{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:45:06Z","timestamp":1791582306892,"version":"4.3.4"},"reference-count":62,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,7]],"date-time":"2023-05-07T00:00:00Z","timestamp":1683417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad de Guadalajara","award":["PIN-2021-II"],"award-info":[{"award-number":["PIN-2021-II"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed to analyze the biochemical, histological, and gene expression alterations produced in a hepatocarcinogenesis model induced by the chronic administration of diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) in Wistar rats. Thirteen rats weighing 180 to 200 g were divided into two groups: control and treated. Rats in the treated group were administered an intraperitoneal (i.p.) injection of DEN (50 mg\/kg\/week) and an intragastric (i.g.) dose of 2-AAF (25 mg\/kg\/week) for 18 weeks. The treated group had significant increases in their total cholesterol, HDL-C, AST, ALT, ALKP, and GGT levels. Furthermore, a histological analysis showed the loss of normal liver architecture with nuclear pleomorphism in the hepatocytes, atypical mitosis, and fibrous septa that were distributed between the portal triads and collagen fibers through the hepatic sinusoids. The gene expressions of 24 genes related to fibrosis, inflammation, apoptosis, cell growth, angiogenesis, lipid metabolism, and alpha-fetoprotein (AFP) were analyzed; only TGF\u03b2, COL1\u03b11, CYP2E1, CAT, SOD, IL6, TNF-\u03b1, and ALB showed significant differences when both groups were compared. Additionally, lung histopathological alterations were found in the treated group, suggesting metastasis. In this model, the chronic administration of DEN+2-AAF induces characteristic alterations of hepatocellular carcinoma in Wistar rats without AFP gene expression changes, highlighting different signatures in hepatocellular carcinoma heterogeneity.<\/jats:p>","DOI":"10.3390\/ijms24098387","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T03:34:53Z","timestamp":1683516893000},"page":"8387","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Chronic Administration of Diethylnitrosamine and 2-Acetylaminofluorene Induces Hepatocellular Carcinoma in Wistar Rats"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4333-2294","authenticated-orcid":false,"given":"Jaime","family":"S\u00e1nchez-Meza","sequence":"first","affiliation":[{"name":"Instituto de Enfermedades Cr\u00f3nico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7317-1490","authenticated-orcid":false,"given":"Marina","family":"Campos-Valdez","sequence":"additional","affiliation":[{"name":"Instituto de Enfermedades Cr\u00f3nico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8560-5855","authenticated-orcid":false,"given":"Jos\u00e9 Alfredo","family":"Dom\u00ednguez-Rosales","sequence":"additional","affiliation":[{"name":"Instituto de Enfermedades Cr\u00f3nico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6779-1017","authenticated-orcid":false,"given":"Juliana Marisol","family":"God\u00ednez-Rub\u00ed","sequence":"additional","affiliation":[{"name":"Laboratorio de Patolog\u00eda Diagn\u00f3stica e Inmunohistoqu\u00edmica, Departamento de Microbiolog\u00eda y Patolog\u00eda, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarai Citlalic","family":"Rodr\u00edguez-Reyes","sequence":"additional","affiliation":[{"name":"Instituto de Nutrigen\u00e9tica y Nutrigen\u00f3mica Traslacional, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Mart\u00ednez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Instituto de Nutrigen\u00e9tica y Nutrigen\u00f3mica Traslacional, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1257-4637","authenticated-orcid":false,"given":"Guillermo M.","family":"Z\u00fa\u00f1iga-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Laboratorio de Mutag\u00e9nesis, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Ver\u00f3nica","family":"S\u00e1nchez-Orozco","sequence":"additional","affiliation":[{"name":"Instituto de Enfermedades Cr\u00f3nico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,7]]},"reference":[{"key":"ref_1","first-page":"863","article-title":"Hepatocellular Carcinoma: A Comprehensive Review of Biomarkers, Clinical Aspects, and Therapy","volume":"18","author":"Tunissiolli","year":"2017","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2147\/JHC.S300182","article-title":"Hepatocellular Carcinoma: An Overview of the Changing Landscape of Treatment Options","volume":"8","author":"Koulouris","year":"2021","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_3","first-page":"20","article-title":"Hepatocellular carcinoma and hepatitis C virus infection in Latin America: Epidemiology, diagnosis and treatment","volume":"6","year":"2020","journal-title":"Hepatoma Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrgastro.2011.196","article-title":"Hepatocellular carcinoma: Insight from animal models","volume":"9","author":"Li","year":"2011","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Jilkova, Z., Kurma, K., and Decaens, T. (2019). Animal Models of Hepatocellular Carcinoma: The Role of Immune System and Tumor Microenvironment. Cancers, 11.","DOI":"10.3390\/cancers11101487"},{"key":"ref_6","unstructured":"IARC\/WHO (2021, March 20). GLOBOCAN 2021: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2020. Cancer Today Data Base, Population Fact Sheets. Available online: https:\/\/gco.iarc.fr\/today\/fact-sheets-cancers."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/hep.29466","article-title":"Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease","volume":"67","author":"Estes","year":"2018","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1016\/j.jhep.2021.08.012","article-title":"Epidemiology and risk-stratification of NAFLD-associated HCC","volume":"75","author":"Ioannou","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0163-7258(96)00062-9","article-title":"N-nitrosodiethylamine mechanistic data and risk assessment: Bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation","volume":"71","author":"Verna","year":"1996","journal-title":"Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/bs.mcb.2020.08.006","article-title":"Diethylnitrosamine-induced liver tumorigenesis in mice","volume":"163","author":"Schulien","year":"2021","journal-title":"Methods Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/0165-1110(94)90025-6","article-title":"Genetic toxicity of 2-acetylaminofluorene, 2-aminofluorene and some of their metabolites and model metabolites","volume":"318","author":"Heflich","year":"1994","journal-title":"Mutat. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"328","DOI":"10.4254\/wjh.v13.i3.328","article-title":"Promotive action of 2-acetylaminofluorene on hepatic precancerous lesions initiated by diethylnitrosamine in rats: Molecular study","volume":"13","author":"Hasanin","year":"2021","journal-title":"World J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/BF01225261","article-title":"Fifty years of research on N-acetyl-2-aminofluorene, one of the most versatile compounds in experimental cancer research","volume":"118","author":"Kriek","year":"1992","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1010428317695923","DOI":"10.1177\/1010428317695923","article-title":"Animal models as a tool in hepatocellular carcinoma research: A Review","volume":"39","author":"Santos","year":"2017","journal-title":"Tumour Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1177\/0023677215570086","article-title":"Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice","volume":"49","author":"Tolba","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104715","DOI":"10.1016\/j.yexmp.2021.104715","article-title":"Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment","volume":"123","author":"Ghufran","year":"2021","journal-title":"Exp. Mol. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.bbadis.2018.08.009","article-title":"Animal models for hepatocellular carcinoma","volume":"1865","author":"Zhang","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/mc.23298","article-title":"Enrichment of progenitor cells by 2-acetylaminofluorene accelerates liver carcinogenesis induced by diethylnitrosamine in vivo","volume":"60","year":"2021","journal-title":"Mol. Carcinog."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Romualdo, G.R., Leroy, K., Costa, C.J.S., Prata, G.B., Vanderborght, B., da Silva, T.C., Barbisan, L.F., Andraus, W., Devisscher, L., and C\u00e2mara, N.O.S. (2021). In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling. Cancers, 13.","DOI":"10.3390\/cancers13215583"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.3748\/wjg.v26.i26.3720","article-title":"Intratumoral heterogeneity of hepatocellular carcinoma: From single-cell to population-based studies","volume":"26","author":"Zhang","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7385","DOI":"10.1158\/0008-5472.CAN-09-1089","article-title":"Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma","volume":"69","author":"Hoshida","year":"2009","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E9879","DOI":"10.1073\/pnas.1811029115","article-title":"Integrative genomic analysis of mouse and human hepatocellular carcinoma","volume":"115","author":"Dow","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.dld.2012.10.008","article-title":"Liver carcinogenesis: Rodent models of hepatocarcinoma and cholangiocarcinoma","volume":"45","author":"Kisseleva","year":"2013","journal-title":"Dig. Liver Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1292\/jvms.15-0299","article-title":"Strain differences in cytochrome P450 mRNA and protein expression, and enzymatic activity among Sprague Dawley, Wistar, Brown Norway and Dark Agouti rats","volume":"78","author":"Nishiyama","year":"2016","journal-title":"J. Vet. Med. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/carcin\/23.1.1","article-title":"Tissue-specific resistance to cancer development in the rat: Phenotypes of tumor-modifier genes","volume":"23","author":"Wood","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/0041-008X(83)90161-8","article-title":"Acetaminophen nephrotoxicity in the rat. Renal metabolic activation in vitro","volume":"70","author":"Newton","year":"1983","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2217\/hep-2016-0012","article-title":"Dysregulated fatty acid metabolism in hepatocellular carcinoma","volume":"3","author":"Wang","year":"2016","journal-title":"Hepat. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81250","DOI":"10.18632\/oncotarget.17131","article-title":"Subclinical involvement of the liver is associated with prognosis in treatment na\u00efve cancer patients","volume":"8","author":"Pavo","year":"2017","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hann, H.W., Wan, S., Myers, R.E., Hann, R.S., Xing, J., Chen, B., and Yang, H. (2012). Comprehensive analysis of common serum liver enzymes as prospective predictors of hepatocellular carcinoma in HBV patients. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047687"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108732","DOI":"10.1016\/j.biopha.2019.108732","article-title":"Melatonin maximizes the therapeutic potential of non-preconditioned MSCs in a DEN-induced rat model of HCC","volume":"114","author":"Mohamed","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111335","DOI":"10.1016\/j.biopha.2021.111335","article-title":"Phyllanthin prevents diethylnitrosamine (DEN) induced liver carcinogenesis in rats and induces apoptotic cell death in HepG2 cells","volume":"137","author":"You","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112409","DOI":"10.1016\/j.biopha.2021.112409","article-title":"Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF\/c-Met, Wnt\/\u03b2-catenin, and PI3K\/Akt\/mTOR signaling pathways","volume":"145","author":"Yassin","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s00432-017-2364-z","article-title":"Hepatic inflammation-fibrosis-cancer axis in the rat hepatocellular carcinoma induced by diethylnitrosamine","volume":"143","author":"Ding","year":"2017","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3748\/wjg.v25.i1.42","article-title":"Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma","volume":"25","author":"Mahmoudvand","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tu, S., Huang, W., Huang, C., Luo, Z., and Yan, X. (2019). Contextual Regulation of TGF-\u03b2 Signaling in Liver Cancer. Cells, 8.","DOI":"10.3390\/cells8101235"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"861601","DOI":"10.3389\/fonc.2022.861601","article-title":"High Expression of TGF-\u03b21 Contributes to Hepatocellular Carcinoma Prognosis via Regulating Tumor Immunity","volume":"12","author":"Jin","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1369\/0022155415627681","article-title":"TGF-\u03b2\/SMAD Pathway and Its Regulation in Hepatic Fibrosis","volume":"64","author":"Xu","year":"2016","journal-title":"J. Histochem. Cytochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bbrc.2011.02.009","article-title":"Silencing tissue inhibitors of metalloproteinases (TIMPs) with short interfering RNA reveals a role for TIMP-1 in hepatic stellate cell proliferation","volume":"407","author":"Fowell","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.canlet.2004.07.019","article-title":"Oxidative stress in carcinogenesis. Correlation between lipid peroxidation and induction of preneoplastic lesions in rat hepatocarcinogenesis","volume":"217","year":"2005","journal-title":"Cancer Lett."},{"key":"ref_41","first-page":"595","article-title":"Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis","volume":"88","author":"Solt","year":"1977","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.fct.2018.11.014","article-title":"Neferine suppresses diethylnitrosamine-induced lung carcinogenesis in Wistar rats","volume":"123","author":"Sivalingam","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1124\/jpet.102.041582","article-title":"Mechanisms of down-regulation of CYP2E1 expression by inflammatory cytokines in rat hepatoma cells","volume":"304","author":"Hakkola","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s12967-022-03396-6","article-title":"CYP2E1 plays a suppressive role in hepatocellular carcinoma by regulating Wnt\/Dvl2\/\u03b2-catenin signaling","volume":"20","author":"Zhu","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e23078","DOI":"10.1002\/jbt.23078","article-title":"Suppressive effects of thymoquinone on the initiation stage of diethylnitrosamine hepatocarcinogenesis in rats","volume":"36","author":"Ibrahim","year":"2022","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.18632\/aging.100967","article-title":"Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner","volume":"8","author":"Wang","year":"2016","journal-title":"Aging"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1016\/j.febslet.2010.04.048","article-title":"Downregulation of catalase by reactive oxygen species via hypermethylation of CpG island II on the catalase promoter","volume":"584","author":"Min","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Tawfik, N.G., Mohamed, W.R., Mahmoud, H.S., Alqarni, M.A., Naguib, I.A., Fahmy, A.M., and Ahmed, O.M. (2022). Isatin Counteracts Diethylnitrosamine\/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways. Antioxidants, 11.","DOI":"10.3390\/antiox11040699"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1080\/01480545.2019.1683187","article-title":"Quercetin and naringenin abate diethylnitrosamine\/acetylaminofluorene-induced hepatocarcinogenesis in Wistar rats: The roles of oxidative stress, inflammation and cell apoptosis","volume":"45","author":"Ahmed","year":"2022","journal-title":"Drug Chem. Toxicol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"E10127","DOI":"10.1073\/pnas.1722100115","article-title":"iNOS promotes CD24+CD133+ liver cancer stem cell phenotype through a TACE\/ADAM17-dependent Notch signaling pathway","volume":"115","author":"Wang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/toxres\/tfab118","article-title":"The chemoprevention of spirulina platensis and garlic against diethylnitrosamine induced liver cancer in rats via amelioration of inflammatory cytokines expression and oxidative stress","volume":"11","author":"Abouzed","year":"2021","journal-title":"Toxicol. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1053\/jhep.2002.31432","article-title":"The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough","volume":"35","author":"Wiest","year":"2002","journal-title":"Hepatology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1186\/s12935-022-02759-9","article-title":"Pomegranate juice and punicalagin-mediated chemoprevention of hepatocellular carcinogenesis via regulating miR-21 and NF-\u03baB-p65 in a rat model","volume":"22","author":"Hussein","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Pocasap, P., Weerapreeyakul, N., and Wongpoomchai, R. (2021). Chemopreventive Effect of Cratoxylum formosum (Jack) ssp. pruniflorum on Initial Stage Hepatocarcinogenesis in Rats. Molecules, 26.","DOI":"10.3390\/molecules26144235"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1007\/s12032-010-9600-6","article-title":"Angiogenesis and clinicopathologic characteristics in different hepatocellular carcinoma subtypes defined by EpCAM and \u03b1-fetoprotein expression status","volume":"28","author":"Shan","year":"2011","journal-title":"Med. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"961530","DOI":"10.3389\/fonc.2022.961530","article-title":"Combined clinical features and MRI parameters for the prediction of VEGFR2 in hepatocellular carcinoma patients","volume":"12","author":"Zhang","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1159\/000491779","article-title":"Development of a Genetic and Clinical Data-Based (GC) Risk Score for Predicting Survival of Hepatocellular Carcinoma Patients After Tumor Resection","volume":"48","author":"Chen","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.jhep.2015.07.039","article-title":"CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt\/mTOR\/SREBP1c and P38\/PPAR\u03b1 pathways","volume":"63","author":"Li","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Refolo, M.G., Messa, C., Guerra, V., Carr, B.I., and D\u2019Alessandro, R. (2020). Inflammatory Mechanisms of HCC Development. Cancers, 12.","DOI":"10.3390\/cancers12030641"},{"key":"ref_60","first-page":"453","article-title":"HCC with low- and normal-serum alpha-fetoprotein levels","volume":"15","author":"Carr","year":"2018","journal-title":"Clin. Pract."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1159\/000471807","article-title":"Role of Albumin in Growth Inhibition in Hepatocellular Carcinoma","volume":"93","author":"Atabey","year":"2017","journal-title":"Oncology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0304-3835(00)00589-9","article-title":"Significant down-regulation of alpha-albumin in human hepatoma and its implication","volume":"160","author":"Wu","year":"2000","journal-title":"Cancer Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8387\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:30:47Z","timestamp":1760124647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,7]]},"references-count":62,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24098387"],"URL":"https:\/\/doi.org\/10.3390\/ijms24098387","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,7]]}}}