Hepatocellular carcinoma cells cause different responses in expressions of cancer-promoting genes in different cancer-associated fibroblasts

AbstractCancer-associated fibroblast (CAF) is one of the most crucial components of the tumor microenvironment to promote the invasiveness of cancer cells. The interactions between cancer cells and CAFs are bidirectional. Our recent study showed that up-regulations of chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 26 (CCL26), interleukin 6 (IL6), and lysyl oxidase-like 2 (LOXL2) genes in cancer cells were parts of the common effects of CAFs on hepatocellular carcinoma (HCC) cells to promote proliferation, migration and invasion of cancer cells. However, the subject of how HCC cells to influence the gene expressions of CAFs still needs to be clarified. The purpose of this study was to investigate this issue. Two human HCC (HCC24/KMUH, HCC38/KMUH) and two human CAF cell lines (F26/KMUH, F28/KMUH) were studied. Influence of HCC38/KMUH cancer cells on differential expressions of genes in F28/KMUH CAFs was detected by microarray to select target genes for further analysis. Both HCC cell lines increased proliferation (all p < 0.005) and migration (all p < 0.0001) of two CAF cell lines. HCC24/KMUH cancer cells had stronger ability to promote migration of F26/KMUH CAFs than HCC38/KMUH cancer cells did (p < 0.0001). Eleven up-regulated cancer-promoting genes, including apelin (APLN), CCL2, CCL26, fibroblast growth factor 1 (FGF1), fibroblast growth factor 2 (FGF2), IL6, mucin 1 (MUC1), LOXL2, platelet-derived growth factor alpha polypeptide (PDGFA), phosphoglycerate kinase 1 (PGK1), and vascular endothelial growth factor A (VEGFA) detected by microarray showed good correlation with results of quantitative reverse transcriptase-polymerase chain reaction study. Among these genes, HCC24/KMUH cancer cells had same tendency of effects on differential expressions of genes in F28/KMUH CAFs as HCC38/KMUH cancer cells did. However, the responses of F26/KMUH CAFs to different HCC cell lines were variable. Only PGK1 gene was consistently up-regulated and PDGFA gene was consistently down-regulated caused by both HCC cell lines in F26/KMUH CAFs. Besides PGK1 gene, HCC38/KMUH cancer cells only up-regulated APLN, LOXL2, and VEGFA genes and HCC24/KMUH cancer cells only up-regulated FGF2 gene in F26/KMUH CAFs. In conclusion, HCC cells can promote proliferation and migration of CAFs. However, the impact of HCC cells on differential expressions of cancer-promoting genes in CAFs is influenced by the characteristics of CAFs. This implies that blocking single or several particular cancer-promoting genes in CAFs is unable to become a common stratagem for the treatment of HCC