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Metastasis and recurrence severely impact the treatment effect of hepatocellular carcinoma (HCC). HCC complicated with cholestasis is more prone to recurrence and metastasis. Previous studies have implicated pathogenesis of HCC by bile acid; however, the underlying mechanism is unknown yet. Glycochenodeoxycholate (GCDC) is one of most important component of bile acid (BA). In the present study, the role of GCDC in HCC cells invasion was detected by in vitro and in vivo assays. GCDC was found to significantly enhance the invasive potential of HCC cells; Further studies showed that GCDC could induce autophagy activation and higher invasive capability in HCC cells. Interestingly, inhibition of autophagy by chloroquine (CQ) reversed this phenomenon. Subsequently, the correlation between TBA expression level and clinicopathological characteristics was analyzed in HCC patients. Clinically, high TBA level in HCC tissue was found to be associated with more invasive and poor survival in HCC patients. Mechanistic study showed that bile acid induced autophagy by targeting the AMPK/mTOR pathway in HCC cells. Therefore, our results suggest that bile acid may promote HCC invasion via activation of autophagy and the level of bile acid may serve as a potential useful indicator for prognosis of HCC patients., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatic progenitor cells (HPCs) are bipotential stem cells that can differentiate into mature hepatocytes or biliary epithelial cells (BECs). They are thought to be involved in repair of liver injury and the incidence of hepatic carcinoma. Their physiology is closely associated with the microenvironment where they reside. Lipopolysaccharide (LPS), an important component of the hepatic pathological microenvironment, is stored in the liver and affects many types of cells in various hepatosis. HPCs may also be influenced by LPS. In this paper, mouse ED13.5 E-cadherin + foetal liver cells were isolated as mouse hepatic progenitor cells (mHPCs). Proliferation of mHPCs was promoted under LPS conditions both in vivo and in vitro. Moreover, LPS enhanced colony formation ability of mHPCs, and blocked them differentiation into mature hepatocytes and formation of a bile duct-liked structure. More importantly, long-term treatment with LPS promoted tumorigenesis of mHPCs in nude mice. Thus, we conclude that LPS may promote aberrant proliferation of mHPCs and restrict their normal differentiation. Long-term exposure of mHPCs to LPS increased the risk of tumour formation. These data provide insight into the links between LPS, HPCs fate, and tumorigenesis, and present novel insight into the relationship between HPCs and their microenvironment., (Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.)

Due to the existence of cancer stem cells (CSCs), persistence and relapse of human hepatocellular carcinoma (HCC) are common after treatment with existing anti-cancer therapies. Emerging evidence indicates that lipopolysaccharide (LPS) plays a crucial role in aggravating HCC, but information about the effect of LPS on CSCs of HCC remains scant. Here, we report that the stemness of CD133(+) CSCs sorted from the human HCC cell line Huh7 was maintained well when cells were cultured with LPS. The reduction of CD133 expression was much lesser in cultured CSCs in the presence of LPS. In response to LPS stimulation, CSCs showed an increase in their activity of clonogenesis and tumorigenesis. LPS also supported maintaining CSC abilities of migration, invasion, and chemo-resistance. Treatment with HIF-1α-specific siRNA significantly reduced CD133 expression by CSCs at both mRNA and protein levels. Further, the expression of HIF-1α and CD133 was reduced in LPS-stimulated CSCs when the NF-κB inhibitor was added to the cell culture. HIF-1α-specific siRNA also effectively counteracted the effect of LPS on maintaining CSC abilities of migration and invasion. These data indicate that LPS, an important mediator in the liver tumor microenvironment, supports the maintenance of CSC stemness through signaling of the NF-κB/HIF-1α pathway. Our current study highlights LPS as a potential target for developing new therapeutic approaches to eliminate CSCs during the treatment of HCC., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Cancer stem cells (CSCs) or tumor-initiating cells (TICs), a small subset of tumor cells, are involved in tumor initiation, progression, recurrence and metastasis. In human hepatocellular carcinoma (HCC), TICs are enriched with cell surface markers and play a key role in chemotherapy resistance, tumor invasion and migration. Toll like receptor 4 (TLR4), acting as a receptor for lipopolysaccharide (LPS), has been reported to be responsible for carcinogenesis, invasion, metastasis and cancer progression. In our study, two HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasive ability of TLR4 positive HCC cells in vitro and in vivo. Stem-like features were also detected in TLR4 positive HCC cells. A total of 88 clinical samples from HCC patients were used to evaluate the association of TLR4 and stem-cell marker expression, and the relationship between TLR4 expression and clinicopathological characteristics was analyzed. The in vitro and in vivo experiments indicated that TLR4 positive HCC cells displayed significantly enhanced invasion and migration, and stem-like properties were also detected in TLR4 positive HCC cells. Clinically, TLR4 expression levels were found to be significantly higher in HCC tissues with microvascular invasion. Additionally, high expression of TLR4 in HCC tissues was strongly associated with both early recurrence and poor survivals in patients. Our results indicated that there was a relationship between TLR4 expression and CSC's features, TLR4 may act as a CSC marker, prompting tumor invasion and migration, which contributes to the poor prognosis of HCC., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Liver cancer stem cells (LCSCs) can drive and maintain hepatocellular carcinoma (HCC) growth, metastasis, and recurrence. Therefore, they are potentially responsible for the poor prognosis of HCC. Oxygen and nutrient deficiencies are common characteristics of the tumor microenvironment. However, how LCSCs adapt to oxygen- and nutrient-deprived conditions is unclear. Here, we used immunofluorescent staining and flow cytometry analysis to show that CD133+ cells were significantly enriched after hypoxia and nutrient starvation (H/S) in the human HCC cell line Huh7. Sorted CD133+ cells showed higher survival, less apoptosis, and possess higher clonogenic ability under H/S compared to the CD133- population. Under H/S, electron microscopy revealed more advanced autophagic vesicles in CD133+ cells. Additionally, CD133+ cells had higher autophagy levels as measured by both RT-qPCR and Western blotting. CD133+ cells had more accumulated GFP-LC3 puncta, which can be detected by fluorescence microscopy. The autophagic inhibitor chloroquine (CQ) significantly increased apoptosis and decreased the clonogenic capacity of CD133+ cells under H/S. Pre-culturing in H/S enhanced the sphere-forming capacity of CD133+ cells. However, CQ significantly impaired this process. Therefore, autophagy is essential for LCSCs maintenance. CD133+ cells were also found to have a higher tumor-forming ability in vivo, which could be inhibited by CQ administration. Collectively, our results indicate that the involvement of autophagy in maintenance of CD133+ LCSCs under the oxygen- and nutrient-deprived conditions that are typical of the tumor microenvironment in HCC. Therefore, autophagy inhibitors may make LCSCs more sensitive to the tumor microenvironment and be useful in improving anti-cancer treatments., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)