Inflammation and liver tumorigenesis

Abstract

Inflammation has been considered as one of the hallmarks of cancer, and chronic hepatitis is a major cause of liver cancer. This review will focus on the pathogenic role of inflammation in hepatocarcinogenesis and will discuss recent advances in understanding the chronic hepatitis-liver cancer link based on hot spots in liver cancer research, including cellular interaction, cytokines, microRNA and stem cells. All of these mechanisms should be taken into consideration because they are crucial for the development of more efficacious therapeutic strategies for preventing and treating human chronic hepatitis and hepatocellular carcinoma.

Keywords

hepatocellular carcinoma / hepatitis / cytokine / stem cell / miRNA

Introduction

Primary liver cancer (PLC) originates in the liver and includes hepatocellular carcinoma (HCC), cholangiocarcinoma and hepatoblastma. PLC ranks sixth in frequency and third in mortality in the world with an estimated number of 626 000 new cases every year. In developing countries, incidence rates are twofold to threefold higher than in developed countries. The geographic areas at highest risk are located in eastern Asia. HCC, which originates in the hepatocytes, is the most common form of PLC. The cause of most cases of liver cancer is not known and several factors have been shown to contribute to the development of PLC. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), cirrhosis, diabetes, nonalcoholic fatty liver disease (NAFLD), exposure to aflatoxins, excessive alcohol consumption and obesity are seven of the most common and well-accepted causes of liver cancer. Most of these causes induce liver injury that further transforms to chronic liver damage, contributing to hepatic nonresolvable chronic inflammation. Compensatory proliferation accompanied by cell division occurs with chronic injury. On one hand, new cells restore liver function to baseline; on the other hand, excessive compensatory proliferation can induce serial pathological changes including structural abnormality in hepatic lobules, fibrosis and cirrhosis until the development of hepatocarcinogenesis. The connection between chronic inflammation and cancer is likely to be mediated, in part, by cellular interactions between non-mesenchymal and mesenchymal areas, secretion of cytokines, cell signaling activation and crosstalk. This review will focus on the pathogenic role of inflammation in hepatocarcinogenesis and will discuss recent advances in understanding the inflammation-PLC link based on basic mechanistic studies carried out in mouse models that were confirmed in human clinical studies.

Cellular interaction

The tumor microenvironment of HCC is composed of fibroblasts, endothelial cells, tumor-associated macrophages (TAMs), T lymphocytes, neutrophils and myeloid-derived suppressor cells (MDSCs) [1]. Cellular interaction is very complicated and has a critical function in malignant transformation, tumor development, metastasis and immunoescape. Cytokine balance is also critical for regulating the type, extent, function and outcome of inflammatory cell infiltrates. According to a recent hypothesis, hepatocyte malignant transformation occurs through a pathway of increased liver cell turnover induced by chronic liver injury and compensatory regeneration in the context of inflammation and oxidative DNA damage [2]. In this context, the host immune response against pathogens becomes relevant for HCC development and tumor progression. Pathogenic proteins interact with many host cell factors and affect a wide range of cellular and humoral activities, including cell signaling, transcriptional modulation, transformation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation [3]. In addition, cytokine and chemokine production is affected. Inflammatory cells and immunomodulatory mediators (chemo-/cytokines) present in the microenvironment polarize the host immune response toward specific phenotypes impacting tumor initiation and progression [1]. The cellular interaction mediated by both acute and chronic hepatic inflammation will be subsequently discussed in detail.

Cellular interaction in acute liver injury

Acute liver injury is often observed in patients without liver disease. Sustaining a liver injury may result in rapid liver dysfunction. Several different factors may primarily be responsible: drugs, toxins, chemicals, ischemia/reperfusion (I/R), and viral hepatitis. When hepatocytes are severely injured, the innate immune response is rapidly activated. Innate immune cells, such as Kupffer cells (KCs), neutrophils, natural killer cells (NKs), natural killer T cells (NKTs), and liver sinusoidal endothelial cells (LSECs) have a significant function during the acute phase response.

In the acutely injured liver, the hepatic insult activates KCs to secrete abundant amounts of pro-inflammatory mediators, such as tumor necrosis factor α (TNF-α), interleukins (IL-1 and IL-6), chemokines and reactive oxygen species (ROS) [4]. These inflammatory mediators exacerbate the initial liver injury and cause the recruitment of inflammatory cells, such as neutrophils and macrophages. Recently, Yan et al. reported that gadolinium chloride inhibition of KCs completely prevented concanavalin A (ConA)-induced liver injury and cytokine release [5]. Due to the suppression of KC activation, kinsenoside alleviates CCl₄-induced liver injury [6].

Neutrophils are phagocytic leukocytes representing one of the first lines of defense during infection and injury. Once activated, neutrophils mediate hepatocyte death through the initiation of respiratory bursts and neutrophil degranulation [7,8]. Neutrophil-derived oxidants diffuse into hepatocytes and trigger intracellular oxidative stress, mitochondrial dysfunction and, eventually, cause liver cell death. Neutrophil-induced hepatocyte injury has been implicated in I/R [9] and acetaminophen (APAP) [10] models of acute liver injury.

NK/NKT cells, another major component of innate immunity, are also enriched in the liver more than in the lymphoid organs and peripheral blood [11]. Upon stimulation, NK/NKT cells release large amounts of IL-4, IL-5 and, especially, interferon (IFN)-γ, which have a critical function in liver injury through the induction of hepatocyte apoptosis [12] and chemokine production [13]. NK and NKT cells also directly induce hepatocyte death, through the upregulation of FasL expression in the liver, thus contributing to the severity and progression of liver injury [13]. In a ConA-induced acute liver injury model, NKT cells are responsible for the induction of IL-33 in hepatocytes [14], which are specifically released during necrotic cell death associated with tissue damage. IL-33 is now hence referred to as one of the “alarmins.”

LSECs also actively participate in acute liver injury. A distinct function of these cells is their unique ability to clear pro-inflammatory substances, such as lipopolysaccharides. Enhanced production of anti-inflammatory mediators (TGF-β [15] and IL-10 [16]), reduces LSEC expression of adhesion and antigen presentation/co-stimulator molecules (MHC class II, CD80/86 [17]). LSECs also express MHC class I and costimulatory molecules characterized by active stimulatory antigen-presenting cells (APC) [18]. However, the ability of LSECs to activate cloned CD4⁺ T cells antigen was specifically downregulated by IL-10 [19]. The main effect caused by LSECs in this suppression seems to be the induction of T cell tolerance [20]. LSECs are also regarded as APCs in the progression of warm hepatic I/R injury by expressing B7-1 and B7-2 [21].

Cellular interactions in chronic hepatitis and liver cancer

Chronic hepatitis is characterized by the sustained destruction of a number of liver cells with various inflammatory cells in the liver tissue, as induced by a series of causative factors including viruses, bacteria, drugs, toxins, metabolic disorders and autoimmune diseases. Aside from the continuous stimulation of causative factors, cellular interaction of type 2 macrophages, myeloid-derived suppressive cells and various types of T cells have an essential function in sustained inflammation within the liver. In the tumor or inflammation microenvironment of chronic HCC, macrophages can be classified into type I and type II both of which play a central role in modulating inflammation and resolving tumor promotion through interaction with lymphocyte subsets (Fig. 1).

Type 1 macrophages emerge in the very early stage of inflammation in response to inflammatory mediators. They release inflammatory cytokines and chemokines, such as CXCL19 and CXCL10, encouraging Th1, Th17, and NK cell development and differentiation within the liver by directly upregulating the transcription of IL-12p35, IL-12p40, IL-23 and TNF-α [22-25]. Type 1 macrophages are activated by pathogens and can be polarized by GM-CSF and IFN-γ by expressing phenotypic markers of interferon-regulatory factor 5 (IRF5). However, with long-term inflammation and tumor advance, most macrophages become polarized to type 2 macrophage-related cells. This result reverses the effect of type 1 macrophages by releasing factors that encourage Th2 differentiation and recruitment [26]. First, type 2 macrophages secrete a set of cytokines and chemokines, including CCL17, CCL22 and CCL24, fostering regulatory T cell (Treg) recruitment and development; second, type 2 macrophages support liver compensatory regeneration, as well as angiogenesis through the production of vascular endothelial growth factor (VEGF) or EGF [27]. In summary, macrophages can be pro-inflammatory with type 1 cells promoting cell growth and recruitment through the production of chemokines and cytokines, such as IL-6, TNF-α, IL-23 and IL-12 [28-29]. Macrophages may promote tumor development and immunoregulation through type 2 macrophages by inmmunosuppressive modulation through the production of transforming growth factor β1 (TGF-β) and IL-10 [27].

MDSCs represent a heterogeneous population that might include macrophages, dendritic cells or granulocytes. MDSCs regulate T cell responses through nitric oxide, ROS, and TGF-β secretion while promoting T-reg induction and favoring anti-inflammatory responses [30]. The immunosuppressive function of MDSCs has been established in both mice and humans. First, the immunosuppressive functions of MDSCs have been demonstrated in HBV transgenic mice. Subsequently, clinical data outcomes indicated similar observations [31]. MDSCs mediated by the MyD88-NF-κB pathway can exert suppressive functions by secreting cytokines, such as IL-10. MDSCs inhibited TLR-ligand-induced IL-12 production of DC by IL-10 production. Moreover, MDSCs also suppressed T cell stimulatory activity of DC [32]. MDSCs were found to exert their immunosuppressive function through the induction of CD4⁺CD25⁺Foxp3⁺ regulatory T cells in cocultured CD4⁺ T cells [33]. MDSCs also inhibit NKs in patients with HCC via the NKp30 receptor [34]. Research on cellular interactions in hepatitis and PLC are preliminary. However, cytokines functioning as messengers that connect different cells have been systematically studied.

Cytokines

Cytokines are cell-signaling protein molecules secreted by various types of cells in the liver and used extensively in intercellular communication. A well-accepted causative connection between inflammation and cancer has been mechanistically established. Inflammation has already been defined as one of the hallmarks of cancer. Malignant transformation from chronic inflammation has aroused the interest of many scientists. Cytokines, such as TNF-α, IL-6, TGF-β and IFN-γ, have been reported to serve as growth and survival factors that act on premalignant cells, stimulate angiogenesis, tumor progression and metastasis and also maintain tumor-promoting inflammation [28,29,35].

IL-6

Previous studies have shown that IL-6, a multifunctional cytokine upregulated in response to liver inflammation, is an essential factor contributing to hepatocarcinogenesis in both humans and mice [36-41]. Based on a mouse model, IL-6 is also considered as a mediator of sexual disparity in hepatocarcinogenesis. The same result was obtained in rats indicating that estrogen has the potential to inhibit lung metastasis from rat HCCs in vivo due to the modulation of the inflammatory tumor microenvironment by suppression of HGF and IL-6 production [42]. Furthermore, gender differences in IL-6 expression have been manifested from clinical investigation, which indicated that excessive IL-6 was detected only in male tumor adjacent tissue stimulated by IL-1a via MyD88 signaling [43]. Moreover, IL-6-induced ISX regulates tumor growth and survival in HCC [44]. IL-6 was also considered as a bridge connecting hepatic inflammation and metabolism disorder. Choline-deficient, ethionine-supplemented (CDE) diet-treated mice lacking IL-6 and gp130-STAT signaling in hepatocytes were prone to hepatic metabolic changes and inflammation. This ultimately led to progressive steatohepatitis with signs of liver remodeling [45]. Another study focused on glycosis, revealing that IL-6 enhanced glycolysis in mouse embryonic fibroblasts and human cell lines. Moreover, IL-6-activated STAT3 enhanced the expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), suggesting a novel mechanism for inflammation-associated oncogenesis [46]. Very recently, two studies indicated that endogenous IL-6 was confirmed in a human HCC cell line, similar to exogenous IL-6. Endogenous IL-6 has been confirmed to have an anti-apoptosis effect through STAT3 activation in a human HCC cell line. Moreover, endogenous IL-6 was regarded as a cause of doxorubicin resistance in SNU-449 cells [47]. Both of these studies indicated that IL-6/STAT3 is a valuable potential therapeutic target. The gp-130-mediated pathway is considered to provide downstream signaling to exert an IL-6 effect [48]. The effect was also investigated in MDSCs, a cell population mainly known for anti-inflammatory properties in cancer, gp130-dependent communication between the liver and MDSCs through acute phase proteins controlling inflammatory responses during infection. gp130-STAT3 activation is also essential for mobilization and tissue accumulation of MDSCs [49].

TNF-α

TNF-α is a potent pleiotropic proinflammatory cytokine, which is produced by many cell types including macrophages, neutrophils, fibroblasts, keratinocytes, NK cells, T and B cells, and tumor cells [50]. Previous research has indicated that TNF-α is essential in liver development and regeneration. However, it is also indispensable for hepatocarcinogenesis [51]. Furthermore, recent clinical studies on HBV-related HCC revealed that TNF-α and related signaling were altered in HBV-related HCC. Ruchi et al. showed that the increased level of HBx in cells cooperated with TNF-α to activate NF-κB and expression of NF-κB-regulated genes, indicating a positive feedback loop between HBx and NF-κB signaling [52]. Polymorphism analysis of TNF-α and a correlation study of HCC risk revealed that TNF-α-308 and-238 are associated with a moderate decrease in HCC risk in a Chinese population [53,54]. TNF-α signaling has also been investigated in clinical samples. Sorafenib, an effective anticancer medicine in HCC treatment, sensitizes resistant HCC cells to TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis at clinical achievable concentrations via the inhibition of STAT3 [55]. Recent research has confirmed that FoxM1 expression was regulated by the TNF-α/reactive oxygen species/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis [56]. The expression of receptors belonging to the superfamily of TNF-R, such as TNF-R1, CD95 and TRAIL receptor-1 (TRAIL-R1) and TRAIL-R2, is altered in patients with HCC, especially those in advanced stages of de-differentiation. The disruption of death receptor (DR)-dependent cell signaling is related to poor survival in patients with HCC [57,58]. Therefore, TNF-α signaling is becoming a target for HCC treatment and prevention.

TGF-β

TGF-β, a potent inhibitor of cell proliferation, is frequently overexpressed in HCC. The role of TGF-β signaling during HCC development remains controversial [59,60]. TGF-β inhibits cell proliferation and promotes tumor cell invasion by inducing epithelial-mesenchymal transition (EMT) [61]. Coulouarn et al. examined HCC cell lines using a cluster analysis of microarray data sub-classifying HCC by the early or late response of the cells to TGF-β [62].Their finding suggested that reduced expression of the TGF-β receptor might be a key factor in shifting to the late response to TGF-β. This hypothesis was verified by a study that reduced TGFBR2 expression in HCC, which was correlated with intrahepatic metastasis [63]. TGF-β signaling is also involved in angiogenesis during cancer progression. Ito et al. showed that plasma TGF-β levels correlated positively with tumor vascularity [64]. Mazzocca et al. demonstrated that crosstalk between HCC and endothelial cells was blocked by LY210976, an inhibitor of TGFBR1, through suppressing angiogenesis via VEGF, which is a gene involved in the late response to TGF-β [62,65]. Thus, TGF-β promotes HCC cells to secrete VEGF, which induces hypervascularization, one of the features of advanced HCC. Furthermore, hepatoma-initiating cells may be derived from hepatic progenitor cells exposed to chronic and constant TGF-β stimulation in cirrhotic liver [66]. Deregulation of TGF-β levels or TGF-β signaling induces hepatocarcinogenesis in a multi-step manner, which is very complicated. However, considering that TGF-β may have a significant impact on the molecular classification of HCC, they are worth further investigation.

Th17-linked cytokines

The Th17 cells are a subset of CD⁺ T helper cells. These IL-17-secreting cells have potent pro-inflammatory properties and play an active role in inflammation and autoimmune diseases [67-69]. IL-23 and several key cytokines, including IL-1β, IL-6, TNF-α and TGF-β, can create a cytokine milieu promoting the expansion of human Th17 cells [70-73]. Many inflammatory damages previously ascribed to Th1 responses are considered as responses to the cytokines linked to Th17 cells, including IL-17, IL-22 and IL-23 [73]. The function of IL-17 in HCC development is controversial. Recently, more studies have focused on the role of Th17 cells in human HCC, revealing that Th17 cells are positively correlated with micro-vessel density in tumors [74]. Moreover, IL-17 has been established to promote angiogenesis and metastasis by recruiting neutrophils [75,76]. IL-17 was also shown to mediate hepatic inflammation and tumor development. Intrahepatic-activated monocytes in peritumoral stroma is correlated with Th17 in the same area [77]. Meanwhile, IL-17 could activate monocytes to express B7-H1 in a dose-dependent manner, indicating that such IL-17-mediated immune tolerance should be considered for anti-cancer therapies [78]. Another Th17-linked cytokine is IL-23, which is a heterodimeric cytokine comprised of IL-12p40 and an IL-23-specific p19 subunit discovered in 2000 [79]. IL-23 was considered as the causative molecule in a number of inflammatory disorders and tumors [80,81]. Recently, several functions for IL-23 in liver disease have been revealed [82]. Hu et al. reported IL-23 as a candidate gene therapy agent against HCC in a mouse model. However, high doses of IL-23 have moderate anti-HCC effects and IL-23 was observed to have negative effects on the regulation of hepatic T cells, NK and NKT in number and activation, which might lead to non-resolvable inflammation [83], whereas IL-17A could promote IL-23 expression in HCC tumor cells [84]. Very recently, in one of our studies, we discovered excessive expression of IL-23 in human HCC tissue and adjacent cirrhotic tissue acting as a necessary cytokine composing a microenvironment of IL-22-producing T cells [85]. IL-22 is another Th17-linked cytokine reported early in 2002 as an activator for multiple signaling pathways, such as JAK/STAT, ERK, JNK and p38 MARPK in rat hepatoma cells [86]. However, very few reports of its function in tumors have been published. Zhang indicated that its anti-apoptotic effect is enhanced through IL-22 in an autocrine manner in lung cancer, and knockdown research using siRNA showed its therapeutic effect in a xenograft model [87]. The function of IL-22 in acute liver injury was also investigated by Lauren, who claimed that IL-22, not IL-17, protected hepatocytes by STAT3 activation during ConA-induced acute liver injury [88]. Very recently, two studies disclosed the function of STAT3 in chronic hepatitis and tumorigenesis. Both studies showed that sustained expression of IL-22 during chronic hepatic injury can enhance tumorigenesis in the liver through STAT3 activation [85,89].

microRNAs linked to inflammation and liver cancer

In the past decades, PLC mechanism studies have focused mainly on investigating the genes and proteins underlying the development and progression of liver cancer [90]. Recently, an increasing number of reports have described a new class of small regulatory RNA-nominated microRNAs (miRNAs) involved in HCC progression [91]. miRNAs are evolutionarily endogenous non-coding RNAs that have been identified as post-transcriptional regulators of gene expression [92]. The miRNAs bind to complementary sequences on target mRNA transcripts (mRNAs), usually resulting in translational repression or target degradation and gene silencing. Computational analysis illustrated that>30% of protein-coding genes may be directly modulated by miRNAs. By affecting gene regulation, miRNAs are likely to be involved in most biological processes linking inflammation to liver cancer. Aberrant expression of miRNAs has been observed in a wide range of human diseases, including cancer [93]. In human cancer, miRNAs can function as tumor promoter or suppressor during tumor development and progression [94]. The deregulation of miRNAs in PLC was recently identified, and some specific miRNAs were found to be related to the essential characteristics of PLC, such as cell proliferation, avoidance of apoptosis, metastasis, recurrence and prognosis [95-97]. A large number of studies have focused on the effect of inflammation on the development of PLC involving viral infection, nonalcoholic steatohepatitis and liver regeneration (Table 1).

miRNAs have been reported to necessarily play a paradoxical role in the pathophysiological process of hepatitis virus infection and replication. On one hand, IFN-mediated miRNAs can inhibit HCV replication by targeting HCV genomic RNA. miR-122 can also inhibit viral replication and cell proliferation in HBV-related HCC [108,109]. On the other hand, IFN treatment also downregulates the expression of miR-122, which attenuates HCV replication and accumulation by interaction with HCV RNA 5′-UTR [110]. Furthermore, the inhibition of miR-122 attenuates chronic HCV infection in chimpanzees [110]. Similar to miR-122, miR-1 was also reported to regulate the expression of several host genes to enhance HBV replication and reverse cancer cell phenotypes, which is apparently beneficial for HBV replication [111]. However, no positive correlation between intrahepatic miR-122 or the IFN-induced miRNAs and HCV RNA levels was observed in tissue samples from HCV-infected patients [112], suggesting that the role of miRNAs in humans may be more complicated.

NAFLD is characterized by hepatic fat accumulation without significant alcohol consumption or other underlying etiology from steatosis/steatohepatitis (NASH) to cirrhosis [113]. Recently, the participation of miRNAs in NAFLD has been suggested by the transition transfection of 327 unique human miRNAs. This finding reveals that 11 miRNAs were able to alter lipid droplet (LD) formation/retention, wherein miR-181d was the most efficacious inhibitor, decreasing LDs by about 60%. miRNA-181d was also confirmed to reduce cellular triglycerides and cholesterol ester via biochemical assays [114]. Another recent study using microarray analysis showed that miR-10b regulates steatosis levels in L02 cells by targeting the peroxisome proliferator-activated receptor (PPAR) in a single binding site [115]. The role of miRNAs in the 15% possibility transformation from NASH to end-stage cirrhosis in humans has also been reported, and miRNA expression profiles are altered in NASH. miR-122 is significantly underexpressed (63%) in NASH cases compared with those without the metabolic syndrome. Overexpression of miR-122 in HepG2 cells results in a significant decrease in sterol regulatory element binding proteins (SREBP1-c and SREBP2), FAS and 3-hydroxy-3-methyl-glutaryl-CoA reductase [116].

Hepatocytes are capable of undergoing multiple divisions as a result of hepatic injury. Liver compensatory regeneration is a complex process that involves the influence of miRNAs on cell cycle progression. Recent studies have revealed related mechanisms that may be associated with rapid tissue repair. These results indicate that miR-21 and miR-378 contribute to liver regeneration through suppression of Btg2 and ornithine decarboxylase, respectively, promoting DNA synthesis in hepatocytes after 2/3 hepatectomy [117]. The same result was obtained by Castro et al. who reported that miR-21 expression, which is increased following rat hepatectomy, can be modulated by ursodeoxycholic acid, a pro-survival agent in hepatic regeneration. Furthermore, miRNA profiles from rats have shown that miR-21 levels are highest at 24, 36 and 72 h PH. Inhibition of miR-21 reduces hepatocyte proliferation and increases levels of lactate dehydrogenase [118]. However, as previously noted, miR-21 has been identified as an onco-miRNA due to repressed PTEN signaling promoting HCC development [119]. Additional experiments have shown that miR-21 was upregulated in the early stages of regeneration and its overexpression inhibited NF-κB signaling which is equally essential in liver compensatory regeneration and hepatocarcinogenesis [120]. Therefore, miRNAs, such as miR-21, which is essential for liver regeneration, often have promotion effects on PLC development. However, the detailed mechanism needs to be further clarified.

Stem cells and inflammation

Liver stem cells (LSCs) or liver progenitor cells are induced during chronic liver inflammation, replacing damaged hepatocytes and cholangiocytes in various liver diseases including alcoholic and non-alcoholic fatty liver disease, HBV and HCV induced hepatitis. Early in 1999, Lowes et al. reported that oval cell numbers correlated with disease severity [121]. Strikingly, LSCs were almost always accompanied by an inflammatory reaction, located directly adjacent to the inflammatory cells [122]. LSCs have been revealed to have a strong relationship with liver regeneration following acute and chronic damage via cellular interactions with liver immune cells through paracrine signals, especially from growth factors that underwent a regeneration process [123]. However, during the regeneration, LSCs were also considered as a dangerous target in hepatocarcinogenesis by the interaction or modulating inflammation niche involved in tissue repair. LSCs have been reported to initiate HCC and cholangiocarcinoma (CC) [124], and the function of LSCs in carcinogenesis is supported by a histological investigation of liver cancer that exhibits features of both HCC and CC accompanied by the presence of numerous LSCs [125]. Furthermore, p53 null CD133⁺ LSCs, which can differentiate into both hepatocytes and cholangiocytes, can result in the formation of tumors with some characteristics of HCC and CC via subcutaneous injection into immunodeficient mice [126]. Aside from normal LSCs, increasing evidence has indicated that many human tumors exhibit heterogeneity, in which some subset of tumor cells demonstrated properties of stem cells promoting tumor growth and metastasis [127,128]. Furthermore, due to their characteristic of relative resistance to radiation and chemotherapy, cancer stem cells (CSCs) may generate tumors through self-renewal and differentiation into multiple cell types [129-131]. Recent studies suggest that LSCs play a key role in liver carcinogenesis. A small subset of cancer cells with CSC properties has been identified and characterized from HCC cell lines, animal models and human primary HCCs, which can be identified by several cell surface antigens, including CD133, CD90, CD44, EpCAM and CD13 [132-136].

Considerable clinical evidence points to links between inflammatory states and cancer development. Etiological studies have demonstrated associations between viral hepatitis and the development of liver cancer. Just as normal stem cells are regulated by their microenvironment, or niche, LSCs interact with and in turn are regulated by cells in the tumor microenvironment. The development of hepatic chronic inflammation has been associated with the production of cytokines involving the TNF super family such as TNF-α and the TNF-like weak inducer of apoptosis [137,138], lymphotoxin β [139], members of the IL-6-like family including IL-6 [140], oncostatin M [141] and IFNα [142]. Most of these cytokines produced by various inflammatory cells will activate cell signaling, such as NF-κB and STAT3, in both LSCs involved in tumor cells and inflammatory cells, thus promoting inflammation and tumor growth. Except for cytokines traditionally regarded as mediators in inflammation, miRNAs have attracted significant attention as regulators of various biological processes, including proliferation and differentiation of stem cells and progenitor cells [143]. Moreover, they subsequently modulate the expression of gene products involved in phenotypic characteristics of LSCs. Conserved let-7 and miR-181 family members were upregulated in LSCs by global microarray-based microRNA profiling; inhibition of let-7 increases the chemosensitivity of LSCs to sorafenib and doxorubicin, whereas silencing of miR-181 led to a reduction in LSC motility and invasion [144]. Conserved miR-181 family members were upregulated in LSCs, and inhibition of miR-181 led to a reduction in EpCAM⁺ LSC quantity and tumor initiating ability, whereas exogenous miR-181 expression in HCC cells resulted in an enrichment of EpCAM⁺ LSCs. miR-181 could directly target hepatic transcriptional regulators of differentiation, such as caudal-type homeobox transcription factor 2 (CDX2) and GATA binding protein 6 (GATA6) and an inhibitor of Wnt/β-catenin signaling (nemo-like kinase) [145]. In summary, cytokines and miRNAs collaborate and in turn activate signaling regarding Wnt/β-catenin and STAT3/NF-κB in both LSCs and inflammatory cells. Further upregulation of cytokines and miRNA production is stimulated, which generates positive feedback loops that in turn drive LSC self-renewal. These cytokine loops and the pathways they regulate resemble those activated during chronic inflammation and wound healing and may contribute to the known link between inflammation and cancer.

Summary and conclusions

In this article, we summarized the most relevant and recent experimental investigations indicating the central issues linking inflammation and HCC development. The hypothesis between cancer and inflammation has been suspected almost two centuries ago. However, in the past decades, we have witnessed the rapid identification of some key factors associating chronic inflammation and cancer. Most of these achievements have been possible through the availability of various genetically modified mouse models, where the relevant contribution of specific transcription factors, cytokines, growth factors and their receptors has been established. Moreover, the clinical studies that have been performed have revealed some results that agree with and verify the outcomes from mouse models. However, some results did not provide verification. In any case, this information is crucial for the development of more efficacious therapeutic strategies for preventing and treating human chronic hepatitis and HCC.

Compliance with ethics guidelines

All the studies conducted by the authors involved in this review have been approved by Ethics Committee of the First affiliated Hospital of Nanjing Medical University.

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