Reversal of liver cancer-associated stellate cell-induced stem-like characteristics in SMMC-7721 cells by 8-bromo-7-methoxychrysin via inhibiting STAT3 activation

Abstract

Hepatic stellate cells (HSCs) that are activated by human hepatocellular carcinoma (HCC) cells secrete a variety of cytokines, which are the main component of the HCC microenvironment. We aimed to determine whether 8-bromo-7-methoxychrysin (BrMC) could interfere in cross-talk of the human hepatic stellate cell line LX-2 and liver cancer stem-like cells (LCSLCs) to inhibit the characteristics of LCSLCs endowed with the capacity of sustaining human hepatocellular carcinoma (HCC) self-renewal and progression, and to identify its potential mechanism of action. We found that the levels of fibroblast activation protein (FAP) were augmented in LX-2 cells treated with the conditioned medium of LCSLCs (LCSLC-CM) compared to those cultured with routine medium, indicating that the LCSLC-CM can activate LX-2 cells to become liver cancer-associated stellate cells (LCAHSCs). Furthermore, sphere forming capability of SMMC-7721 cells was enhanced and stem cell-related protein expression was significantly increased following treatment with the conditioned medium of LCAHSCs (LCAHSC-CM). Moreover, the level of p-STAT3 was increased in LX-2 cells treated with LCSLC-CM and BrMC reduced expression of p-STAT3. Combination of BrMC and the selective inhibitor of STAT3 cucurbitacin I (JSI-124) synergistically suppressed the LCSLC characteristics in SMMC-7721 cells. Collectively, our data showed that BrMC inhibited the interaction between LX-2 cells and HCC-derived CSCs, and did so potentially through modulation of the STAT3 pathway. Future therapeutic strategies employing anti-CSC therapy should confirm the potential of cucurbitacin I (JSI-124) and BrMC as potent therapeutic agents.

<p>Modulation of MnSOD and FoxM1 Is Involved in Invasion and EMT Suppression by Isovitexin in Hepatocellular Carcinoma Cells</p>

“… 17 Studies also showed that FoxM1 upregulated by MnSOD overexpressionis associated with stemness in CSLCs. 17 , 29 , 31 – 34 Consistent with these results, the present study found that change of MnSOD expression markedly affected FoxM1 expression, whereas FoxM1 level change did not alter MnSOD expression. In addition, overexpression of FoxM1 reversed the inhibitory effects of MnSOD silencing on migratory and invasive abilities and EMT in MHCC97H cells.…”

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

“…Fibroblasts and MSCs co-cultured directly with tumor cell lines show marked up-regulation of FAP( 56 , 57 ), but no-contact co-culture with adenoma explants could also induce FAP expression by bone-marrow MSCs (BM-MSCs)( 15 ), as could conditioned media from myeloma cells( 57 , 58 ). Additionally, conditioned media from liver cancer cells enhanced FAP expression on umbilical cord MSCs( 59 ) and hepatic stellate cells( 60 ), the latter in a STAT3- dependent manner. Various factors may be implicated in tumor-mediated up-regulation of FAP.…”

The Cancer Stem Cell in Hepatocellular Carcinoma

“…In cancer, these cells share many of the same functions as CAFs at the level of the CSC niche. It has been reported that HSCs secrete HGF or IL-6 that induce the expression of stemness markers in CSCs, and this increased expression is mediated through STAT3 signaling [218,219]. The investigation of the crosstalk between HSCs and CSCs resulted in the identification of the transcription factor Forkhead Box M1 (FOXM1) as a main player in HSC activation and maintenance of stemness in CSCs in vitro.…”