Fig 2: Scheme for the mechanism of acetylation of AKR1C1 and its role in the metastasis of NSCLC.

Fig 3: AKR1C1 and SERPINE1 were the key differentially expressed genes of lenvatinib targets. (A) RNA-seq was used to examine the transcriptome alterations in MHCC-97H cells treated with varying doses of lenvatinib. Genes with high or low expression in the four treatment groups were simultaneously shown by a volcano plot. Blue represents downregulated genes, red represents upregulated genes, and grey represents no difference genes. (B) The PPI network of the hub genes from upregulated genes. (C) PPI network of the hub genes from downregulated genes. (D,E) High expressions of AKR1C1 and SERPINE1 predicted poor prognosis in HCC patients. (F) The KEGG analysis revealed that AKR1C1 is involved in the Wnt signaling pathway, calcium signaling pathway, gastric cancer, etc. (G) The KEGG analysis also showed that AKR1C1 is involved in the PI3K/AKT signaling pathway, the Wnt signaling pathway, the IL-17 signaling pathway, and other pathways. (H) According to the expression level of AKR1C1, the data were divided into two groups. The ratios of activated dendritic cells, macrophages (M0), activated memory CD4 T cells, and eosinophils were characterized in two groups. (I) Similarly, for SERPINE1, the ratios of the proportions of activated NK cells, neutrophils, macrophages (M0), resting memory CD4 T cell, resting mast cells, and activated mast cells showed marked changes. (J) AKR1C1 and SERPINE1 are significantly correlated with macrophages (M0) (red indicates that AKR1C1 and SERPINE1 expression are positively correlated with immune cells. Blue indicates that AKR1C1 and SERPINE1 expression are negatively correlated with immune cells. The larger the difference in the ratios of the proportions of immune cells, the larger the circle size). *P<0.05, **P<0.01, ***P<0.001. PPI, protein-protein interaction; KEGG, Kyoto Encyclopedia of Genes and Genomes; LIHC, liver cancer; HCC, hepatocellular carcinoma; NC, negative control; NS, no sense.

Fig 4: Knockdown of AKR1C1 inhibits the proliferation of MHCC-97H cells. (A) The mRNA expression level of AKR1C1 in MHCC-97H cells was determined by qRT-PCR analysis after transduction. The proliferation of MHCC-97H cells was assessed by CCK-8 assays (B), wound healing assay (C), and EdU (D), respectively (×20). **P<0.01, ***P<0.001, ****P<0.0001. NC, negative control; OD, optical density; EdU, 5-ethynyl-2'-deoxyuridine; DAPI, 4'-6-diamidino-2-phenylindole.

Fig 5: The AKR1C1 expression was elevated in LR-HCC cells. (A) Seven up-regulated genes in LR Hep3B and Huh7 cells. (B) Three down-regulated genes in LR Hep3B and Huh7 cells. AKR1C1 was increased in HCC cell lines that were resistant to lenvatinib compared with the control group, (C) Hep3B, and (D) Huh7, respectively. (E) AKR1C1 was elevated in HCC cells and LEN-HepG2 (LR-HepG2 cells). **P<0.01, ****P<0.0001. LR, lenvatinib-resistant; HCC, hepatocellular carcinoma; NC, negative control; LEN, lenvatinib; NS, no sense.