ABSTRACT
The pregnane X receptor (PXR), a liver and intestine specific receptor,, has been reported to be related with the repression of inflammation as well as activation of cytochromosome P450 3A (CYP3A) expression. We examined the effect of PXR on tetrachloromethane (CCl4)-induced mouse liver inflammation in this work. Ginkgolide A, one main component of Ginkgo biloba extracts (GBE), activated PXR and enhanced PXR expression level, displayed both significant therapeutic effect and preventive effect against CCl4-induced mouse hepatitis. siRNA-mediated decrease of PXR expression significantly reduced the efficacy of Ginkgolide A in treating CCl4-induced inflammation in mice. Flavonoids, another important components of GBE, were shown anti-inflammatory effect in a different way from Ginkgolide A which might be independent on PXR because flavonoids significantly inhibited CYP3A11 activities in mice. The results indicated that anti-inflammatory effect of PXR might be mediated by enhancing transcription level of IκBα through binding of IκBα. Inhibition of NF-κB activity by NF-κB-specific suppressor IκBα is one of the potential mechanisms of Ginkgolide A against CCl4-induced liver inflammation.
ABSTRACT
BACKGROUND: The presence of cancer stem cells (CSCs) is currently regarded as one of the main culprits of tumor formation and therapy failure. It is known that chronic inflammation is associated with CSCs, but it is not clear yet how inflammation affects the development of CSCs. In the present study we aimed to examine the relationship between cancer cell stimulation mediated by immune cells and the acquisition of a CSC-like phenotype. METHODS: Cancer cells derived from single hepatocarcinoma HepG2 cells were treated with mouse splenic B cells (MSBCs) and mouse peritoneal macrophage cells (MPMCs), respectively. The stem cell-like characteristics of the resulting HepG2 cells (MSBC-HepG2 and MPMC-HepG2) were evaluated using different assays, including biomarker assays, in vitro tumoroid and colony forming assays, in vivo tumor forming assays and signal transduction pathway activation assays. RESULTS: Various stemness characteristics of HepG2 cells, including self-renewal, proliferation, chemoresistance and tumorigenicity were evaluated. The expression levels of stemness-related genes and its encoded proteins in the MSBC-HepG2 and MPMC-HepG2 cells were assessed using RT-PCR and FACS analyses. We found that MSBC-HepG2 and MPMC-HepG2 cells possess hepatic CSC properties, including persistent self-renewal, extensive proliferation, drug resistance, high tumorigenic capacity and over-expression of CSC-related genes and proteins (i.e., EpCAM, ALDH, CD133 and CD44), compared to the parental cells. We also found that 1x10(3) MSBC-HepG2 and MPMC-HepG2 cells were able to form tumors in NOD/SCID mice and that the Notch and SHH signaling pathways were highly activated in MSBC-HepG2 cells. CONCLUSIONS: We conclude that the immune system may have a double-edge effect on cancer development. On one hand, immune cells such as B lymphocytes and macrophages may recognize, attack and eliminate cancer cells, whereas on the other hand, they may promote a subset of cancer cells to acquire stem cell-like characteristics.
