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/eIF2?/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.

Public Health Relevance

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer mortality, which usually occurs in patients with non-alcoholic steatohepatitis (NASH). In collaboration with Dr. Karin we developed a murine model that closely mimics the process from NASH to HCC in humans, in which endoplasmic reticulum stress (ER stress) and the unfolded protein response (UPR) play essential roles. We propose to exploit this unique model to further dissect the mechanisms by which ER stress and UPR signaling promotes progression of NASH and HCC in mice and humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA198103-03
Application #
9477515
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Zhang, Shuping; Macias-Garcia, Alejandra; Velazquez, Jason et al. (2018) HRI coordinates translation by eIF2?P and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. Blood 131:450-461
Chandrahas, Vishwanatha K; Han, Jaeseok; Kaufman, Randal J (2018) Coordinating Organismal Metabolism During Protein Misfolding in the ER Through the Unfolded Protein Response. Curr Top Microbiol Immunol 414:103-130
Kim, Ju Youn; Garcia-Carbonell, Ricard; Yamachika, Shinichiro et al. (2018) ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell 175:133-145.e15
Wang, Jie-Mei; Qiu, Yining; Yang, Zhao et al. (2018) IRE1? prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 11:
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Poothong, Juthakorn; Sopha, Pattarawut; Kaufman, Randal J et al. (2017) IRE1? nucleotide sequence cleavage specificity in the unfolded protein response. FEBS Lett 591:406-414
Jin, Jung-Kang; Blackwood, Erik A; Azizi, Khalid et al. (2017) ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. Circ Res 120:862-875

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