Inflammation Promotes Expression of Stemness-Related Properties in HBV-Related Hepatocellular Carcinoma

Abstract

The expression of cancer stemness is believed to reduce the efficacy of current therapies against hepatocellular carcinoma (HCC). Understanding of the stemness-regulating signaling pathways incurred by a specific etiology can facilitate the development of novel targets for individualized therapy against HCC. Niche environments, such as virus-induced inflammation, may play a crucial role. However, the mechanisms linking inflammation and stemness expression in HCC remain unclear. Here we demonstrated the distinct role of inflammatory mediators in expressions of stemness-related properties involving the pluripotent octamer-binding transcription factor 4 (OCT4) in cell migration and drug resistance of hepatitis B virus-related HCC (HBV-HCC). We observed positive immunorecognition for macrophage chemoattractant protein 1 (MCP-1)/CD68 and OCT4/NANOG in HBV-HCC tissues. The inflammation-conditioned medium (inflamed-CM) generated by lipopolysaccharide-stimulated U937 human leukemia cells significantly increased the mRNA and protein levels of OCT4/NANOG preferentially in HBV-active (HBV+HBsAg+) HCC cells. The inflamed-CM also increased the side population (SP) cell percentage, green fluorescent protein (GFP)-positive cell population, and luciferase activity of OCT4 promoter-GFP/luciferase in HBV-active HCC cells. Furthermore, the inflamed-CM upregulated the expressions of insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) and activated IGF-IR/Akt signaling in HBV-HCC. The IGF-IR phosphorylation inhibitor picropodophyllin (PPP) suppressed inflamed-CM-induced OCT4 and NANOG levels in HBV+HBsAg+ Hep3B cells. Forced expression of OCT4 significantly increased the secondary sphere formation and cell migration, and reduced susceptibility of HBV-HCC cells to cisplatin, bleomycin, and doxorubicin. Taking together, our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-IR activation, and the upregulation of OCT4 contributes to cancer migration and drug resistance of HBV-HCC cells. Findings in this paper would provide potential targets for a therapeutic strategy targeting on inflammatory environment for HBV-HCC.

RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo

“…An aspect here that remains elusive to the scope of the present study is how the loss of RhoA (which alters the mechanical and biochemical properties of normal stromal fibroblasts) can trigger a stem-like phenotype in these PC3 prostate cancer cells. Probably, increased level of proinflammatory genes plays role in inducing the expression of stemness-related properties of tumor cells (38,39). We have demonstrated that loss of RhoA changed the cytoskeleton, the contractile forces and cell stiffness of the cells, induced a proinflammatory state, and interfered with Rho signaling cascades.…”

Peripheral blood neutrophil count as a prognostic factor for patients with hepatocellular carcinoma treated with sorafenib

“…However, several studies have indicated that tumor pathogenesis and progression are closely associated with the tumor microenvironment, as well as tumor cells themselves (13). Recent studies have suggested that a systemic inflammatory state is associated with the malignant biological behavior of the tumor (14,15). In particular, the neutrophil-lymphocyte ratio (NLR) has been evaluated as a predictor of prognosis in various types of solid tumor, including gastric, colorectal, pancreatic, breast and lung cancers (16)(17)(18)(19)).…”

Inflammation Shapes Stem Cells and Stemness during Infection and Beyond

“…The expression of stemness-related genes in cancer is likely linked to the generation and evolution of the compartment of cells able to regenerate tumor diversity, the cancer stem cells (CSCs) (Kuo et al, 2016; Uthaya Kumar et al, 2016). Upregulation of OCT4 has been shown to contribute to tumor cell migration and resistance to cancer therapeutics (Ma et al, 2011; Chang et al, 2015, 2016; Bhatt et al, 2016). …”