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

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.

The Crosstalk Between Regulatory Non-Coding RNAs and Nuclear Factor Kappa B in Hepatocellular Carcinoma

“…Given the central role of sorafenib in HCC therapy, it is urgent to further study the exact mechanisms of sorafenib resistance in HCC so as to improve chemosensitivity of HCC to sorafenib. Recent studies have revealed that the activation of NF-kB is identified as a crucial molecule leading to sorafenib resistance in HCC (102)(103)(104). Meanwhile, ncRNAs have been considered to be vital regulators in sorafenib resistance of HCC (105).…”

Review: Challenges of In Vitro CAF Modelling in Liver Cancers

“…In HCC, CAFs were found to increase chemoresistance against sorafenib and cisplatin through the HGF-Met-ERK pathway [53,54]. Two other studies further confirmed that CAFs induce drug resistance against sorafenib, which in turn leads to an increase in liver cancer cell aggressiveness [55,56].…”

“…Only eight studies so far (representing 14%) have investigated the effect of the tumour cells on the CAF population and of that two-thirds of the papers used the LX-2 cell line as CAF surrogate (Table 2). The presence of cancer cell lines can promote the CAF phenotype in LX-2 as shown by the induction of α-SMA, MMP-9, VEGF, and FGF [55,61,73,78]. This is likely mediated by secreted factors as the majority of the papers used CM transfer, exosome transfer, or transwell assays (Table 2).…”

“…The presence of cancer cell lines can promote the CAF phenotype in LX-2 as shown by the induction of α-SMA, MMP-9, VEGF, and FGF [ 55 , 61 , 73 , 78 ]. This is likely mediated by secreted factors as the majority of the papers used CM transfer, exosome transfer, or transwell assays ( Table 2 ).…”

The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment

“…Chemoresistance serves as another significant mechanism mediating HCC progression and metastasis after radical surgery. A recent study found that co-culture with CAFs maintains sorafenib resistance in HCC cells through B-cell-activating factor (BAFF)/NF-κB-dependent pathway ( 42 ); otherwise, overexpressed immunosuppressive cell differentiation (CD)-73 in cancer cells induced by CAFs can facilitate the resistance of sorafenib and cisplatin in HCC patients ( 60 , 61 ).…”