GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications

References

• Bootcov MR, Bauskin AR, Valenzuela SM, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci USA. 1997;94(21):11514–11519. doi:10.1073/pnas.94.21.11514
   PubMed Web of Science ®Google Scholar
• Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE. Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol. 2001;59(4):901–908. doi:10.1124/mol.59.4.901
   PubMed Web of Science ®Google Scholar
• Hsu JY, Crawley S, Chen M, et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature. 2017;550:255–259. doi:10.1038/nature24042
   PubMed Web of Science ®Google Scholar
• Bauskin AR, Zhang HP, Fairlie WD, et al. The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1. EMBO J. 2000;19(10):2212–2220. doi:10.1093/emboj/19.10.2212
   PubMed Web of Science ®Google Scholar
• Yang W, Mok MT, Li MS, et al. Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development. Oncogene. 2016;35(16):2133–2144. doi:10.1038/onc.2015.276
   PubMed Web of Science ®Google Scholar
• Levine AJ, Brivanlou AH GDF3, a BMP inhibitor, regulates cell fate in stem cells and early embryos; 2006.
   Google Scholar
• Miyamoto Y, Mabuchi A, Shi D, et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nature Genet. 2007;39(4):529–533. doi:10.1038/2005
   PubMed Web of Science ®Google Scholar
• Capellini TD, Chen H, Cao J, et al. Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk. Nature Genet. 2017;49(8):1202–1210. doi:10.1038/ng.3911
   PubMed Web of Science ®Google Scholar
• Lee KJ, Mendelsohn M, Jessell TM. Neuronal patterning by BMPs: a requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord. Genes Dev. 1998;12(21):3394–3407. doi:10.1101/gad.12.21.3394
   PubMed Web of Science ®Google Scholar
• Paralkar VM, Vail AL, Grasser WA, et al. Cloning and characterization of a novel member of the transforming growth factor-β/bone morphogenetic protein family. J Biol Chem. 1998;273(22):13760–13767. doi:10.1074/jbc.273.22.13760
   PubMed Web of Science ®Google Scholar
• Emmerson PJ, Duffin KL, Wu X. GDF15 and growth control. Front Physiol. 2018;9:411437. doi:10.3389/fphys.2018.01712
   Web of Science ®Google Scholar
• Yang L, Chang CC, Sun Z, et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017;23(10):1158–1166. doi:10.1038/nm.4394
   PubMed Web of Science ®Google Scholar
• Mullican SE, Lin-Schmidt X, Chin CN, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23(10):1150–1157. doi:10.1038/nm.4392
   PubMed Web of Science ®Google Scholar
• Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42(2):581–588. doi:10.1016/0092-8674(85)90115-1
   PubMed Web of Science ®Google Scholar
• Olsen OE, Skjærvik A, Størdal BF, Sundan A, Holien T. TGF-β contamination of purified recombinant GDF15. PLoS One. 2017;12(11):e0187349. doi:10.1371/journal.pone.0187349
   PubMed Web of Science ®Google Scholar
• Shlomai A, de Jong YP, Rice CM. Virus Associated Malignancies: The Role of Viral Hepatitis in Hepatocellular Carcinoma. Elsevier; 2014:78–88.
   Google Scholar
• Baecker A, Liu X, La Vecchia C, Zhang ZF. Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors. Eur J Cancer Prev. 2018;27(3):205–212. doi:10.1097/cej.0000000000000428
   PubMed Web of Science ®Google Scholar
• Donne R, Lujambio A. The liver cancer immune microenvironment: therapeutic implications for hepatocellular carcinoma. Hepatology. 2023;77(5):1773–1796. doi:10.1002/hep.32740
   PubMed Web of Science ®Google Scholar
• Ogunwobi OO, Harricharran T, Huaman J, et al. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol. 2019;25(19):2279. doi:10.3748/wjg.v25.i19.2279
   PubMed Web of Science ®Google Scholar
• Liu H, Huang Y, Lyu Y, Dai W, Tong Y, Li Y. GDF15 as a biomarker of ageing. Exp Gerontology. 2021;146:111228. doi:10.1016/j.exger.2021.111228
   PubMed Web of Science ®Google Scholar
• Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol. 2021;17(10):592–607. doi:10.1038/s41574-021-00529-7
   PubMed Web of Science ®Google Scholar
• Li C, Wang J, Kong J, et al. GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget. 2016;7(1):860. doi:10.18632/oncotarget.6205
   PubMedGoogle Scholar
• Gao Y, Xu Y, Zhao S, et al. Growth differentiation factor-15 promotes immune escape of ovarian cancer via targeting CD44 in dendritic cells. Exp Cell Res. 2021;402(1):112522. doi:10.1016/j.yexcr.2021.112522
   PubMed Web of Science ®Google Scholar
• Wang Z, He L, Li W, et al. GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma. J Immunoth Can. 2021;9(9). doi:10.1136/jitc-2021-002787
   Web of Science ®Google Scholar
• M-Z M, Zhang X-H, Li B, Liang T-J, Yang C-M, Liu J-Y. Growth differentiation factor 15 (GDF15) contributes to invasion and anti-anoikis of hepatocellular cancer through TGF-β/Smad-associated signaling. Int J Clin Exp Med. 2018;11(12):12964–12973.
   Web of Science ®Google Scholar
• Fang L, Li F, Gu C. GDF-15: a multifunctional modulator and potential therapeutic target in cancer. Curr. Pharm. Des. 2019;25(6):654–662. doi:10.2174/1381612825666190402101143
   PubMed Web of Science ®Google Scholar
• Spanopoulou A, Gkretsi V. Growth differentiation factor 15 (GDF15) in cancer cell metastasis: from the cells to the patients. Clin Exp Metastasis. 2020;37(4):451–464. doi:10.1007/s10585-020-10041-3
   PubMed Web of Science ®Google Scholar
• Emmerson PJ, Wang F, Du Y, et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nature Med. 2017;23(10):1215–1219. doi:10.1038/nm.4393
   PubMed Web of Science ®Google Scholar
• Xu Q, H-X X, J-P L, et al. Growth differentiation factor 15 induces growth and metastasis of human liver cancer stem-like cells via AKT/GSK-3β/β-catenin signaling. Oncotarget. 2017;8(10):16972. doi:10.18632/oncotarget.15216
   PubMedGoogle Scholar
• Benkheil M, Paeshuyse J, Neyts J, Van Haele M, Roskams T, Liekens S. HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis. Biochem Pharmacol. 2018;155:305–315. doi:10.1016/j.bcp.2018.07.011
   PubMed Web of Science ®Google Scholar
• Dong G, Zheng QD, Ma M, et al. Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF 15. Cancer Med. 2018;7(3):820–830. doi:10.1002/cam4.1330
   PubMed Web of Science ®Google Scholar
• Yu J, Shen B, Chu ES, et al. Inhibitory role of peroxisome proliferator‐activated receptor gamma in hepatocarcinogenesis in mice and in vitro. Hepatology. 2010;51(6):2008–2019. doi:10.1002/hep.23550
   PubMed Web of Science ®Google Scholar
• Suriben R, Chen M, Higbee J, et al. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Nat Med. 2020;26(8):1264–1270. doi:10.1038/s41591-020-0945-x
   PubMed Web of Science ®Google Scholar
• Tsui K-H, Hsu S-Y, Chung L-C, et al. Growth differentiation factor-15: a p53-and demethylation-upregulating gene represses cell proliferation, invasion and tumorigenesis in bladder carcinoma cells. Sci Rep. 2015;5(1):12870. doi:10.1038/srep12870
   PubMedGoogle Scholar
• Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT. Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol Cancer Ther. 2003;2(10):1023–1029.
   PubMed Web of Science ®Google Scholar
• Shin DY, Kim GY, Kim ND, et al. Induction of apoptosis by pectenotoxin-2 is mediated with the induction of DR4/DR5, Egr-1 and NAG-1, activation of caspases and modulation of the Bcl-2 family in p53-deficient Hep3B hepatocellular carcinoma cells. Oncol Rep. 2008;19(2):517–526.
   PubMed Web of Science ®Google Scholar
• Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993;366(6456):701–704. doi:10.1038/366701a0
   PubMed Web of Science ®Google Scholar
• Marhenke S, Buitrago-Molina LE, Endig J, et al. p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury. Gut. 2014;63(9):1501–1512. doi:10.1136/gutjnl-2013-304829
   PubMed Web of Science ®Google Scholar
• Roth P, Junker M, Tritschler I, et al. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin Cancer Res. 2010;16(15):3851–3859. doi:10.1158/1078-0432.CCR-10-0705
   PubMed Web of Science ®Google Scholar
• Ratnam NM, Peterson JM, Talbert EE, et al. NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. J Clin Invest. 2017;127(10):3796–3809. doi:10.1172/JCI91561
   PubMed Web of Science ®Google Scholar
• Vaňhara P, Hampl A, Kozubík A, Souček K. Growth/differentiation factor-15: prostate cancer suppressor or promoter? Prost Can Prost Dis. 2012;15(4):320–328. doi:10.1038/pcan.2012.6
   PubMed Web of Science ®Google Scholar
• Carloni V, Luong TV, Rombouts K. Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever. Liver Int. 2014;34(6):834–843. doi:10.1111/liv.12465
   PubMed Web of Science ®Google Scholar
• Myojin Y, Hikita H, Sugiyama M, et al. Hepatic stellate cells in hepatocellular carcinoma promote tumor growth via growth differentiation factor 15 production. Gastroenterology. 2021;160(5):1741–1754. e16. doi:10.1053/j.gastro.2020.12.015
   PubMed Web of Science ®Google Scholar
• Quiroz Reyes AG, Lozano Sepulveda SA, Martinez-Acuña N, et al. Cancer stem cell and hepatic stellate cells in hepatocellular carcinoma. Technol Cancer Res Treat. 2023;22:15330338231163677. doi:10.1177/15330338231163677
   Web of Science ®Google Scholar
• Dong G, Ma M, Lin X, et al. Treatment-damaged hepatocellular carcinoma promotes activities of hepatic stellate cells and fibrosis through GDF15. Exp Cell Res. 2018;370(2):468–477. doi:10.1016/j.yexcr.2018.07.011
   PubMed Web of Science ®Google Scholar
• Bendixen SM, Jakobsgaard PR, Hansen D, et al. Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module. J Hepatol. 2024;80(3):467–481. doi:10.1016/j.jhep.2023.11.001
   PubMedGoogle Scholar
• Kuchay MS, Choudhary NS, Mishra SK. Pathophysiological mechanisms underlying MAFLD. Diabetes Metab Syndr. 2020;14(6):1875–1887. doi:10.1016/j.dsx.2020.09.026
   PubMed Web of Science ®Google Scholar
• Park S, Hwang S, Sun J, et al. A novel A2a adenosine receptor inhibitor effectively mitigates hepatic fibrosis in a metabolic dysfunction-associated steatohepatitis mouse model. Int J Bio Sci. 2024;20(5):1855. doi:10.7150/ijbs.92371
   Google Scholar
• Luo Q, Wang CQ, Yang LY, et al. FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett. 2018;417:21–34. doi:10.1016/j.canlet.2017.12.021
   PubMed Web of Science ®Google Scholar
• Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11(12):834–848. doi:10.1038/nrm3012
   PubMed Web of Science ®Google Scholar
• Song J, Ge Z, Yang X, et al. Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin. Cancer Lett. 2015;356(2):713–720. doi:10.1016/j.canlet.2014.10.021
   PubMed Web of Science ®Google Scholar
• Kim KH, Kim SH, Han DH, Jo YS, Lee Y-H, Lee M-S. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice. Sci Rep. 2018;8(1):6789. doi:10.1038/s41598-018-25098-0
   PubMedGoogle Scholar
• Chung HK, Ryu D, Kim KS, et al. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J Cell Biol. 2017;216(1):149–165. doi:10.1083/jcb.201607110
   PubMed Web of Science ®Google Scholar
• Gordon EJ, Fukuhara D, Weström S, et al. The endothelial adaptor molecule TSAd is required for VEGF-induced angiogenic sprouting through junctional c-Src activation. Sci Signal. 2016;9(437):ra72. doi:10.1126/scisignal.aad9256
   PubMed Web of Science ®Google Scholar
• Zimmers TA, Jin X, Gutierrez JC, et al. Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis. J Cancer Res Clin Oncol. 2008;134:753–759. doi:10.1007/s00432-007-0336-4
   PubMed Web of Science ®Google Scholar
• Wei X, Zou S, Xie Z, et al. EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization. Cardiov Res. 2022;118(9):2179–2195. doi:10.1093/cvr/cvab269
   PubMed Web of Science ®Google Scholar
• Rochette L, Méloux A, Zeller M, Cottin Y, Vergely C. Functional roles of GDF15 in modulating microenvironment to promote carcinogenesis. Bioch et Bioph Acta. 2020;1866(8):165798. doi:10.1016/j.bbadis.2020.165798
   Web of Science ®Google Scholar
• Larionova I, Kazakova E, Gerashchenko T, Kzhyshkowska J. New angiogenic regulators produced by TAMs: perspective for targeting tumor angiogenesis. Cancers. 2021;13(13):3253. doi:10.3390/cancers13133253
   PubMed Web of Science ®Google Scholar
• Husaini Y, Tsai VW, Manandhar R, et al. Growth differentiation factor-15 slows the growth of murine prostate cancer by stimulating tumor immunity. PLoS One. 2020;15(6):e0233846. doi:10.1371/journal.pone.0233846
   PubMed Web of Science ®Google Scholar
• Evans WJ, Morley JE, Argilés J, et al. Cachexia: a new definition. Clin Nutr. 2008;27(6):793–799. doi:10.1016/j.clnu.2008.06.013
   PubMed Web of Science ®Google Scholar
• Navarro IBK, Schraner M, Riediger T. Brainstem prolactin-releasing peptide contributes to cancer anorexia-cachexia syndrome in rats. Neuropharmacology. 2020;180:108289. doi:10.1016/j.neuropharm.2020.108289
   PubMed Web of Science ®Google Scholar
• Suzuki H, Mitsunaga S, Ikeda M, et al. Clinical and tumor characteristics of patients with high serum levels of growth differentiation factor 15 in advanced pancreatic cancer. Cancers (Basel). 2021;13(19):4842. doi:10.3390/cancers13194842
   PubMed Web of Science ®Google Scholar
• Ahmed DS, Isnard S, Lin J, Routy B, Routy JP. GDF15/GFRAL pathway as a metabolic signature for cachexia in patients with cancer. J Cancer. 2021;12(4):1125–1132. doi:10.7150/jca.50376
   PubMed Web of Science ®Google Scholar
• Zhang Y, Wang X, Zhang M, Zhang Z, Jiang L, Li L. GDF15 promotes epithelial-to-mesenchymal transition in colorectal [corrected]. Artif Cells Nan Bio. 2018;46(sup2):652–658. doi:10.1080/21691401.2018.1466146
   PubMed Web of Science ®Google Scholar
• Mohan CD, Rangappa S, Nayak SC, Sethi G, Rangappa KS. Paradoxical functions of long noncoding RNAs in modulating STAT3 signaling pathway in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188574. doi:10.1016/j.bbcan.2021.188574
   PubMed Web of Science ®Google Scholar
• Berasain C, Avila MA. The EGFR signalling system in the liver: from hepatoprotection to hepatocarcinogenesis. J Gastroenterol. 2014;49(1):9–23. doi:10.1007/s00535-013-0907-x
   PubMed Web of Science ®Google Scholar
• Komposch K, Sibilia M. EGFR signaling in liver diseases. Int J Mol Sci. 2015;17(1). doi:10.3390/ijms17010030
   PubMed Web of Science ®Google Scholar
• Win S, Than TA, Le BH, García-Ruiz C, Fernandez-Checa JC, Kaplowitz N. Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol. 2015;62(6):1367–1374. doi:10.1016/j.jhep.2015.01.032
   PubMed Web of Science ®Google Scholar
• Urakawa N, Utsunomiya S, Nishio M, et al. GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways. Lab Invest. 2015;95(5):491–503. doi:10.1038/labinvest.2015.36
   PubMed Web of Science ®Google Scholar
• Kochetkova I, Thornburg T, Callis G, Pascual DW. Segregated Regulatory CD39+ CD4+ T Cell Function: TGF-β–Producing Foxp3− and IL-10–Producing Foxp3+ cells are interdependent for protection against collagen-induced arthritis. J Immunol. 2011;187(9):4654–4666. doi:10.4049/jimmunol.1100530
   PubMed Web of Science ®Google Scholar
• Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–1061. doi:10.1126/science.1079490
   PubMed Web of Science ®Google Scholar
• Zhou Z, Li W, Song Y, et al. Growth differentiation factor-15 suppresses maturation and function of dendritic cells and inhibits tumor-specific immune response. PLoS One. 2013;8(11):e78618. doi:10.1371/journal.pone.0078618
   PubMed Web of Science ®Google Scholar
• Chen S, Huang C, Liao G, et al. Distinct single-cell immune ecosystems distinguish true and de novo HBV-related hepatocellular carcinoma recurrences. Gut. 2023;72(6):1196–1210. doi:10.1136/gutjnl-2022-328428
   PubMed Web of Science ®Google Scholar
• Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:7593):253–7. doi:10.1038/nature16969
   Web of Science ®Google Scholar
• Si Y, Liu X, Cheng M, et al. Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes. PLoS One. 2011;6(5):e19967. doi:10.1371/journal.pone.0019967
   PubMed Web of Science ®Google Scholar
• Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–1570. doi:10.1126/science.1203486
   PubMed Web of Science ®Google Scholar
• Jung SB, Choi MJ, Ryu D, et al. Reduced oxidative capacity in macrophages results in systemic insulin resistance. Nat Commun. 2018;9(1):1551. doi:10.1038/s41467-018-03998-z
   PubMed Web of Science ®Google Scholar
• Liu P, Chen L, Zhang H. Natural killer cells in liver disease and hepatocellular carcinoma and the NK cell-based immunotherapy. J Immunol Res. 2018;2018:1–8. doi:10.1155/2018/1206737
   Web of Science ®Google Scholar
• Han B, He J, Chen Q, et al. ELFN1-AS1 promotes GDF15-mediated immune escape of colorectal cancer from NK cells by facilitating GCN5 and SND1 association. Disc Oncol. 2023;14(1):56. doi:10.1007/s12672-023-00675-6
   PubMedGoogle Scholar
• Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol. 2013;4:42790. doi:10.3389/fimmu.2013.00057
   Web of Science ®Google Scholar
• Chen Y, Hao X, Sun R, Wei H, Tian Z. Natural killer cell–derived interferon‐gamma promotes hepatocellular carcinoma through the epithelial cell adhesion molecule–epithelial‐to‐mesenchymal transition axis in hepatitis B virus transgenic mice. Hepatology. 2019;69(4):1735–1750. doi:10.1002/hep.30317
   PubMed Web of Science ®Google Scholar
• Anis ZM, Ahmed AY, Soliman HH, Nagy HM. Serum growth differentiation factor 15 levels as a marker for liver cirrhosis and hepatocellular carcinoma on top of liver cirrhosis. Tanta Med J. 2022;50(4):251–259. doi:10.4103/tmj.tmj_173_20
   Google Scholar
• Chen J, Tang D, Xu C, et al. Evaluation of serum GDF15, AFP, and PIVKA-II as diagnostic markers for HBV-associated hepatocellular carcinoma. Lab Med. 2021;52(4):381–389. doi:10.1093/labmed/lmaa089
   PubMed Web of Science ®Google Scholar
• Cillo U, Vitale A, Grigoletto F, et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol. 2006;44(4):723–731. doi:10.1016/j.jhep.2005.12.015
   PubMed Web of Science ®Google Scholar
• Myojin Y, Hikita H, Tahata Y, et al. Serum growth differentiation factor 15 predicts hepatocellular carcinoma occurrence after hepatitis C virus elimination. Aliment. Pharmacol. Ther. 2022;55(4):422–433. doi:10.1111/apt.16691
   PubMed Web of Science ®Google Scholar
• Villanueva A, Minguez B, Forner A, Reig M, Llovet JM. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Ann Rev Med. 2010;61:317–328. doi:10.1146/annurev.med.080608.100623
   PubMed Web of Science ®Google Scholar
• Bauskin AR, Brown DA, Kuffner T, et al. Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. Cancer Res. 2006;66(10):4983–4986. doi:10.1158/0008-5472.Can-05-4067
   PubMed Web of Science ®Google Scholar
• Liu X, Chi X, Gong Q, et al. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. PLoS One. 2015;10(5):1.
   Web of Science ®Google Scholar
• Wu K, Lin F. Lipid metabolism as a potential target of liver cancer. J Hepatocell Carcinoma. 2024;11:327–346. doi:10.2147/JHC.S450423
   PubMed Web of Science ®Google Scholar
• Vitale A, Morales RR, Zanus G, et al. Barcelona clinic liver cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study. Lancet Oncol. 2011;12(7):654–662. doi:10.1016/S1470-2045(11)70144-9
   PubMed Web of Science ®Google Scholar
• Chen J, Dai W, Zhu C, Liu H, Li Y, Zhang P. Circulating levels of growth differentiation factor 15 and sex hormones in male patients with HBV-associated hepatocellular carcinoma. Biomed. Pharmacother. 2020;121:109574. doi:10.1016/j.biopha.2019.109574
   PubMed Web of Science ®Google Scholar
• Rybicki BA, Sadasivan SM, Chen Y, et al. Growth and differentiation factor 15 and NF‐κB expression in benign prostatic biopsies and risk of subsequent prostate cancer detection. Cancer Med. 2021;10(9):3013–3025. doi:10.1002/cam4.3850
   PubMed Web of Science ®Google Scholar
• Suyama K, Iwase H. Lenvatinib: a promising molecular targeted agent for multiple cancers. Cancer Control. 2018;25(1):1073274818789361. doi:10.1177/1073274818789361
   Web of Science ®Google Scholar
• Eso Y, Marusawa H. Novel approaches for molecular targeted therapy against hepatocellular carcinoma. Hepatol Res. 2018;48(8):597–607. doi:10.1111/hepr.13181
   PubMed Web of Science ®Google Scholar
• Hidman J, Larsson A, Thulin M, Karlsson T. Increased plasma GDF15 is associated with altered levels of soluble VEGF receptors 1 and 2 in symptomatic multiple myeloma. Acta Haematolog. 2022;145(3):326–333. doi:10.1159/000519888
   PubMed Web of Science ®Google Scholar
• Duan S, Guo W, Xu Z, et al. Natural killer group 2D receptor and its ligands in cancer immune escape. Mol Cancer. 2019;18:1–14. doi:10.1186/s12943-019-0956-8
   PubMed Web of Science ®Google Scholar
• Tai W-T, Chu P-Y, Shiau C-W, et al. STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma. Clin Cancer Res. 2014;20(22):5768–5776. doi:10.1158/1078-0432.CCR-14-0725
   PubMed Web of Science ®Google Scholar
• Fujita H, Hirose K, Sato M, et al. Metformin attenuates hypoxia‑induced resistance to cisplatin in the HepG2 cell line. Oncol Lett. 2019;17(2):2431–2440. doi:10.3892/ol.2018.9869
   PubMed Web of Science ®Google Scholar
• Zheng J, Li C, Wu X, et al. Huaier polysaccharides suppresses hepatocarcinoma MHCC97-H cell metastasis via inactivation of EMT and AEG-1 pathway. Int J Biol Macromol. 2014;64:106–110. doi:10.1016/j.ijbiomac.2013.11.034
   PubMed Web of Science ®Google Scholar
• Bao H, Liu P, Jiang K, et al. Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MAPK. Oncol Lett. 2016;12(2):1058–1066. doi:10.3892/ol.2016.4686
   PubMed Web of Science ®Google Scholar
• Li C, Wu X, Zhang H, et al. A Huaier polysaccharide restrains hepatocellular carcinoma growth and metastasis by suppression angiogenesis. Int J Biol Macromol. 2015;75:115–120. doi:10.1016/j.ijbiomac.2015.01.016
   PubMed Web of Science ®Google Scholar
• Sung Y-C, Liu Y-C, Chao P-H, et al. Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development. Theranostics. 2018;8(4):894. doi:10.7150/thno.21168
   PubMed Web of Science ®Google Scholar
• Li J, Li H, Yu Y, et al. Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway. Oncoimmunology. 2019;8(2):e1527650. doi:10.1080/2162402X.2018.1527650
   PubMed Web of Science ®Google Scholar
• Wu M, Miao H, Fu R, Zhang J, Zheng W. Hepatic stellate cell: a potential target for hepatocellular carcinoma. Curr Molec Pharmacol. 2020;13(4):261–272. doi:10.2174/1874467213666200224102820
   PubMed Web of Science ®Google Scholar
• Matsuki M, Hoshi T, Yamamoto Y, et al. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med. 2018;7(6):2641–2653. doi:10.1002/cam4.1517
   PubMed Web of Science ®Google Scholar
• Ikeda K, Kudo M, Kawazoe S, et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2017;52:512–519. doi:10.1007/s00535-016-1263-4
   PubMed Web of Science ®Google Scholar
• Cheng A-L, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). Am Soc Clin Oncol. 2017;2017:1.
   Google Scholar
• Tang W, Chen Z, Zhang W, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Thera. 2020;5(1):87. doi:10.1038/s41392-020-0187-x
   PubMed Web of Science ®Google Scholar
• Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. doi:10.1016/S1470-2045(08)70285-7
   PubMed Web of Science ®Google Scholar
• Huang X, Wang M, Zhang D, Zhang C, Liu P. Advances in targeted drug resistance associated with dysregulation of lipid metabolism in hepatocellular carcinoma. J Hepatocell Carcinoma. 2024;11:113–129. doi:10.2147/JHC.S447578
   PubMed Web of Science ®Google Scholar
• Abou-Elkacem L, Arns S, Brix G, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013;12(7):1322–1331. doi:10.1158/1535-7163.MCT-12-1162
   PubMed Web of Science ®Google Scholar
• Mitra A, Mishra L, Li S. EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget. 2015;6(13):10697. doi:10.18632/oncotarget.4037
   PubMed Web of Science ®Google Scholar
• Pang WC, Poon TP. Cancer stem cell as a potential therapeutic target in hepatocellular carcinoma. Curr Cancer Drug Targets. 2012;12(9):1081–1094. doi:10.2174/156800912803987995
   PubMed Web of Science ®Google Scholar
• He B, Dai L, Zhang X, et al. The HDAC inhibitor quisinostat (JNJ-26481585) supresses hepatocellular carcinoma alone and synergistically in combination with sorafenib by G0/G1 phase arrest and apoptosis induction. Int J Bio Sci. 2018;14(13):1845. doi:10.7150/ijbs.27661
   Google Scholar
• Zhang Q, Huang H, Zheng F, et al. Resveratrol exerts antitumor effects by downregulating CD8+ CD122+ Tregs in murine hepatocellular carcinoma. Oncoimmunology. 2020;9(1):1829346. doi:10.1080/2162402X.2020.1829346
   PubMed Web of Science ®Google Scholar