The long-term goal of this proposal is to contribute to the understanding of the molecular signaling mechanisms whereby hepatic stellate cells (HSC) promote hepatocellular carcinoma (HCC) progression. Fibrosis and the inflammatory microenvironment are hallmarks of non-alcoholic steatohepatitis (NASH), and that are increasingly recognized as conducive to cirrhosis, HCC, and end-stage liver disease. This requires liver transplantation, and quite often is the next step in liver disease progression for a significant subset of patients with fatty liver (up to 10 million in the US). Therefore, the identification of the cellular and molecular factors that account for NASH development and how that leads to HCC is a major gap in the understanding of its pathogenesis. Recent results indicate that hepatic stellate cells (HSCs), which differentiate to myofibroblasts upon liver injur and orchestrate the production of extracellular components that form the fibrotic scar and inflammation, are central players in the control of HCC development. This proposal in based on our preliminary in vitro and in vivo studies in mice, and in the analysis of human HCC data sets, strongly suggesting that the signaling adapters p62 and NBR1 are critical players in NASH and HCC development, and that they act by regulating the function and activity of HSCs through a new paradigm involving the negative regulation of TGF? signaling. Here we will test this hypothesis by addressing the following Aims:
(Aim 1) Determine the molecular mechanisms of action of p62 and NBR1 in HSC activation at a cell autonomous level by: (1.1) determining the impact that NBR1 ablation has on TGF? signaling in HSC activation; and (1.2) unraveling the detailed biochemical links between p62 and NBR1 with different components of the TGF? signaling cascade.
(Aim 2) Determine the contribution of the p62/NBR1 signaling cascade in HSCs to the control of NASH and HCC in cell-specific in vivo mouse models by: (2.1) characterizing HSC-specific knockout mice for p62 and/or NBR1 and determining their contribution to NASH and HCC development; (2.2) determining the signaling pathways altered by p62 and/or NBR1 deficiency in HSCs in vivo; and (2.3) determining the clinical relevance of p62 and NBR1 in HSCs. Results from these studies will serve to identify new biomarkers to predict the NAFLD-NASH- HCC transition, as well as new therapeutic targets for prevention and treatment of these liver pathologies.
Fibrosis and the inflammatory microenvironment are hallmarks of steatohepatitis (NASH), which is increasingly recognized as conducive to hepatocellular carcinoma (HCC). There are no effective treatments for NASH or HCC and it is difficult to identify the individuals who are at highest risk of liver disease progression from steatosis. Our preliminary data identifies p62 and NBR1 as a key step in this process by repressing the activation of hepatic stellate cells in the non-parenchymal tumor microenvironment. Here we will investigate in vitro and in vivo the regulatory signaling pathways that link p62 and NBR1 to TGF? signaling, a key pathway in the activation of these cells, to identify new biomarkers and therapeutic targets.
|Shelton, Phillip M; Duran, Angeles; Nakanishi, Yuki et al. (2018) The Secretion of miR-200s by a PKC?/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer. Cell Rep 23:1178-1191|
|Reina-Campos, Miguel; Shelton, Phillip M; Diaz-Meco, Maria T et al. (2018) Metabolic reprogramming of the tumor microenvironment by p62 and its partners. Biochim Biophys Acta Rev Cancer 1870:88-95|
|Huang, Jianfeng; Duran, Angeles; Reina-Campos, Miguel et al. (2018) Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor. Cancer Cell 33:770-784.e6|
|Zhang, Yi; Mun, Su Ran; Linares, Juan F et al. (2018) ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nat Commun 9:4373|
|Reina-Campos, Miguel; Moscat, Jorge; Diaz-Meco, Maria (2017) Metabolism shapes the tumor microenvironment. Curr Opin Cell Biol 48:47-53|
|Linares, Juan F; Cordes, Thekla; Duran, Angeles et al. (2017) ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma. Cell Metab 26:817-829.e6|
|Pan, Ji-An; Sun, Yu; Jiang, Ya-Ping et al. (2016) TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Mol Cell 61:720-733|
|Nakanishi, Yuki; Reina-Campos, Miguel; Nakanishi, Naoko et al. (2016) Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKC?/?. Cell Rep 16:3297-3310|
|Moscat, Jorge; Karin, Michael; Diaz-Meco, Maria T (2016) p62 in Cancer: Signaling Adaptor Beyond Autophagy. Cell 167:606-609|
|Umemura, Atsushi; He, Feng; Taniguchi, Koji et al. (2016) p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell 29:935-948|
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