The up-regulated expression of FasL has been found in various types of tumors, including melanoma, lymphoma, gastric carcinoma, and breast carcinoma [
16]. It has been reported that high levels of FasL expression are associated with the presence of tumor-infiltrating lymphocytes (TIL), leading to high susceptibility of activated T cells in tumor tissues to apoptosis triggers due to high levels of Fas expression by activated T cells [
17]. Indeed, engagement of Fas by the FasL can promote the formation of death-inducing signaling complex, resulting in activated T cell apoptosis. This may partially contribute to tumor cells escaping from immune surveillance and leading to tumor progression.
Due to the important role of Fas in the tumor progression and metastasis, the Fas-mediated apoptosis might be a target for cancer therapy. Notably, the apoptotic cascade is a sequential process of many events that can be regulated at different stages. Several agents have been found to directly or indirectly inhibit cellular apoptosis. The arsenic trioxide and tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL) can modulate the intrinsic and extrinsic pathways, respectively [
18]. The caspase activators can regulate the common pathway, and ONY-015 can regulate modulators of the apoptosis pathways [
19]. CpG-ODN can activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activated protein 1 through the Toll-like receptor (TLR) sigaling pathway [
20], and has been thought to act as a potent adjuvant for inducing Th1 response. The NF-κB can regulate the expression of the FasL gene, exhibiting both anti-apoptotic and pro-apoptotic functions [
19]. In this study, we examined the effects of CpG-ODN treatment on the HepG2 cell-induced Jurkat cell apoptosis. We found that CpG-ODN inhibited the expression of FasL in HepG2 in a dose- and time-dependent manner (Figure
1). Treatment with CpG-ODN at 1 μM for 24 h greatly inhibited the expression of FasL in HepG2 cells
in vitro. Furthermore, we found that treatment with CpG-ODN effectively down-regulated the expression of Fas in human Jurkat cells (Figure
2). Jurkat cells are derived from human T lymphocyte leukemia cells, mimic the activated T lymphocyte cells, and have been widely used as experimental models to study the functions of T cells [
21]. In addition, co-culturing the unmanipulated HepG2 cells with Jurkat cells triggered a high frequency of Jurkat cells undergoing apoptosis, which was effectively abrogated by pre-treatment of either HepG2 or Jurkat cells with anti-FasL antibody. These data indicated that HepG2 cells induced Jurkat cell apoptosis
via the Fas/FasL pathway. More importantly, pre-treatment of Jurkat cells or HepG2 cells with CpG-ODN efficiently inhibited the HepG2-mediated Jurkat cell apoptosis (Figure
3) and the caspase activation in Jurkat cells (Figure
4). CpG-ODN can suppress apoptosis of macrophages via TLR9 through PKB/Akt/FOXO pathway [
22], since macrophages and T cells play an important role in anti-tumor immune, our study showed CpG-ODN suppresses apoptosis through FasL/Fas pathway, maybe PKB/Akt/FOXO is another way in anti-apoptosis anti-cancer therapeutic strategies of CpG-ODN.
Currently, treatment of HCC relies on surgery, conventional chemotherapy, and radiation therapy at clinic. Other therapeutic strategies, such as an antibody targeting the specific molecules, are currently in trials. DNA-based drugs, such as CpG-ODN and antisense ODN, are regarded as a new alternative therapy for the brain tumors [
23]. The regulation of the complex signaling pathways in tumors has been a new strategy for the rational design of anticancer strategies. Escaping from immune surveillance and being resistant to apoptosis triggers play an important role in the progression and metastasis of tumors. Our results indicated that CpG-ODN down-regulated the FasL expression in HepG2 cells and Fas in Jurkat cells, and suppressed the HepG2 cells-mediated caspase-dependent apoptosis of Jurkat cells. Conceivably, CpG-ODN treatment may be a promising strategy for the intervention of HCC.