacol Res 2020; 152: 104623. doi: 10.1016/j.phrs.2019.104623 PMID: 31899315
  18. Gao WB, Han JD, Du M. Observation on efficiency of shelian capsule as adjuvant of embolismic chemotherapy on primary hepatic carcinoma. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 2005; 25(11): 980-2. PMID: 16355611
  19. Hopkins AL. Network pharmacology: The next paradigm in drug discovery. Nat Chem Biol 2008; 4(11): 682-90. doi: 10.1038/nchembio.118 PMID: 18936753
  20. Li J, Bi D, Zhang X, Cao Y, Lv K, Jiang L. Network pharmacology and inflammatory microenvironment strategy approach to finding the potential target of Siraitia grosvenorii (Luo Han Guo) for glioblastoma. Front Genet 2021; 12: 799799. doi: 10.3389/fgene.2021.799799 PMID: 34987553
  21. Li C, Du X, Liu Y, et al. A systems pharmacology approach for identifying the multiple mechanisms of action for the rougui-fuzi herb pair in the treatment of cardiocerebral vascular diseases. Evid Based Complement Alternat Med 2020; 2020: 5196302. doi: 10.1155/2020/5196302
  22. Bateman A, Martin M-J, Orchard S, et al. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res 2021; 49(D1): D480-9. doi: 10.1093/nar/gkaa1100 PMID: 33237286
  23. Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: Archive for functional genomics data sets-update. Nucleic Acids Res 2012; 41(D1): D991-5. doi: 10.1093/nar/gks1193 PMID: 23193258
  24. Debrabant B. The null hypothesis of GSEA, and a novel statistical model for competitive gene set analysis. Bioinformatics 2017; 33(9): 1271-7. doi: 10.1093/bioinformatics/btw803 PMID: 28453686
  25. Langfelder P, Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 2008; 9(1): 559. doi: 10.1186/1471-2105-9-559 PMID: 19114008
  26. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12. doi: 10.1093/nar/gkaa1074 PMID: 33237311
  27. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017; 45(W1): W98-W102. doi: 10.1093/nar/gkx247 PMID: 28407145
  28. Burley SK, Bhikadiya C, Bi C, et al. RCSB Protein Data Bank: Powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences. Nucleic Acids Res 2021; 49(D1): D437-51. doi: 10.1093/nar/gkaa1038 PMID: 33211854
  29. Lohning AE, Levonis SM, Williams-Noonan B, Schweiker SS. A practical guide to molecular docking and homology modelling for medicinal chemists. Curr Top Med Chem 2017; 17(18): 2023-40. doi: 10.2174/1568026617666170130110827 PMID: 28137238
  30. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7(1): 42717. doi: 10.1038/srep42717 PMID: 28256516
  31. Bureau of Medical Administration. National health commission of the People’s Republic of China. Zhonghua Gan Zang Bing Za Zhi 2022; 30: 367-88. doi: 10.3760/cma.j.cn501113-20220413-00193
  32. Wong KM, King GG, Harris WP. The treatment landscape of advanced hepatocellular carcinoma. Curr Oncol Rep 2022; 24: 917-27. doi: 10.1007/s11912-022-01247-7
  33. Guo M, Zhang H, Zheng J, Liu Y. Glypican-3: A new target for diagnosis and treatment of hepatocellular carcinoma. J Cancer 2020; 11(8): 2008-21. doi: 10.7150/jca.39972 PMID: 32127929
  34. Ruan W, Yang Y, Yu Q, et al. FUT11 is a target gene of HIF1α that promotes the progression of hepatocellular carcinoma. Cell Biol Int 2021; 45(11): 2275-86. doi: 10.1002/cbin.11675 PMID: 34288238
  35. Ni S, Wei Q, Yang L. ADORA1 promotes hepatocellular carcinoma progression via PI3K/AKT pathway. OncoTargets Ther 2020; 13: 12409-19. doi: 10.2147/OTT.S272621 PMID: 33293832
  36. Xin R-Q, Li W-B, Hu Z-W, Wu Z-X, Sun W. MiR-329-3p inhibits hepatocellular carcinoma cell proliferation and migration through USP22-Wnt/β-catenin pathway. Eur Rev Med Pharmacol Sci 2020; 24(19): 9932-9. doi: 10.26355/eurrev_202010_23204 PMID: 33090397
  37. Yang JD, Heimbach JK. New advances in the diagnosis and management of hepatocellular carcinoma. BMJ 2020; 371: m3544. doi: 10.1136/bmj.m3544 PMID: 33106289
  38. Huang L, Xu H, Wu T, Li G. Hedyotis diffusa Willd. suppresses hepatocellular carcinoma via downregulating AKT/mTOR pathways. Evid Based Complement Alternat Med 2021; 2021: 5210152. doi: 10.1155/2021/5210152
  39. Li Y, Zhang J, Zhang K, et al. Scutellaria barbata inhibits hepatocellular carcinoma tumorigenicity by inducing ferroptosis of hepatocellular carcinoma cells. Front Oncol 2022; 12: 693395. doi: 10.3389/fonc.2022.693395 PMID: 35321425
  40. Zhijun D, Xiaoxu L, Zongzheng J, et al. The effect-enhancing and toxicity-reducing action of the extract of herba Scutellariae barbatae for chemotherapy in hepatoma H22 tumor-bearing mice. J Tradit Chin Med 2008; 28(3): 205-10. doi: 10.1016/S0254-6272(08)60048-5 PMID: 19004205
  41. Kaya P, Lee S, Lee Y, et al. Curcumae radix extract decreases mammary tumor-derived lung metastasis via suppression of C-C chemokine receptor type 7 expression. Nutrients 2019; 11(2): 410. doi: 10.3390/nu11020410 PMID: 30781353
  42. Luo Y, Feng Y, Song L, et al. A network pharmacology-based study on the anti-hepatoma effect of Radix Salviae miltiorrhizae. Chin Med 2019; 14(1): 27. doi: 10.1186/s13020-019-0249-6 PMID: 31406500
  43. Wu J, Huang G, Li Y, Li X. Flavonoids from Aurantii fructus Immaturus and Aurantii fructus: Promising phytomedicines for the treatment of liver diseases. Chin Med 2020; 15(1): 89. doi: 10.1186/s13020-020-00371-5 PMID: 32863858
  44. Qi CY, Wang J, Wu X, et al. Botanical, traditional use, phytochemical, and toxicological of arisaematis rhizoma. Evid Based Complement Alternat Med 2021; 2021: 9055574. doi: 10.1155/2021/9055574
  45. Helms S. Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev 2004; 9(3): 259-74. PMID: 15387718
  46. Wu H, Pan L, Gao C, et al. Quercetin inhibits the proliferation of glycolysis-addicted HCC cells by reducing hexokinase 2 and Akt-mTOR pathway. Molecules 2019; 24(10): 1993. doi: 10.3390/molecules24101993 PMID: 31137633
  47. Salama YA, El-karef A, El Gayyar AM, Abdel-Rahman N. Beyond its antioxidant properties: Quercetin targets multiple signalling pathways in hepatocellular carcinoma in rats. Life Sci 2019; 236: 116933. doi: 10.1016/j.lfs.2019.116933 PMID: 31614146
  48. Lee RH, Cho JH, Jeon YJ, et al. Quercetin induces antiproliferative activity against human hepatocellular carcinoma (HepG2) cells by suppressing specificity protein 1 (Sp1). Drug Dev Res 2015; 76(1): 9-16. doi: 10.1002/ddr.21235 PMID: 25619802
  49. Ji Y, Li L, Ma YX, et al. Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice. J Nutr Biochem 2019; 69: 108-19. doi: 10.1016/j.jnutbio.2019.03.018 PMID: 31078904
  50. Chen Z, Huang C, Ma T, et al. Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells. Phytomedicine 2018; 43: 37-45. doi: 10.1016/j.phymed.2018.03.040 PMID: 29747752
  51. Zhao J, Zhao J, Jiao H. Synergistic growth-suppressive effects of quercetin and cisplatin on HepG2 human hepatocellular carcinoma cells. Appl Biochem Biotechnol 2014; 172(2): 784-91. doi: 10.1007/s12010-013-0561-z PMID: 24122665
  52. Dai W, Gao Q, Qiu J, Yuan J, Wu G, Shen G. Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma. Tumour Biol 2016; 37(5): 6307-13. doi: 10.1007/s13277-015-4501-0 PMID: 26628295
  53. Qi SZ, Zhang XX, Jin Y, et al. Phenylpropanoid-conjugated pentacyclic triterpenoids from the whole plants of Leptopus lolonum induced cell apoptosis via MAPK and Akt pathways in human hepatocellular carcinoma cells. Bioorg Chem 2021; 111: 104886. doi: 10.1016/j.bioorg.2021.104886 PMID: 33836342
  54. Ditty MJ, Ezhilarasan D. β-sitosterol induces reactive oxygen species-mediated apoptosis in human hepatocellular carcinoma cell line. Avicenna J Phytomed 2021; 11(6): 541-50. doi: 10.22038/AJP.2021.17746 PMID: 34804892
  55. Li J, Duan B, Guo Y, et al. Baicalein sensitizes hepatocellular carcinoma cells to 5-FU and Epirubicin by activating apoptosis and ameliorating P-glycoprotein activity. Biomed Pharmacother 2018; 98: 806-12. doi: 10.1016/j.biopha.2018.01.002 PMID: 29571250
  56. Guo H, Ren F, Zhang L, et al. Kaempferol induces apoptosis in HepG2 cells via activation of the endoplasmic reticulum stress pathway. Mol Med Rep 2016; 13(3): 2791-800. doi: 10.3892/mmr.2016.4845 PMID: 26847723
  57. Han B, Yu YQ, Yang QL, Shen CY, Wang XJ. Kaempferol induces autophagic cell death of hepatocellular carcinoma cells via activating AMPK signaling. Oncotarget 2017; 8(49): 86227-39. doi: 10.18632/oncotarget.21043 PMID: 29156790
  58. Guo H, Lin W, Zhang X, et al. Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway. Oncotarget 2017; 8(47): 82207-16. doi: 10.18632/oncotarget.19200 PMID: 29137257
  59. Ju PC, Ho YC, Chen PN, et al. Kaempferol inhibits the cell migration of human hepatocellular carcinoma cells by suppressing MMP-9 and Akt signaling. Environ Toxicol 2021; 36(10): 1981-9. doi: 10.1002/tox.23316 PMID: 34156145
  60. Mylonis I, Lakka A, Tsakalof A, Simos G. The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions. Biochem Biophys Res Commun 2010; 398(1): 74-8. doi: 10.1016/j.bbrc.2010.06.038 PMID: 20558139
  61. Sánchez-Crisóstomo I, Fernández-Martínez E, Cariño-Cortés R, Betanzos-Cabrera G, Bobadilla-Lugo RA. Phytosterols and triterpenoids for prevention and treatment of metabolic-related liver diseases and hepatocellular carcinoma. Curr Pharm Biotechnol 2019; 20: 197-214. doi: 10.2174/1389201020666190219122357
  62. Varshosaz J, Jafarian A, Salehi G, Zolfaghari B. Comparing different sterol containing solid lipid nanoparticles for targeted delivery of quercetin in hepatocellular carcinoma. J Liposome Res 2014; 24(3): 191-203. doi: 10.3109/08982104.2013.868476 PMID: 24354715
  63. Lee WJ, Wu LF, Chen WK, Wang CJ, Tseng TH. Inhibitory effect of luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways. Chem Biol Interact 2006; 160(2): 123-33. doi: 10.1016/j.cbi.2006.01.002 PMID: 16458870
  64. Lee HJ, Wang CJ, Kuo HC, Chou FP, Jean LF, Tseng TH. Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. Toxicol Appl Pharmacol 2005; 203(2): 124-31. doi: 10.1016/j.taap.2004.08.004 PMID: 15710173
  65. Feng XQ, Rong LW, Wang RX, et al. Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation. Oncol Lett 2018; 16(1): 648-53. doi: 10.3892/ol.2018.8640 PMID: 29928452
  66. Fujiwara Y, Hoon DSB, Yamada T, et al. PTEN/MMAC1 mutation and frequent loss of heterozygosity identified in chromosome 10q in a subset of hepatocellular carcinomas. Jpn J Cancer Res 2000; 91(3): 287-92. doi: 10.1111/j.1349-7006.2000.tb00943.x PMID: 10760687
  67. Liao J, Jin H, Li S, et al. Apatinib potentiates irradiation effect via suppressing PI3K/AKT signaling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res 2019; 38(1): 454. doi: 10.1186/s13046-019-1419-1 PMID: 31694662
  68. Liu JS, Huo CY, Cao HH, et al. Aloperine induces apoptosis and G2/M cell cycle arrest in hepatocellular carcinoma cells through the PI3K/Akt signaling pathway. Phytomedicine 2019; 61: 152843. doi: 10.1016/j.phymed.2019.152843 PMID: 31039533
  69. Idriss HT, Naismith JH. TNF? and the TNF receptor superfamily: Structure-function relationship(s). Microsc Res Tech 2000; 50(3): 184-95. doi: 10.1002/1097-0029(20000801)50:33.0.CO;2-H PMID: 10891884
  70. Olsson I, Gatanaga T, Gullberg U, Lantz M, Granger GA. Tumour necrosis factor (TNF) binding proteins (soluble TNF receptor forms) with possible roles in inflammation and malignancy. Eur Cytokine Netw 1993; 4(3): 169-80. PMID: 8218941
  71. Aroucha DC, Carmo RF, Vasconcelos LRS, et al. TNF-α and IL-10 polymorphisms increase the risk to hepatocellular carcinoma in HCV infected individuals. J Med Virol 2016; 88(9): 1587-95. doi: 10.1002/jmv.24501 PMID: 26890368
  72. Liao R, Sun J, Wu H, et al. High expression of IL-17 and IL-17RE associate with poor prognosis of hepatocellular carcinoma. J Exp Clin Cancer Res 2013; 32(1): 3. doi: 10.1186/1756-9966-32-3 PMID: 23305119
  73. Yu J, Xia X, Dong Y, et al. CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling. Theranostics 2021; 11(5): 2123-36. doi: 10.7150/thno.49368 PMID: 33500715
  74. Chen H, Shen Z-Y, Xu W, et al. Expression of P450 and nuclear receptors in normal and end-stage Chinese livers. World J Gastroenterol 2014; 20(26): 8681-90. doi: 10.3748/wjg.v20.i26.8681 PMID: 25024626
  75. Cai H, Shao B, Zhou Y, Chen Z. High expression of TOP2A in hepatocellular carcinoma is associated with disease progression and poor prognosis. Oncol Lett 2020; 20(5): 1. doi: 10.3892/ol.2020.12095 PMID: 32968454
  76. Wang T, Lu J, Wang R, Cao W, Xu J. TOP2A promotes proliferation and metastasis of hepatocellular carcinoma regulated by miR-144-3p. J Cancer 2022; 13(2): 589-601. doi: 10.7150/jca.64017 PMID: 35069905
  77. Yin J, Ding J, Huang L, et al. SND1 affects proliferation of hepatocellular carcinoma cell line SMMC-7721 by regulating IGFBP3 expression. Anat Rec 2013; 296(10): 1568-75. doi: 10.1002/ar.22737 PMID: 23878061
  78. Yumoto E, Nakatsukasa H, Hanafusa T, et al. IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-beta and/or Rb signaling pathways. Int J Oncol 2005; 27(5): 1223-30. PMID: 16211216
  79. Wang H, Wang H, Li K, Li S, Sun B. IGFBP-3 is the key target of sanguinarine in promoting apoptosis in hepatocellular carcinoma. Cancer Manag Res 2020; 12: 1007-15. doi: 10.2147/CMAR.S234291 PMID: 32104082

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers