A novel function for HEG1 in promoting metastasis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths around the globe. For patients receiving liver tumour resection, the risk of reoccurrence and metastasis is high. Cancer metastasis can occur as a consequence of a physical change known as epithelial to mesenchymal transition (EMT). In this instance, cancer cells acquire migratory and invasive characteristics that allow the cells to move into adjacent tissue or enter the bloodstream to reach a secondary site, where they begin to form a new tumour. Targetting proteins involved in the signalling pathways that induce the mesenchymal phenotype has been an ongoing field of research. A recently published study has described a novel role for the heart development protein with EGF-like domains (HEG1) in promoting EMT. This research provides new insights into the biological function of this protein in HCC. Furthermore, the research indicates a new target for future prognostic and therapeutic research in HCC

A novel role for polymeric immunoglobulin receptor in tumour development: beyond mucosal immunity and into hepatic cancer cell transformation

Chronic inflammation is well known as a significant driver of carcinogenesis in settings of human disease, including liver disease and hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is one of the major causes of HCC due to the oncogenic nature of the virus and the robust inflammatory response in the infected host. Fc receptors (FcR) are specialized receptors found on innate immune cells that recognize and bind to antigen-presenting antibodies, linking the innate and adaptive immune system to respond to circulating foreign bodies, such as viral DNA (1). Increased B-cell activation and antibody production in response to HBV infected liver will lead to increased FcR signalling on circulating innate immune cells and resident-macrophages (Kupffer cells), further enhancing the inflammatory response. Progression to chronic liver inflammation is associated with hyperactivity of B cell immunity, increasing the risk of cancer development due to constant infiltration of immune cells and accumulation of damaged hepatocytes. FcR activation has been previously implicated in carcinogenesis by creating a ‘pro-tumour microenvironment’ within inflammation-mediated damaged tissue through promotion of angiogenesis, epithelial mesenchymal transition (EMT), and increased cell survival (2). Of recent interest is the polymeric immunoglobulin receptor (pIgR), a member of the Fc receptor family, that is widely expressed on epithelial cells and is responsible for transcytosis of IgA/IgM at mucosal surfaces. Few studies have investigated the role of pIgR in cancer, although most have implicated pIgR to be downregulated in cancers of various epithelial origin (3). In this sense, the dysregulation of pIgR in mucosal membranes could limit the first line of defence for immunity against carcinogenic cells, and possibly contribute to malignant transformation

The functional roles of T-cadherin in mammalian biology

T-cadherin is a cadherin and cell adhesion molecule that is anchored to the cell surface membrane through a glycosylphosphatidylinositol moiety. T-cadherin lacks a transmembrane and cytoskeletal domain, suggesting that it must interact with other membrane-bound molecules to elicit cellular signaling to modulate normal cellular functions, and alternatively its absence can be a factor in promoting neoplasia. Moreover, apart from binding to itself it can sequester adiponectin to the cell surface. Consistent with these observations, recent research has expanded the scope of T-cadherin's role in cancer, neuronal function, metabolism and cardiovascular disease. In this context, we highlight the experimental and genomic evidence that links T-cadherin with these diseases. In particular, we discuss how T-cadherin homophilic and heterophilic interactions impact on signaling pathways and cellular behavior

A sweet connection? Fructose’s role in hepatocellular carcinoma

Hepatocellular carcinoma is one of few cancer types that continues to grow in incidence and mortality worldwide. With the alarming increase in diabetes and obesity rates, the higher rates of hepatocellular carcinoma are a result of underlying non-alcoholic fatty liver disease. Many have attributed disease progression to an excess consumption of fructose sugar. Fructose has known toxic effects on the liver, including increased fatty acid production, increased oxidative stress, and insulin resistance. These effects have been linked to non-alcoholic fatty liver (NAFLD) disease and a progression to non-alcoholic steatohepatitis (NASH). While the literature suggests fructose may enhance liver cancer progression, the precise mechanisms in which fructose induces tumor formation remains largely unclear. In this review, we summarize the current understanding of fructose metabolism in liver disease and liver tumor development. Furthermore, we consider the latest knowledge of cancer cell metabolism and speculate on additional mechanisms of fructose metabolism in hepatocellular carcinoma

Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma

Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments

Recent Advances in Cancer Fusion Transcript Detection

Extensive investigation of gene fusions in cancer has led to the discovery of novel biomarkers and therapeutic targets. To date, most studies have neglected chromosomal rearrangement-independent fusion transcripts and complex fusion structures such as double or triple-hop fusions, and fusion-circRNAs. In this review, we untangle fusion-related terminology and propose a classification system involving both gene and transcript fusions. We highlight the importance of RNA-level fusions and how long-read sequencing approaches can improve detection and characterization. Moreover, we discuss novel bioinformatic tools to identify fusions in long-read sequencing data and strategies to experimentally validate and functionally characterize fusion transcripts

The role of micronutrients in the infection and subsequent response to hepatitis C virus

Micronutrient deficiencies develop for a variety of reasons, whether geographic, socioeconomic, nutritional, or as a result of disease pathologies such as chronic viral infection. As micronutrients are essential for a strong immune response, deficiencies can significantly dampen both the innate and the adaptive arms of antiviral immunity. The innate immune response in particular is crucial to protect against hepatitis C virus (HCV), a hepatotropic virus that maintains chronic infection in up to 80% of individuals if left untreated. While many micronutrients are required for HCV replication, an overlapping group of micronutrients are also necessary to enact a potent immune response. As the liver is responsible for the storage and metabolism of many micronutrients, HCV persistence can influence the micronutrients’ steady state to benefit viral persistence both directly and by weakening the antiviral response. This review will focus on common micronutrients such as zinc, iron, copper, selenium, vitamin A, vitamin B12, vitamin D and vitamin E. We will explore their role in the pathogenesis of HCV infection and in the response to antiviral therapy. While chronic hepatitis C virus infection drives deficiencies in micronutrients such as zinc, selenium, vitamin A and B12, it also stimulates copper and iron excess; these micronutrients influence antioxidant, inflammatory and immune responses to HCV

The effects of fructose and metabolic inhibition on hepatocellular carcinoma

Hepatocellular carcinoma is rapidly becoming one of the leading causes of cancer-related deaths, largely due to the increasing incidence of non-alcoholic fatty liver disease. This in part may be attributed to Westernised diets high in fructose sugar. While many studies have shown the effects of fructose on inducing metabolic-related liver diseases, little research has investigated the effects of fructose sugar on liver cancer metabolism. The present study aimed to examine the metabolic effects of fructose on hepatocellular carcinoma growth in vitro and in vivo. Fructose sugar was found to reduce cell growth in vitro, and caused alterations in the expression of enzymes involved in the serine-glycine synthesis and pentose phosphate pathways. These biosynthesis pathways are highly active in cancer cells and they utilise glycolytic by-products to produce energy and nucleotides for growth. Hence, the study further investigated the efficacy of two novel drugs that inhibit these pathways, namely NCT-503 and Physcion. The study is the first to show that the combination treatment of NCT-503 and Physcion substantially inhibited hepatocellular carcinoma growth in vitro and in vivo. The combination of fructose diet and metabolism-inhibiting drugs may provide a unique metabolic environment that warrants further investigation in targeting hepatocellular carcinoma

The role of AdipoR1 and AdipoR2 in liver fibrosis

Activation of the adiponectin (APN) signaling axis retards liver fibrosis. However, understanding of the role of AdipoR1 and AdipoR2 in mediating this response is still rudimentary. Here, we sought to elucidate the APN receptor responsible for limiting liver fibrosis by employing AdipoR1 and AdipoR2 knock-out mice in the carbon tetrachloride (CCl4) model of liver fibrosis. In addition, we knocked down receptor function in primary hepatic stellate cells (HSCs) in vitro. Following the development of fibrosis, AdipoR1 and AdipoR2 KO mice had no quantitative difference in fibrosis by Sirius red staining. However, AdipoR2 KO mice had an enhanced fibrotic signature with increased Col1-α1, TGFß-1, TIMP-1, IL-10, MMP-2 and MMP-9. Knockdown of AdipoR1 or AdipoR2 in HSCs followed by APN treatment demonstrated that AdipoR1 and AdipoR2 did not affect proliferation or TIMP-1 gene expression, while AdipoR2 modulated Col1-α1 and α-SMA gene expression, HSC migration, and AMPK activity. These finding suggest that AdipoR2 is the major APN receptor on HSCs responsible for mediating its anti-fibrotic effects