The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2–dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease.

The liver is a major metastatic site (organ) for gastrointestinal cancers (such as colorectal, gastric, and pancreatic cancers) as well as non-gastrointestinal cancers (such as lung, breast, and melanoma cancers). Due to the innate anatomical position of the liver, the apoptosis of T cells in the liver, the unique metabolic regulation of hepatocytes and other potential mechanisms, the liver tends to form an immunosuppressive microenvironment and subsequently form a pre-metastatic niche (PMN), which can promote metastasis and colonization by various tumor cells(TCs). As a result, the critical role of immunoresponse in liver based metastasis has become increasingly appreciated. T cells, a centrally important member of adaptive immune response, play a significant role in liver based metastases and clarifying the different roles of the various T cells subsets is important to guide future clinical treatment. In this review, we first introduce the predisposing factors and related mechanisms of liver metastasis (LM) before introducing the PMN and its transition to LM. Finally, we detail the role of different subsets of T cells in LM and advances in the management of LM in order to identify potential therapeutic targets for patients with LM.

Increasing evidence indicates that preoperative prognostic indices can serve as independent predictors of survival in patients with cancer. However, the applicability of these indices in patients with hepatocellular carcinoma (HCC) is controversial. This study aims to investigate the prognostic value of these indices in patients with HCC after curative hepatectomy. We retrospectively analyzed the data of 215 patients who underwent curative resection for HCC. Prognostic indices including prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were evaluated by comparing by the area under the curve (AUC). Univariate analysis and multivariate analysis were performed to identify independent prognostic factors. Additionally, risk factors were combined to predict the survival of patients. We found that serum albumin concentration, tumor diameter, tumor stage, degree of differentiation, PNI, and NLR were independent prognostic factors for overall survival (OS). Vascular invasion, tumor stage, degree of differentiation, and PNI were independent prognostic factors for recurrence-free survival (RFS). The cutoff value of the PNI and NLR was 43.75 and 3.29, respectively. Patients with low NLR and high PNI had the best outcomes, potentially indicative of the intensive antitumor effects of the immune system. Moreover, patients with at least three risk factors had a significantly lower OS and RFS compared with those with two or fewer risk factors. This new nomogram based on PNI and NLR may provide an accessible and individualized prediction of survival and recurrence for HCC patients.

Infiltration of eosinophils is associated with and contributes to liver regeneration. Chemotaxis of eosinophils is orchestrated by the eotaxin family of chemoattractants. We report here that expression of eotaxin-1 (referred to as eotaxin hereafter), but not that of either eotaxin-2 or eotaxin-3, were elevated, as measured by quantitative PCR and ELISA, in the proliferating murine livers compared to the quiescent livers. Similarly, exposure of primary murine hepatocytes to hepatocyte growth factor (HGF) stimulated eotaxin expression. Liver specific deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated eosinophil infiltration and down-regulated eotaxin expression in mice. Brg1 deficiency also blocked HGF-induced eotaxin expression in cultured hepatocytes. Further analysis revealed that Brg1 could directly bind to the proximal eotaxin promoter to activate its transcription. Mechanistically, Brg1 interacted with nuclear factor kappa B (NF-κB)/RelA to activate eotaxin transcription. NF-κB knockdown or pharmaceutical inhibition disrupted Brg1 recruitment to the eotaxin promoter and blocked eotaxin induction in hepatocytes. Adenoviral mediated over-expression of eotaxin overcame Brg1 deficiency caused delay in liver regeneration in mice. On the contrary, eotaxin depletion with RNAi or neutralizing antibodies retarded liver regeneration in mice. More important, Brg1 expression was detected to be correlated with eotaxin expression and eosinophil infiltration in human liver specimens. In conclusion, our data unveil a novel role of Brg1 as a regulator of eosinophil trafficking by activating eotaxin transcription.

Background and Aims: Myofibroblasts are considered the major effector cell type of liver fibrosis and primarily derived from hepatic stellate cells (HSCs). In the present study, we investigated the contribution of C-C motif chemokine (CCL11) to HSC-myofibroblast trans-differentiation and its implication in liver fibrosis. Approach and Results: We report that CCL11 levels were elevated in HSCs, but not in hepatocytes or Kupffer cells, isolated from mice with liver fibrosis compared with the control mice. CCL11 levels were also up-regulated by 2 pro-fibrogenic growth factors TGF-β and platelet derived growth factor in cultured HSCs. Mechanistically, zinc finger factor 281 bound to the CCL11 promoter and mediated CCL11 trans-activation in HSCs. Depletion of CCL11 attenuated whereas treatment with recombinant CCL11 promoted HSC activation. Further, global CCL11 deletion (CCL11 ^−/−) or HSC/myofibroblast-specific CCL11 knockdown mitigated fibrogenesis in mice. RNA-sequencing revealed that CCL11 might regulate HSC activation by stimulating the transcription of Jagged 1. Reconstitution of Jagged 1 restored the fibrogenic response in CCL11 ^−/− mice. Finally, several targeting strategies that aimed at blockading CCL11 signaling, either by administration of an antagonist to its receptor C-C motif chemokine receptor 3 or neutralizing antibodies against CCL11/C-C motif chemokine receptor 3, ameliorated liver fibrosis in mice. Conclusions: Our data unveil a previously unrecognized role for CCL11 in liver fibrosis and provide proof-of-concept evidence that targeting CCL11 can be considered as an effective therapeutic approach.

Mounting evidence has demonstrated that circular RNAs have an important function in tumorigenesis and cancer evolvement. CircCRIM1 has been shown to be a poor prognostic element in multiple human malignancies. However, the clinical significance and mechanism of circCRIM1 in hepatocellular carcinoma (HCC) is still unclear. The present study confirmed the expression level of circCRIM1 using quantitative real-time PCR. In addition, circCRIM1 siRNA and overexpression vectors were used for transfection into LM3 or Huh7 cells to down- or up-regulate the expression of circCRIM1. In vitro and in vivo experiments were performed to explore the function of circCRIM1 in HCC. RNA pull-down, RNA immunoprecipitation, fluorescent in situ hybridization, and luciferase reporter assays were conducted to confirm the relationship between miR-378a-3p and circCRIM1 or S-phase kinase-associated protein 2 (SKP2) in HCC. Then, circCRIM1 was up-regulated in HCC and its expression level was significantly associated with poor prognosis and clinicopathologic characteristics. CircCRIM1 enhanced the proliferation and angiogenesis of HCC cells in vitro and promoted xenograft growth in vivo. Moreover, circCRIM1 upregulated the expression of SKP2 by functioning as a sponge for miR-378a-3p. These findings suggest that circCRIM1 boosts the HCC progression via the miR-378-3p/SKP2 axis and may act as a crucial epigenetic therapeutic molecule target in HCC.