Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1

Abstract Background: Due to the high drug resistance of hepatocellular carcinoma (HCC), Sorafenib has limited efficacy in the treatment of advanced HCC. Cancer-associated fibroblasts (CAFs) play an important regulatory role in the induction of chemo-resistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to sorafenib in HCC. Methods: Immunohistochemistry and immunofluorescence showed that the activation of CAFs was increased in cancer tissues of HCC. CAFs and para-cancer normal fibroblasts (NFs) were isolated from the cancer and para-cancer tissues of HCC, respectively. Cell cloning assay, Elisa, and flow cytometry were used to detect that CAFs induced sorafenib resistance of HCC cells via CXCL12. Western blot and qPCR detected that CXCL12 induces sorafenib resistance of HCC cells by up-regulating FOLR1. We investigated that FOLR1 was the target molecule of CAFs regulating sorafenib resistance in HCC cells by querying the gene expression dataset platform of human HCC specimens from GEO genomic data platforms. Results: CAFs were increasingly activated in cancer tissues of HCC, compared with pare-cancer tissues of HCC samples. CAFs inhibited the sensitivity of HCC cells to sorafenib. CAFs secreted CXCL12 to induce sorafenib resistance of HCC cells. CXCL12 upregulated the expression of FOLR1 in HCC cells to induce sorafenib resistance. Conclusions: We found that CAFs induce sorafenib resistance of HCC cells through CXCL12/FOLR1.