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In this study, we aimed to understand the different biological characteristics, gene expression profiles, and drug resistance mechanisms of HCC cells cultured under different conditions. A conventional adherence method and a liquid overlay technique were used to prepare two\u2010 and three\u2010dimensional cultures of Bel\u20107402 and 5\u2010fluorouracil (5\u2010Fu)\u2010resistant Bel\u20107402 (Bel\u20107402\/5\u2010Fu) cells. Morphological characteristics were assessed via microscopy, and cell cycle distribution and apoptotic rate were obtained using flow cytometry. Cell sensitivity to different concentrations of drugs was detected with 3\u2010(4,5\u2010dimethylthiazol\u20102\u2010yl)\u20102,5\u2010diphenyltetrazolium bromide assays. Gene expression profiles and signal transduction pathways of Bel\u20107402 and Bel\u20107402\/5\u2010Fu cells under different culture conditions were determined using gene chips. Cells in three\u2010dimensional culture were suspended and they grew into dense multicellular spheroid (MCS) structures, aggregating with each other. In contrast to cells in the two\u2010dimensional culture, cell cycle arrest was observed in MCSs. The sensitivity of Bel\u20107402 cells in the two\u2010dimensional culture to drugs at high concentrations was significantly higher than that of cells in the three\u2010dimensional culture (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.05). The apoptotic rate of Bel\u20107402 and Bel\u20107402\/5\u2010Fu cells was also higher in the two\u2010dimensional culture (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.05). Signal transduction pathway analysis showed that after Bel\u20107402 cells acquired resistance to 5\u2010Fu, CCND1, MCM2, and MCM3 gene expression was upregulated in the G1 to S cell cycle control signal transduction pathway, CDKN1C and CCNG2 gene expression was downregulated, and MCM2 and MCM3 gene expression was upregulated in the DNA replication signal transduction pathway. Therefore, the liquid overlay technique is a simple, low\u2010cost procedure to successfully construct three\u2010dimensional culture models of HCC. This study provides new information and methods for exploring the molecular mechanisms of liver cancer resistance, clinical treatment, development of molecular information, and interventional prevention.<\/jats:p>","DOI":"10.1002\/prp2.715","type":"journal-article","created":{"date-parts":[[2021,1,24]],"date-time":"2021-01-24T14:10:00Z","timestamp":1611497400000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Biological features, gene expression profile, and mechanisms of drug resistance of two\u2010 and three\u2010dimensional hepatocellular carcinoma cell cultures"],"prefix":"10.1002","volume":"9","author":[{"given":"Nan","family":"Mei","sequence":"first","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital of Xi\u2019an Jiaotong University Xi\u2019an Shaanxi Province People\u2019s Republic of 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