Abstract
Hepatitis B virus (HBV) is one of predisposing factors for hepatocellular carcinoma (HCC). The role of HBV x protein (HBx) in mediating the induction and maintenance of cancer stemness during HBV-related HCC attracts considerable attention, but the exact mechanism has not been clearly elucidated. Here, ABCG2-dependent stem-like side population (SP) cells, which are thought to be liver cancer stem cells (LCSCs), were present in HCC cells, and the fraction of this subset was increased in HBx-expressing HCC cells. In addition, glycolysis was upregulated in LCSCs and HBx-expressing HCC cells, and intervention of glycolysis attenuated cancer stem-like phenotypes. Mitochondria play an important role in the maintenance of energy homeostasis, BNIP3L-dependent mitophagy was also activated in LCSCs and HBx-expressing HCC cells, which triggered a metabolic shift toward glycolysis. In summary, we proposed a positive feedback loop, in which HBx induced BNIP3L-dependent mitophagy which upregulated glycolytic metabolism, increasing cancer stemness of HCC cells in vivo and in vitro. BNIP3L might be a potential therapeutic target for intervention of LCSCs-associated HCC. Anti-HBx, a monoclonal antibody targeting intracellular HBx, had the potential to delay the progression of HBV infection related-HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with the high mortality rate, in which hepatitis B virus (HBV) infection is regarded as one of major risk factors [1].Hepatitis B virus (HBV) x protein (HBx), encoded by HBV X gene for HBV replication, which plays an important role in the development and progression of hepatocellular carcinoma (HCC) via regulating a series of biological processes of the host hepatocytes, such as gene transcription, cell cycle, proliferation, and survival [2]
HCC cell lines (Figure 3J; Figure S2E). All of these results showed that liver cancer stem cells (LCSCs) were in favor of glycolytic were in favor of glycolytic metabolism, and HBV x protein (HBx)-expressing triggered a metabolic shift toward metabolism, HBx-expressing triggered a metabolic shift toward glycolysis in HCC cell lines
The mRNA levels of SLC2A1, HK2, PFKL, and lactate dehydrogenase (LDHA) were significantly lower in HBx-expressing Huh7 cells treated with anti-HBx than that in HBx-expressing Huh7 cells (Figure 8J). These results suggested that anti-HBx could reduce the hepatocarcinogenesis associated with HBx-induced BNIP3L-dependent mitophagy and glycolysis metabolism reprogramming in HCC cells
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with the high mortality rate, in which hepatitis B virus (HBV) infection is regarded as one of major risk factors [1].HBV x protein (HBx), encoded by HBV X gene for HBV replication, which plays an important role in the development and progression of HCC via regulating a series of biological processes of the host hepatocytes, such as gene transcription, cell cycle, proliferation, and survival [2]. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with the high mortality rate, in which hepatitis B virus (HBV) infection is regarded as one of major risk factors [1]. Emerging studies suggested that HBx promoted cancer stem cells (CSCs) generation in the pathogenesis of HCC [3]. 3-kinases (PI3K)/protein kinase B (AKT) signal pathway to stimulate normal human liver cells to generate hepatic CSCs, thereby accelerating the malignant transformation of hepatic cells [4]. Activation of the stemness-related octamer-binding transcription factor 4 (OCT4) gene contributed to cell migration, drug resistance, and poor prognosis in HBV-related HCC [6,7]. HBx activated stemness-related proteins, including β-catenin, epithelial cell adhesion molecule (EpCAM), Klf-4, Nanog, and Oct in vivo and in vitro [4]. Exploring the molecular mechanisms by which HBx promoted CSCs generation would be useful to identify a novel interventional target
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