Barry AE, Baldeosingh R, Lamm R, et al (2020) Hepatic Stellate Cells and Hepatocarcinogenesis. Front. Cell Dev. Biol., 8(709).
Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.
Zhang K, Pomyen Y, Barry AE, et al. AGO2 Mediates MYC mRNA Stability in Hepatocellular Carcinoma [published online ahead of print, 2020 Jan 15]. Mol Cancer
We are interested in utilizing several areas of RNA biology, translational, bioinformatics, and molecular biology to identify key oncogenic RBPs involved in transcriptomic alterations associated with disease states. For example, we have recently identified Argonaute 2 (AGO2) as an oncogenic RBP that can regulate the MYC transcript in a RISC-independent manner to promote HCC. By utilizing transcriptomics, we show that activated AGO2 preferentially affects MYC mRNAs by enhancing their stability. We’re now elucidating how AGO2 promotes HCC progression by directly interacting with many mRNA targets independent of miRNAs.
Dang, H et al (2017) Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma. Cancer Cell, 32, 101-114.
Tumor initiation and maintenance require the selection of a unique tumor-promoting transcriptome induced by driver genes. Our study indicates that RNA binding proteins can mediate cancer-associated transcriptomic changes in hepatocellular carcinoma (HCC). Our work is consistent with the hypotheses that NELFE activation drives hepatocarcinogenesis and that the NELFE-MYC axis may be exploited as a viable therapeutic target for HCC.
Chaisaingmongkol, J et al (2017) Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Cancer Cell, 32, 57-70
Primary liver cancers have a complex mutational landscape with vast inter-tumor heterogeneity, which poses a major challenge to define actionable drivers. Here, we demonstrate that common molecular subtypes with key drivers are shared among Asian ICC andHCC patients through systematic integration of the genome, transcriptome, and metabolome. Our results indicate thatICC and HCC, while clinically treated as separate entities, share common molecular determinants, suggesting that a unifiedmolecular landscape of liver cancer is required to improve diagnosis and therapy.
Dang, H et al (2019) NELFE-Dependent MYC Signature Identifes a Unique Cancer Subtype in Hepatocellular Carcinoma. Scientific Reports, 9:3369.
We identified a gene signature to predict a unique subtype of HCC, which is associated with a poor prognosis in three independent cohorts encompassing diverse etiologies, demographics, and viral status. The application of our genes signature offers patients access to personalized risk assessments, which may be utilized to direct future care.