ER stress and UPR in non-alcoholic steatohepatitis and hepatocellular carcinoma

非酒精性脂肪性肝炎和肝细胞癌中的 ER 应激和 UPR

• 批准号: 9267948
• 负责人: RANDAL J. KAUFMAN
• 金额: $ 70.73万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267948
• 关键词: ATF6 gene; Apoptosis; Apoptotic; Attenuated; Blood Coagulation Factor; Cancer Etiology; Carrier Proteins; Cell Death Signaling Process; Cell physiology; Cells; Cirrhosis; Collaborations; Data; Development; Endoplasmic Reticulum; Environment; F8 gene; Factor VIII; Fibrosis; Gene Deletion; Genetic; Grant; Health; Hepatocyte; High Fat Diet; Homeostasis; Human; Inflammation; Length; Link; Liver; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular Chaperones; Mus; Organelles; Outcome; Oxidative Stress; Pathway interactions; Patients; Phosphorylation; Play; Population; Primary carcinoma of the liver cells; Process; Protein Biosynthesis; Proteins; RNA Splicing; Role; Signal Transduction; Steatohepatitis; Stromal Cells; Symptoms; Testing; Therapeutic; Translations; Universities; Urokinase; XBP1 gene; angiogenesis; arm; cancer initiation; cell transformation; endoplasmic reticulum stress; extracellular; human disease; human tissue; insight; lipid biosynthesis; loss of function; misfolded protein; mortality; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; progenitor; protein folding; protein misfolding; protein transport; proteostasis; public health relevance; response; restoration; sensor; transcription factor; transcription factor CHOP; transgene expression; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Almost 25% of the US population suffers from non-alcoholic fatty liver disease (NAFLD) that can progress to steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Our recent studies, as well as others, link endoplasmic reticulum stress (ER stress) with non-alcoholic fatty liver disease (NAFLD). However, it is unknown whether/how ER stress impacts NASH development and/or HCC initiation and progression. In collaboration with Dr. Michael Karin (UCSD), our exciting preliminary data demonstrate that induction of ER stress in hepatocytes by excessive transgene expression of urokinase or a misfolded protein combined with a high fat diet (HFD) activates the unfolded protein response (UPR) and is sufficient to cause symptoms similar to human NASH with progression to HCC. This fundamental finding provides the basis for our proposed studies to identify the role of ER stress and cell death signaling in cell transformation and in the tumor microenvironment through the use of murine models harboring conditional gene deletion of selective UPR signaling components. Although many studies have focused on tumor progression, ours is unique because we will identify factors that initiate tumorigenesis. To elucidate the role of the UPR in cancer initiation we will test four hypotheses through our specific aims (SA). SA1: ER stress can initiate NASH and HCC formation. We will test whether induction of ER stress contributes to NASH and HCC development using two independent models of ER stress. We will also test whether restoration of ER homeostasis decreases tumor formation. Furthermore, in collaboration with Dr. Peter Metrakos (McGill University), we will be able to verify the findings from mouse model in human patients. SA2: Elimination of the proapoptotic arm of the UPR (PERK/eIF2/ATF4/CHOP) will promote NASH and HCC initiation. We will eliminate eIF2 phosphorylation, ATF4 or CHOP in hepatocytes to determine their requirement in HCC development, and test whether the effect increased or decreased ATF4 and/or CHOP in HCC development is cell autonomous by inoculation of HCC progenitors into MUP-uPA mice fed with HFD. SA3: NASH/HCC development is restrained by the PERK/eIF2α/ATF4/CHOP pathway in the microenvironment. ATF4 and CHOP will be specifically deleted and eIF2 phosphorylation eliminated in stromal cells to test their requirement for HCC progression and determine their impact on inflammation and angiogenesis. Although extensive efforts are being directed to target UPR signaling in cancer, it remains unknown whether the UPR promotes or limits tumor initiation and/or development. Our proposed studies will provide essential key unprecedented insight into these questions that should impact efforts to target the UPR in cancer.

 描述（由适用提供）：几乎25％的美国人口患有非酒精性脂肪肝病（NAFLD），可以发展为脂肪性肝炎（NASH），纤维化，肝硬化和肝细胞癌（HCC）。我们最近的研究以及其他研究将内质网应激（ER应激）与非酒精性脂肪肝病（NAFLD）联系起来。但是，尚不清楚/AR应力是否影响NASH的发展和/或HCC计划和进展。与迈克尔·卡林（Michael Karin）博士（UCSD）合作，我们令人兴奋的初步数据表明，通过过度转化尿激酶表达或错误折叠的蛋白质结合高脂肪饮食（HFD）通过过度转化来诱导肝细胞中的ER压力（HFD）激活了与人类NASH相似的症状HCC，并且足以引起与人类NASH相似的症状。这一基本发现为我们提出的研究提供了基础，以确定ER应力和细胞死亡信号传导在细胞转化中以及通过使用带有条件基因缺失的鼠模型的作用，以及在肿瘤微环境中的作用。尽管许多研究集中在肿瘤进展上，但我们的研究是独一无二的，因为我们将确定启动肿瘤发生的因素。为了阐明UPR在癌症倡议中的作用，我们将通过我们的特定目标（SA）检验四个假设。 SA1：ER应力可以启动NASH和HCC形成。我们将使用两个独立的ER应力模型来测试ER应力的诱导是否有助于NASH和HCC的发展。我们还将测试ER稳态的恢复是否会降低肿瘤的形成。此外，与彼得·梅拉科斯（Peter Metrakos）（麦吉尔大学）合作，我们将能够在人类患者中验证小鼠模型的发现。 SA2：消除UPR（PERK/EIF2/ATF4/CHOP）的促凋亡组将促进NASH和HCC计划。我们将消除肝细胞中的EIF2磷酸化，ATF4或CHOP，以确定其在HCC发育中的需求，并通过接种HFD的MUP-UPA小鼠中的HCC祖细胞来测试效果是否增加或降低了HCC发育中的ATF4和/或CHOP。 SA3：微环境中的PERK/EIF2α/ATF4/CHOP途径恢复了NASH/HCC的发展。 ATF4和CHOP将被特异性删除，并在基质细胞中消除EIF2磷酸化，以测试其对HCC进展的需求，并确定其对炎症和血管生成的影响。尽管正在大力努力靶向癌症中的UPR信号，但未知UPR是促进还是限制肿瘤倡议和/或发育。我们提出的研究将为这些问题提供重要的前所未有的洞察力，这些洞察力应影响针对癌症UPR的努力。