Inflammation In Hepatocellular Carcinoma Research Articles

Potential role of predictive models in assessment of liver inflammation in patients with hepatocellular carcinoma: a two-center cohort study

BackgroundHepatic inflammation in patients with hepatocellular carcinoma (HCC) remains unclear. This study aimed to construct a clinically expedient predictive model to grade hepatic inflammation in HCC patients.MethodsThis is a two-center retrospective cohort study of HCC patients comprising Derivation cohort and External Validation cohort of 1201 and 505 patients, respectively. Variables of liver inflammation identified through uni- and multi-variate logistic regression analyses were incorporated into predictive nomograms and applied to Derivation cohort, subject to internal and external validation.ResultsLiver fibrosis severity score, portal hypertension severity, and model for end-stage liver disease-sodium independently predicted hepatic inflammation grade. Performance for distinguishing G1 and non-G1 (≥ G2) patients was good with C-index of 0.810 and 0.817 in Derivation and External Validation cohort, respectively. The nomogram performed poorly to predict grade G2, G3 and G2 + G3, but performed well to predict G4.ConclusionsOur nomogram exhibited good performance for scaling hepatic inflammation (G1 and G4) in HCC, and could be employed as adjunctive diagnostic tools to guide HCC management strategy.

Ferulic acid inhibits tumor proliferation and attenuates inflammation of hepatic tissues in experimentally induced HCC in rats.

Hepatocellular carcinoma (HCC) is a prevalent form of primary liver cancer with a 5-year survival rate of just 18%. Ferulic acid, a natural compound found in fruits and vegetables such as sweet corn, rice bran, and dong quai, is an encouraging drug known for its diverse positive effects on the body, including anti-inflammatory, anti-apoptotic, and neuroprotective properties. Our study aimed to investigate the potential antitumor effects of ferulic acid to inhibit tumor growth and inflammation of HCC in rats. HCC was induced in rats by administering thioacetamide. Additionally, some rats were given 50 mg/kg of ferulic acid three times a week for 16 weeks. Liver function was assessed by measuring serum alpha-fetoprotein (AFP) and examining hepatic tissue sections stained with hematoxylin/eosin or anti-hypoxia induced factor-1α (HIF-1α). The hepatic mRNA and protein levels of HIF-1α, nuclear factor κB (NFκB), tumor necrosis factor-α (TNF-α), mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), cMyc, and cyclin D1 were examined. The results showed that ferulic acid increased the rats' survival rate by reducing serum AFP levels and suppressing hepatic nodules. Furthermore, ferulic acid ameliorated the appearance of vacuolated cytoplasm induced by HCC, reduced apoptotic nuclei, and necrotic nodules. Finally, ferulic acid decreased the expression of HIF-1α, NFκB, TNF-α, mTOR, STAT3, cMyc, and cyclin D1. In conclusion, ferulic acid is believed to possess antitumor properties by inhibiting HCC-induced hypoxia through the suppression of HIF-1α expression. Additionally, it helps in reducing the expression of mTOR, STAT3, cMyc, and cyclin D1, thereby slowing down tumor growth. Lastly, ferulic acid reduced hepatic tissue inflammation by downregulating NFκB and TNF-α.

Higher inflammatory response in hepatocellular carcinoma is associated with immune cell infiltration and a better outcome.

Hepatocellular carcinoma (HCC) often develops from chronic liver inflammation. Inflammation within a tumor can either promote cancer progression or activate an immune response against it. This study aims to determine the clinical significance of enhanced inflammation in HCC. Data from 655 HCC patients across four cohorts (TCGA, GSE6764, GSE76427, GSE89377) were examined. Inflammatory response was quantified using a scoring system derived from the gene set variation analysis of the "INFLAMMATORY_RESPONSE" gene set. A stepwise increase in inflammatory response was noted from normal liver to cirrhosis, with consistently lower levels in HCC across both GSE6764 and GSE89377 cohorts (both p < 0.001). Similar trends were observed in interferon response, pathways such as IL6/JAK/STAT3 and complement signaling, coagulation cascade, and allograft rejection (all p < 0.02). HCCs with high inflammatory response were associated with increased immune cell infiltrations (p < 0.01) and cytolytic activity (p < 0.001). Interestingly, these HCCs had reduced mutation rates, no relationship with cell proliferation, and displayed both immune responses and pro-cancerous signals including epithelial-mesenchymal transition, KRAS, and hypoxia. Further, a high inflammatory score correlated with improved disease-free survival in TCGA (p = 0.034) and overall survival in GSE76427 (p = 0.008). HCC with higher levels of inflammatory response demonstrated increased immune cell infiltration, enhanced immune-related and other pro-cancerous-related signaling, and showed a trend toward a better patient prognosis.

Aquaporin-3 promotes proliferation and inflammation in hepatocellular carcinoma

Aquaporin-3 promotes proliferation and inflammation in hepatocellular carcinoma

An update on the role of complement in hepatocellular carcinoma.

As a main producer of complement, the environment in the liver is greatly affected by the complement system. Although the complement system is considered to have the ability of nonself discrimination, remarkable studies have revealed the tight association between improper complement activation in tumour initiation and progression. As complement activation predominantly occurs within the liver, the protumourigenic role of the complement system may contribute to the development of hepatocellular carcinoma (HCC). Improvement in the understanding of the molecular targets involved in complement-mediated tumour development, metastasis, and tumour-promoting inflammation in HCC would certainly aid in the development of better treatments. This minireview is focused on recent findings of the protumourigenic role of the complement system in HCC.

N6-methyladenosine modification participates in neoplastic immunoregulation and tumorigenesis.

This review aims to provide insight into the role of N6-methyladenosine (m6A) modification in neoplastic immunity and subsequent tumorigenesis. m6A modification, which is catalyzed by methyltransferases, demethylases and reader proteins, has emerged as a widespread regulatory mechanism that controls immune-related gene expression and immune reactions during tumorigenesis. Aberrant m6A modification changes the neoplastic immune response in multiple cancers by regulating immune cell infiltration, tumor-promoting inflammation, immunosuppression, immune surveillance, and antitumor immune responses. m6A modification affects immune cell recruitment and cancer-promoting inflammation in hepatocellular carcinoma (HCC) to alter the progression of HCC. m6A modification has been implicated in the infiltration of immune cells and the activation of immune pathways, changing the proliferation and metastasis of gastric cancer. Immune surveillance and the antitumor immune response in breast cancer were enhanced via m6A modification, which inhibited tumor proliferation. m6A modification participates in neoplastic immunoregulation to influence tumor progression.

Nimbolide attenuates gut dysbiosis and prevents bacterial translocation by improving intestinal barrier integrity and ameliorating inflammation in hepatocellular carcinoma.

Gut microbiota imbalance plays a key pathological role in hepatocellular carcinoma (HCC) progression; however, the mechanism is poorly understood. We previously showed nimbolide impede tumor development by improving hepatic tight junction (TJ) proteins expression and attenuating inflammation in HCC mice. Here, we aimed to study the role of nimbolide in regulating gut microbiota imbalance and bacterial translocation (BT) through modulating intestinal TJ proteins in an experimental hepatocarcinogenesis. Nimbolide (6mg/kg) was administered orally for 4 weeks following induction of HCC in mice at the 28th week. Nimbolide treatment attenuated the gut microbiota imbalance by decreasing 16 s rRNA levels of Escherichia coli, Enterococcus, Bacteroides and increasing Bifidobacterium, and Lactobacillus in the intestinal tissue, which was otherwise altered in HCC mice. Furthermore, nimbolide improved intestinal barrier integrity in HCC mice by upregulating TJ proteins such as occludin and ZO-1 expression and subsequently prevented hepatic BT and decreased BT markers such as LBP, sCD14, and procalcitonin in the plasma of HCC mice. Moreover, nimbolide ameliorated intestinal and hepatic inflammation by downregulating TLR4, MyD88, and NF-κB protein expression in HCC mice. Thus, nimbolide represents a novel therapeutic drug for HCC treatment by targeting the gut-liver axis, which plays an imperative role in HCC pathogenesis.

STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma.

Simple SummaryLiver cancer is the fourth-leading cause of cancer-related mortality worldwide and lacks effective therapies. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of liver cancer and both are associated with underlying inflammatory diseases. Thereby, interleukin-6 (IL-6)-mediated STAT3 signaling is critically involved in early carcinogenesis and disease progression. Here, we assessed the interplay between STAT1 and STAT3 in IL-6 signaling in vitro and studied the activation of STAT1 and STAT3 in a cohort of 124 HCC and a cohort of 138 CCA patients by immunohistochemistry. We found that IL-6 induced STAT1 transcriptional activity upon STAT3 depletion, suggesting that HCC tumor cells may activate both STAT1 and STAT3 signaling under pro-inflammatory conditions. Furthermore, HCC patient tissues showed a strong positive correlation of STAT1 and STAT3 activation in distinct patient groups. These patients also exhibited a high degree of immune cell infiltration, suggesting that these tumors are immune “hot”.Liver cancers, which are mostly hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are very aggressive tumors with poor prognosis. Therapeutic options with curative intent are largely limited to surgery and available systemic therapies show limited benefit. Signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) are key transcription factors activated by pro-inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6 (IL-6). In this study, we combined in vitro cell culture experiments and immunohistochemical analyses of human HCC (N = 124) and CCA (N = 138) specimens. We observed that in the absence of STAT3, IL-6 induced the activation of STAT1 and its target genes suggesting that IL-6 derived from the tumor microenvironment may activate both STAT1 and STAT3 target genes in HCC tumor cells. In addition, STAT1 and STAT3 were highly activated in a subset of HCC, which exhibited a high degree of infiltrating CD8- and FOXP3-positive immune cells and PD-L1 expression. Our results demonstrate that STAT1 and STAT3 are expressed and activated in HCC and tumor infiltrating immune cells. In addition, HCC cases with high STAT1 and STAT3 expression also exhibited a high degree of immune cell infiltration, suggesting increased immunological tolerance.

The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation

Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.

Portal Vein Thrombosis and Markers of Inflammation in Hepatocellular Carcinoma.

Macroscopic portal vein thrombosis (PVT) is a major poor prognosis factor in patients with hepatocellular carcinoma (HCC). Inflammation is increasingly recognized to be part of the hepatocarcinogenic process and its markers are also prognostically useful. To examine the relationship of inflammation biomarkers to the presence of PVT and to survival in PVT patients with HCC. A large HCC cohort was examined for the presence of PVT and analyzed retrospectively. Blood levels of NLR, PLR, ESR, CRP, AFP and GGTP were significantly related to the presence of PVT, but not the Glasgow Index. For patients with low alpha-fetoprotein levels, blood ESR and GGTP levels were also significantly increased in patients with PVT compared with those in patients without PVT. In a Cox regression model, serum GGTP levels had a significantly increased hazard ratio on death (1.52, p = 0.008). Kaplan-Meier analysis showed that PVT patients with low serum GGTP levels had significantly longer survival than PVT patients with high GGTP levels (p = 0.0041). Indices of inflammation, especially serum GGTP levels, related significantly to the presence of PVT and to survival in HCC patients with PVT.

Mesencephalic Astrocyte-Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin-Related Modifier (SUMO)ylation-Related Suppression of NF-κB/Snail Signaling Pathway and Epithelial-Mesenchymal Transition.

Background and AimsEndoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an ER stress‐inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC.Approach and ResultsHere, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse‐free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor‐node‐metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte‐specific deletion of MANF accelerated N‐nitrosodiethylamine (DEN)‐induced HCC by up‐regulating Snail1+2 levels and promoting epithelial‐mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF‐α)‐treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up‐regulated NF‐κB downstream target genes TNF‐α, interleukin (IL)‐6 and IL‐1α expression in vitro and in vivo. Finally, small ubiquitin‐related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF.ConclusionsMANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF‐κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC.

TRAF7 enhances ubiquitin-degradation of KLF4 to promote hepatocellular carcinoma progression.

The tumor necrosis factor receptor-associated factor 7 (TRAF7) is a component of the tumor necrosis factor alpha (TNF-α)/nuclear factor kappa B (NF-κB) pathway and is a putative E3-ubiquitin ligase. Based on importance of chronic inflammation in hepatocellular carcinoma (HCC), we investigated the biological effects and the molecular mechanisms of deregulated TRAF7 signaling in HCC. Our results showed that high TRAF7 expression in HCC samples was inversely associated with Krüppel-like factor 4 (KLF4) expression and the prognosis of HCC patients. TRAF7 could degrade KLF4 protein through ubiquitin by interacting with its N-terminus. The up-regulation of TRAF7 promoted HCC cell migration and invasion in vivo and in vitro, and TRAF7 knockdown had the opposite effects. Restoration of KLF4 abrogated the motility promotion induced by TRAF7. TRAF7 promotes HCC cell motility through inducing KLF4 protein turnover.

Abstract 4319: Hypoxia regulates m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma

Abstract Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to ultimately stabilize the methylated oncogene mRNAs in inflammation-associated hepatocellular carcinoma (HCC). YTHDF2 silenced in human HCC cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed HCC progression. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer. Significance: We show that hypoxia induces downregulation of m6A-reader YTHDF2 and hyper-upregulation of m6A-mRNAs in human HCC, which adapts m6A decoration into a cancer-promoting mechanism. Thus we identify YTHDF2 as a suppressor in tumor growth and metastasis by targeting IL-11 and Serpin E2. Note: This abstract was not presented at the meeting. Citation Format: Jiajie Hou, He Zhang, Jun Liu, Zhenjun Zhao, Jianye Wang, Zhike Lu, Bian Hu, Jiankui Zhou, Zhicong Zhao, Mingxuan Feng, Haiyan Zhang, Bin Shen, Xingxu Huang, Beicheng Sun, Mark J. Smyth, Chuan He, Qiang Xia. Hypoxia regulates m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4319.

Saikosaponin‐b2 inhibits tumor growth and inflammation of hepatocellular carcinoma by regulating STK4 / IRAK1 / NF‐κB signaling in H22 tumor‐bearing mice

The tumor suppressor serine/threonine‐protein kinase 4 (STK4) may regulate inflammatory signaling in macrophages and thereby protective against inflammation‐associated HCC. Saikosaponin (SS)‐b2, a major bioactive ingredient of saikosaponins from Chinese thorowax root, exhibited anti‐cancer, anti‐inflammatory, anti‐viral, and anti‐oxidant activity. However, the anti‐tumor effect and its signaling mechanism of SS‐b2 on H22 hepatocellular carcinoma remain unknown. This study investigated the anti‐tumor effect of SS‐b2 on H22 hepatocellular carcinoma by regulating STK4/IL‐1 receptor associated kinase 1(IRAK1)/NF‐κB signaling. BALB/c mice were randomly divided into model group (normal saline, 10mL·kg−1·d−1, i.p.), different dose SS‐b2 group (3, 6, 12 mg·kg−1·d−1, i.p.) and doxorubicin group (DOX, 2 mg·kg−1, once every other day, i.p.). The mice were administered for 10 days. The results showed that SS‐b2 had a significant anti‐tumor effect on H22 xenograft mice. The tumor inhibiory rate of SS‐b2 was 16.8%, 32.7% and 55.8% respectively at 3 mg·kg−1, 6 mg·kg−1 and 12 mg·kg−1 dose. SS‐b2 decreased the spleen index in a dose‐independence way but it decreased the liver index only at 12 mg·kg−1 dose. SS‐b2 also significantly reduced the levels of AST and ALT in serum at 6 mg·kg−1 and 12 mg·kg−1. HE Staining revealed that SS‐b2 significantly attenuated the pathological morphology changes. Tumor tissue showed large necrotic, nucleus lysis and vacuole areas in mice with SS‐b2 treatment. Immunohistochemistry results showed that the positive expression of STK4 protein in tumor tissue increased however IRAK1 protein expression decrease significantly in SS‐b2 groups compared with the model group. Moreover, Western blot analysis also showed that the protein expression of STK4 increased whereas the expressions of IRAK1 and NF‐κB protein were decreased in tumor tissue, spleen, and serum in SS‐b2 treatment group. These results suggest that SS‐b2 exerts a significant anti‐tumor effect on H22 xenograft mice by regulating STK4/IRAK1/NF‐κB pathway.Support or Funding InformationThis study was supported by Science and Technology Key Research Fund funded projects of Henan Province, China (No. 142102310137), the Science and Technology Development Project of Luoyang City (No. 1603001A‐3).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Resveratrol suppresses hyperglycemia-induced activation of NF-κB and AP-1 via c-Jun and RelA gene regulation.

Background: Resveratrol (RSV) provides several important biological functions in wide variety of cells. In this study, we investigated the molecular mechanisms underlying anti-inflammatory effect of RSV on HepG2 cells by assessing the gene expression of RelA and c-Jun- subunits of NF-κB and AP-1 transcription factors. Methods: HepG2 cells were settled in a serum- free medium with high concentrations of glucose (30 mM) and insulin (1 µM) overnight and were then incubated with RSV (5, 10, and 20 µM) for 24 and 48 hours. Real time quantitative polymerase chain reaction (qRT-PCR) was used to determine RelA and c-Jun expression. Results: RSV diminished hyperglycemia/hyperinsulinemia stimulated expression of c-Jun dose- dependently after 24 and 48 hours (p<0.05). In addition, RelA gene expression was decreased dose-dependently in all RSV doses after 48-hour incubation (p<0.05). Our results indicated that RSV may reduce NF-κB and AP-1 activity via RelA and c-Jun gene regulation. Conclusion: The findings of the present study demonstrated that RSV may be considered as a preventative and therapeutic agent for antagonizing inflammation in Hepatocellular carcinoma (HCC).

THU-190 - Ubr Ubiquitin ligases as modulators of inflammation in hepatocellular carcinoma

THU-190 - Ubr Ubiquitin ligases as modulators of inflammation in hepatocellular carcinoma

Mean platelet volume could be possible biomarker in early diagnosis and monitoring of gastric cancer

Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related deaths worldwide. The early diagnosis of gastric cancer is fundamental in decreasing the mortality rates. It has been shown that MPV level is a sign of inflammation in hepatocellular carcinoma and pancreatic adenocarcinoma. The aim of this study is to examine whether MPV would be a useful inflammatory marker for differentiating gastric cancer patients from healthy controls. Thirty-one gastric cancer patients and 31 age-sexes matched healthy subjects included into the study. Patients with hypertension, hematological and renal disease, heart failure, chronic infection, hepatic disorder and other cancer were excluded from the study. MPV level was significantly higher in pre-operative gastric cancer patients compared to healthy subjects (8.31 fL vs. 7.85; p: 0.007). ROC analysis suggested 8.25 fL as the cut-off value for MPV (AUC: 0.717, sensitivity: 61%, specificity: 81%). Surgical tumor resection resulted in a significant decrease in MPV level (8.31 fL vs. 7.55 fL; p: 0.001). No significant difference was found in MPV level between the post-operative group and control subjects. We did not find statistically significant difference between MPV and TNM stages. In conclusion, changes in MPV values may be used as an easily available biomarker for monitoring the healthy patients for GC risk and may prompt physicians to make an early diagnosis of GC.

SUMOylated CPAP is required for IKK-mediated NF-κB activation and enhances HBx-induced NF-κB signaling in HCC

Constitutive activation of NF-κB is an important event involved in chronic inflammation in hepatocellular carcinoma (HCC). CPAP, which plays important roles in centrosomal functions, was previously identified as the transcriptional co-activator of NF-κB. However, the molecular mechanism is unclear. The goal of this study was to investigate the role of CPAP in activating the NF-κB pathway in HCC. SK-Hep1, HuH7, HepG2, HepG2X, Hep3B, and Hep3BX cells with CPAP overexpression or CPAP siRNA were used to evaluate activation of NF-κB under TNF-α stimulation by reporter assay, RT-PCR, Q-PCR, and Western blot analysis. In vivo SUMO modification of CPAP was demonstrated by an in situ PLA assay. Human HCC tissues were used to perform Q-PCR, Western blot, and IHC. CPAP siRNA abolished the interaction between IKKβ and NF-κB, whereas overexpression of CPAP enhanced this interaction and finally led to augmented NF-κB activation by increasing the phosphorylation of NF-κB. CPAP could enter nuclei by associating with NF-κB. Furthermore, CPAP was SUMO-1 modified upon TNF-α stimulus, and this is essential for its NF-κB co-activator activity. SUMO-1-deficient CPAP mutant lost its NF-κB co-activator activity and failed to enter nuclei. Importantly, SUMOylated CPAP could synergistically increase the HBx-induced NF-κB activity. CPAP is essential for the recruitment of the IKK complex to inactivated NF-κB upon TNF-α treatment. Expression of CPAP was positively correlated with a poor prognosis in HBV-HCC. CPAP has the potential to serve as a therapeutic target for inflammation and inflammation-related diseases.

Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents a global health problem. Infections with hepatitis B or C virus, non-alcoholic steatohepatitis disease, alcohol abuse, or dietary exposure to aflatoxin are the major risk factors to the development of this tumor. Regardless of the carcinogenic insult, HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis. Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity for β-galactosides and conserved sequence motifs. Here, we summarize the current literature implicating galectins in the pathogenesis of HCC. Expression of "proto-type" galectin-1, "chimera-type" galectin-3 and "tandem repeat-type" galectin-4 is up-regulated in HCC cells compared to their normal counterparts. On the other hand, the "tandem-repeat-type" lectins galectin-8 and galectin-9 are down-regulated in tumor hepatocytes. The abnormal expression of these galectins correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, postoperative recurrence and poor prognosis. Moreover, these galectins have important roles in other pathological conditions of the liver, where chronic inflammation and/or fibrosis take place. Galectin-based therapies have been proposed to attenuate liver pathologies. Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.