Oncotarget

Research Papers:

Effect of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides on tumorigenesis, inflammation and fibrosis in a hepatocellular carcinoma mouse model

Bart Vanderborght, Kevin De Muynck, Sander Lefere, Anja Geerts, Helena Degroote, Xavier Verhelst, Hans Van Vlierberghe and Lindsey Devisscher _

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Oncotarget. 2020; 11:4504-4520. https://doi.org/10.18632/oncotarget.27830

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Abstract

Bart Vanderborght1,2, Kevin De Muynck1,2, Sander Lefere1,2, Anja Geerts1, Helena Degroote1,2, Xavier Verhelst1, Hans Van Vlierberghe1 and Lindsey Devisscher2

1 Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium

2 Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium

Correspondence to:

Lindsey Devisscher,email: lindsey.devisscher@ugent.be

Keywords: hepatocellular carcinoma; hypoxia-inducible factor; antisense oligonucleotides; tumor microenvironment; experimental mouse model

Received: July 09, 2020     Accepted: November 19, 2020     Published: December 01, 2020

Copyright: © 2020 Vanderborght et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. For advanced HCC, there is still an unmet need for more effective therapeutic strategies. HCC is typically associated with hypoxia and the hypoxia-inducible factor (HIF) regulatory pathway plays an important role in HCC development and progression. Therefore, we investigated the therapeutic potential of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides (ASOs), along with their effect on the inflammatory and fibrotic component of the tumor microenvironment (TME), in an experimental HCC mouse model. Based on its efficacy and safety, a dosage regimen of 20 mg/kg intraperitoneal injection of HIFα ASO twice per week was selected for further investigation in a preventive and therapeutic setting in a N,N-diethylnitrous amide (DEN)-induced HCC mouse model. DEN administration resulted in 100% tumor formation and HIFα ASO administration led to effective and selective hepatic downregulation of its target genes. HIFα ASO treatment had no effect on tumor numbers, but even enhanced the increased hepatic expression of HCC tumor markers, α-fetoprotein and glypican-3, compared to scrambled control ASO treatment in HCC mice. Especially HIF-1α ASO treatment resulted in an enhanced increase of monocytes and monocyte-derived macrophages in the liver and an enhanced hepatic upregulation of inflammatory markers. Both HIFα ASOs aggravated liver fibrosis in HCC mice compared to scrambled ASO treatment. The observed effects of our dosing regimen for HIF-1α and HIF-2α ASO treatment in the DEN-induced HCC mouse model discourage the use of HIFα isoforms as targets for the treatment of HCC.


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