RRC ID 72236
Author Gao L, Morine Y, Yamada S, Saito Y, Ikemoto T, Tokuda K, Miyazaki K, Okikawa S, Takasu C, Shimada M.
Title The BAFF/NFκB axis is crucial to interactions between sorafenib-resistant HCC cells and cancer-associated fibroblasts.
Journal Cancer Sci
Abstract 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.
Volume 112(9)
Pages 3545-3554
Published 2021-9-1
DOI 10.1111/cas.15041
PMID 34159680
PMC PMC8409310
MeSH 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
IF 4.966
Human and Animal Cells HuH-7(RCB1366)