DnaJ-PKAc Fusion Induces Liver Inflammation in a Zebrafish Model of Fibrolamellar Carcinoma

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2020 Feb 28

PMID 32102783

Citations 5

Authors

Sofia de Oliveira

Ruth A Houseright

Benjamin G Korte

Anna Huttenlocher

Affiliations

Soon will be listed here.

Abstract

Fibrolamellar carcinoma (FLC) is a rare liver cancer that affects adolescents and young adults. Genomic analysis of FLC has revealed a 400 kb deletion in chromosome 19 that leads to the chimeric transcript (DnaJ-PKAc), comprised of the first exon of heat shock protein 40 () and exons 2-10 of the catalytic subunit of protein kinase A ). Here, we report a new zebrafish model of FLC induced by ectopic expression of zebrafish Dnaja-Pkaca (zfDnaJa-Pkaca) in hepatocytes that is amenable to live imaging of early innate immune inflammation. Expression of zfDnaJa-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size. In addition, FLC larvae exhibit early innate immune inflammation characterized by early infiltration of neutrophils and macrophages into the liver microenvironment. Increased Caspase-a (the zebrafish homolog for human caspase-1) activity was also found in the liver of FLC larvae, and pharmacological inhibition of Tnfα and caspase-a decreased liver size and inflammation. Overall, these findings show that innate immune inflammation is an early feature in a zebrafish model of FLC and that pharmacological inhibition of TNFα or caspase-1 activity might be targets to treat inflammation and progression in FLC patients.This article has an associated First Person interview with the first author of the paper.

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References

Li X, Chen D, Ouyang F, Chen M, Wu Y, Kuang D . Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma. J Hepatol. 2014; 62(1):131-9. DOI: 10.1016/j.jhep.2014.08.023. View

Evason K, Francisco M, Juric V, Balakrishnan S, Lopez Pazmino M, Gordan J . Identification of Chemical Inhibitors of β-Catenin-Driven Liver Tumorigenesis in Zebrafish. PLoS Genet. 2015; 11(7):e1005305. PMC: 4489858. DOI: 10.1371/journal.pgen.1005305. View

Zheng W, Li Z, Nguyen A, Li C, Emelyanov A, Gong Z . Xmrk, kras and myc transgenic zebrafish liver cancer models share molecular signatures with subsets of human hepatocellular carcinoma. PLoS One. 2014; 9(3):e91179. PMC: 3954698. DOI: 10.1371/journal.pone.0091179. View

Serezani C, Ballinger M, Aronoff D, Peters-Golden M . Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008; 39(2):127-32. PMC: 2720142. DOI: 10.1165/rcmb.2008-0091TR. View

Banner K, Trevethick M . PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease. Trends Pharmacol Sci. 2004; 25(8):430-6. DOI: 10.1016/j.tips.2004.06.008. View

He J, Lu H, Zou Q, Luo L . Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology. 2013; 146(3):789-800.e8. DOI: 10.1053/j.gastro.2013.11.045. View

Li Z, Luo H, Li C, Huo X, Yan C, Huang X . Transcriptomic analysis of a transgenic zebrafish hepatocellular carcinoma model reveals a prominent role of immune responses in tumour progression and regression. Int J Cancer. 2014; 135(7):1564-73. DOI: 10.1002/ijc.28794. View

Bojarczuk A, Miller K, Hotham R, Lewis A, Ogryzko N, Kamuyango A . Cryptococcus neoformans Intracellular Proliferation and Capsule Size Determines Early Macrophage Control of Infection. Sci Rep. 2016; 6:21489. PMC: 4757829. DOI: 10.1038/srep21489. View

Turnham R, Smith F, Kenerson H, Omar M, Golkowski M, Garcia I . An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma. Elife. 2019; 8. PMC: 6533061. DOI: 10.7554/eLife.44187. View

10.

Dinh T, Vitucci E, Wauthier E, Graham R, Pitman W, Oikawa T . Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma. Sci Rep. 2017; 7:44653. PMC: 5356346. DOI: 10.1038/srep44653. View

11.

Davenport N, Sonnemann K, Eliceiri K, Bement W . Membrane dynamics during cellular wound repair. Mol Biol Cell. 2016; 27(14):2272-85. PMC: 4945144. DOI: 10.1091/mbc.E16-04-0223. View

12.

Niethammer P, Grabher C, Look A, Mitchison T . A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature. 2009; 459(7249):996-9. PMC: 2803098. DOI: 10.1038/nature08119. View

13.

Zheng W, Xu H, Lam S, Luo H, Karuturi R, Gong Z . Transcriptomic analyses of sexual dimorphism of the zebrafish liver and the effect of sex hormones. PLoS One. 2013; 8(1):e53562. PMC: 3547925. DOI: 10.1371/journal.pone.0053562. View

14.

Oikawa T, Wauthier E, Dinh T, Selitsky S, Reyna-Neyra A, Carpino G . Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells. Nat Commun. 2015; 6:8070. PMC: 4600730. DOI: 10.1038/ncomms9070. View

15.

de Assuncao T, Jalan-Sakrikar N, Huebert R . Regenerative Medicine and the Biliary Tree. Semin Liver Dis. 2017; 37(1):17-27. PMC: 5479436. DOI: 10.1055/s-0036-1597818. View

16.

Wrighton P, Oderberg I, Goessling W . There Is Something Fishy About Liver Cancer: Zebrafish Models of Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol. 2019; 8(3):347-363. PMC: 6713889. DOI: 10.1016/j.jcmgh.2019.05.002. View

17.

Skalhegg B, Funderud A, Henanger H, Hafte T, Larsen A, Kvissel A . Protein kinase A (PKA)--a potential target for therapeutic intervention of dysfunctional immune cells. Curr Drug Targets. 2005; 6(6):655-64. DOI: 10.2174/1389450054863644. View

18.

Kassahun W . Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments. World J Surg Oncol. 2016; 14(1):151. PMC: 4877801. DOI: 10.1186/s12957-016-0903-8. View

19.

Jang M, Kim H, Chung Y . Clinical aspects of tumor necrosis factor-α signaling in hepatocellular carcinoma. Curr Pharm Des. 2013; 20(17):2799-808. DOI: 10.2174/13816128113199990587. View

20.

Pernicova I, Korbonits M . Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014; 10(3):143-56. DOI: 10.1038/nrendo.2013.256. View