The BAFF/NFκB axis is crucial to interactions between sorafenib-resistant HCC cells and cancer-associated fibroblasts

Cancer Sci. 2021 Sep;112(9):3545-3554. doi: 10.1111/cas.15041. Epub 2021 Jul 16.


The tumor microenvironment affects malignancy in hepatocellular carcinoma (HCC) cells, and cancer-associated fibroblasts (CAFs) play an important role in the microenvironment. As recent studies indicated a difference between CAFs isolated from chemoresistant and non-resistant cancer tissues, therefore we investigated the intracellular mechanism in resistant HCC co-cultured CAFs and interactions between these CAFs with cancer cells. We established a sorafenib-resistant (SR) Huh7 (human HCC) cell line, and characterized it with cytokine assays, then developed CAFs by co-culturing human hepatic stellate cells with resistant or parental Huh7 cells. The 2 types of CAFs were co-cultured with parental Huh7 cells, thereafter the cell viability of these Huh7 cells was checked under sorafenib treatment. The SR Huh7 (Huh7SR ) cells expressed increased B-cell activating factor (BAFF), which promoted high expression of CAF-specific markers in Huh7SR -co-cultured CAFs, showed activated BAFF, BAFF-R, and downstream of the NFκB-Nrf2 pathway, and aggravated invasion, migration, and drug resistance in co-cultured Huh7 cells. When we knocked down BAFF expression in Huh7SR cells, the previously increased malignancy and BAFF/NFκB axis in Huh7SR -co-cultured CAFs reversed, and enhanced chemoresistance in co-cultured Huh7 cells returned as well. In conclusion, the BAFF/NFκB pathway was activated in CAFs co-cultured with cell-culture medium from resistant Huh7, which promoted chemoresistance, and increased the malignancy in co-cultured non-resistant Huh7 cells. This suggests that the BAFF/NFκB axis in CAFs might be a potential therapeutic target in chemoresistance of HCC.

Keywords: B-cell activating factor; cancer-associated fibroblasts; drug resistance; hepatocellular carcinoma; sorafenib.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • B-Cell Activating Factor / genetics
  • B-Cell Activating Factor / metabolism*
  • Cancer-Associated Fibroblasts / metabolism*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Communication / genetics*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Coculture Techniques
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Gene Knockdown Techniques
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • NF-kappa B / metabolism*
  • Signal Transduction / genetics*
  • Sorafenib / pharmacology*
  • Transfection


  • Antineoplastic Agents
  • B-Cell Activating Factor
  • NF-kappa B
  • TNFSF13B protein, human
  • Sorafenib