Osteopontin (OPN) was first identified in 1986. The prefix osteo‐ means bone; however, OPN is expressed in other tissues, including liver. The suffix ‐pontin means bridge and denotes the role of OPN as a link protein within the extracellular matrix. While OPN has well‐established physiological roles, multiple “omics” analyses suggest that it is also involved in chronic liver disease. In this review, we provide a summary of the OPN gene and protein structure and regulation. We outline the current knowledge on how OPN is involved in hepatic steatosis in the context of alcoholic liver disease and non‐alcoholic fatty liver disease. We describe the mechanisms whereby OPN participates in inflammation and liver fibrosis and discuss current research on its role in hepatocellular carcinoma and cholangiopathies. To conclude, we highlight important points to consider when doing research on OPN and provide direction for making progress on how OPN contributes to chronic liver disease.

Doxorubicin (DOX) is one of the preferred drugs for treating breast and liver cancers. However, its clinical application is limited due to severe side effects and the accompanying drug resistance. In this context, we investigated the effect on therapeutic efficacy of DOX by cholesterol depleting agent methyl-β-cyclodextrin (MCD), and explored the involvement of p53. MCD sensitizes MCF-7 and Hepa1–6 cells to DOX, Combination of MCD and marginal dose of DOX reduces the cell viability, and promoted apoptosis through induction of pro-apoptotic protein, Bax, activation of caspase-8 and caspase-7, down regulation of anti-apoptotic protein Bcl-2 and finally promoting PARP cleavage. Mechanistically, sensitization to DOX by MCD was due to the induction of FasR/FasL pathway through p53 activation. Furthermore, inhibition of p53 by pharmacological inhibitor pifithrin-α (PFT-α) or its specific siRNA attenuated p53 function and down-regulated FasR/FasL, thereby preventing cell death. Animal experiments were performed using C57BL/6J mouse isografted with Hepa1–6 cells. Tumor growth was retarded and survival increased in mice administered MCD together with DOX to as compared to either agent alone. Collectively, these results suggest that MCD enhances the sensitivity to DOX for which wild type p53 is an important determinant.

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Elevated glycemic index, an important feature of diabetes is implicated in an increased risk of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of this association are relatively less explored. Present study investigates the effect of hyperglycemia over HCC proliferation. We observed that high glucose culture condition (HG) specifically activates canonical Wnt signaling in HCC cells, which is mediated by suppression of DKK4 (a Wnt antagonist) expression and enhanced β-catenin level. Functional assays demonstrated that a normoglycemic culture condition (NG) maintains constitutive expression of DKK4, which controls HCC proliferation rate by suppressing canonical Wnt signaling pathway. HG diminishes DKK4 expression leading to loss of check at G0/G1/S phases of the cell cycle thereby enhancing HCC proliferation, in a β-catenin dependent manner. Interestingly, in NOD/SCID mice supplemented with high glucose, HepG2 xenografted tumors grew rapidly in which elevated levels of β-catenin, c-Myc and decreased levels of DKK4 were detected. Knockdown of DKK4 by shRNA promotes proliferation of HCC cells in NG, which is suppressed by treating cells exogenously with recombinant DKK4 protein. Our in vitro and in vivo results indicate an important functional role of DKK4 in glucose facilitated HCC proliferation.

BackgroundPCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (HCC) has been documented; however, the underlying cause and implications of such dyslipidemia remain unclear.MethodsThe present study includes the use of HepG2 tumor xenograft model to study the potential role of glucose (by providing 15% glucose via drinking water) in regulating PCSK9 expression and associated hypercholesterolemia. To support in vivo findings, in vitro approaches were used by incubating HCC cells in culture medium with different glucose concentrations or treating the cells with glucose uptake inhibitors. Impact of hypercholesterolemia on chemotherapy was demonstrated by exogenously providing LDLc followed by appropriate in vitro assays.ResultsWe observed that serum and hepatic PCSK9 level is decreased in mice which were provided with glucose containing water. Interestingly, serum and tumor PCSK9 level was upregulated in HepG2-tumor-bearing mice having access to water containing glucose. Additionally, elevated LDLc is detected in sera of these mice. In vitro studies indicated that PCSK9 expression was increased by high glucose availability with potential involvement of reactive oxygen species (ROS) and sterol regulatory element binding protein-1 (SREBP-1). Furthermore, it is also demonstrated that pre-treatment of cells with LDLc diminishes cytotoxicity of sorafenib in HCC cells.ConclusionTaken together, these results suggest a regulation of PCSK9 by high glucose which could contribute, at least partly, towards understanding the cause of hypercholesterolemia in HCC and its accompanied upshots in terms of altered response of HCC cells towards cancer therapy.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0187-2) contains supplementary material, which is available to authorized users.

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Chronic hepatitis B virus (HBV) infection changes the composition of the extracellular matrix (ECM) and enables the onset and progression of hepatocellular carcinoma (HCC). The ensemble of ECM proteins and associated factors is a major component of the tumor microenvironment. Our aim was to unveil the matrisome genes from HBVrelated HCC. Transcriptomic and clinical profiles from 444 patients with HBV-related HCC were retrieved from the Gene Expression Omnibus (GEO) and Cancer Genome Atlas (TCGA) repositories. Matrisome genes associated with HBV-related hepatocarcinogenesis, matrisome gene modules, HCC subgroups, and liver-specific matrisome genes were systematically analyzed, followed by identification of their biological function and clinical relevance. Eighty matrisome genes, functionally enriched in immune response, ECM remodeling, or cancer-related pathways, were identified as associated with HBV-related HCC, which could robustly discriminate HBV-related HCC tumor from nontumor samples. Subsequently, four significant matrisome gene modules were identified as showing functional homogeneity linked to cell cycle activity. Two subgroups of patients with HBV-related HCC were classified based on the highly correlated matrisome genes. The high-expression subgroup (15.0% in the TCGA cohort and 17.9% in the GEO cohort) exhibited favorable clinical prognosis, activated metabolic activity, exhausted cell cycle, strong immune infiltration, and lower tumor purity. Four liver-specific matrisome genes (F9, HPX [hemopexin], IGFALS [insulin-like growth-factor-binding protein, acid labile subunit], and PLG [plasminogen]) were identified as involved in HBV-related HCC progression and prognosis. Conclusion: This study identified the expression and function of matrisome genes from HBV-related hepatocarcinogenesis, providing major insight to understand HBV-related HCC and develop potential therapeutic opportunities. (Hepatology Communications 2021;0:1-15). C hronic hepatitis B virus (HBV) infectionaccounts for approximately 80% of patients with virus-related hepatocellular carcinoma (HCC), especially in Eastern Asian and most African countries, posing a serious threat to human health and quality of life. (1) More than 250 million people worldwide will suffer from chronic HBV infection between 2015 and 2030, and about 5 million deaths will be attributed to HCC progression. (1) Suppression of HBV reduces the risk of HCC (2) ; yet, it is vital to understand the mechanisms underlying HBV-related carcinogenesis to develop therapeutic options for HCC treatment.To date, little progress has been made on the mechanisms driving carcinogenesis in HBV infection. A few