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.
Highlights
Epidemiological and experimental studies have shown that the inflammatory microenvironment is an indispensable participant in the neoplastic process, including development, proliferation, survival, and migration of many cancers [1]
Our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-I receptor (IGF-IR) activation, and the upregulation of octamer-binding transcription factor 4 (OCT4) contributes to cancer migration and drug resistance of hepatitis B virus (HBV)-Hepatocellular carcinoma (HCC) cells
There is a higher significantly positive association between CD68/MCP1 and OCT4 in hepatitis B virus-related HCC (HBV-HCC) (S1A Fig) when compared to that of HBV-negative HCC (S1B Fig). These results highlight that niche immune cell infiltration and inflammatory stimulation may be associated with the expression of OCT4/NANOG in HCC
Summary
Epidemiological and experimental studies have shown that the inflammatory microenvironment is an indispensable participant in the neoplastic process, including development, proliferation, survival, and migration of many cancers [1]. With the paucity of effective therapy for HCC per se, determining the underlying mechanisms involved in the interaction between tumor and inflammatory microenvironment could theoretically enable the development of synergistic therapeutic strategies targeting on niche inflammation [4]. The exponential progress in cancer stem cell (CSC) research in the past two decades has held promise for improved cancer treatment strategies [5]. In mouse HCC models, CD44+ HCC progenitor cells could give rise to cancer only when these cells were introduced into a liver with a chronic inflammation background [12]. These observations highlight the causal relationship between inflammation and cancer stemness properties, for HCC
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