Well-differentiated liver cancers reveal the potential link between ACE2 dysfunction and metabolic breakdown

Lise Desquilles,Luis Cano,Nicolas Mouchet,Romain Désert,Bruno Clément,Orlando Musso,Clémence Landreau,Gevorg Ghukasyan,Anne Corlu,Bruno Turlin

doi:10.1038/s41598-021-03710-0

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19). Transmembrane serine protease 2 (TMPRSS2) is a coreceptor. Abnormal hepatic function in COVID-19 suggests specific or bystander liver disease. Because liver cancer cells express the ACE2 viral receptor, they are widely used as models of SARS-CoV-2 infection in vitro. Therefore, the purpose of this study was to analyze ACE2 and TMPRSS2 expression and localization in human liver cancers and in non-tumor livers. We studied ACE2 and TMPRSS2 in transcriptomic datasets totaling 1503 liver cancers, followed by high-resolution confocal multiplex immunohistochemistry and quantitative image analysis of a 41-HCC tissue microarray. In cancers, we detected ACE2 and TMPRSS2 at the biliary pole of tumor hepatocytes. In whole mount sections of five normal liver samples, we identified ACE2 in hepatocyte’s bile canaliculi, biliary epithelium, sinusoidal and capillary endothelial cells. Tumors carrying mutated β-catenin showed ACE2 DNA hypomethylation and higher mRNA and protein expression, consistently with predicted β-catenin response sites in the ACE2 promoter. Finally, ACE2 and TMPRSS2 co-expression networks highlighted hepatocyte-specific functions, oxidative stress and inflammation, suggesting a link between inflammation, ACE2 dysfunction and metabolic breakdown.

Highlights

Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19)
We first searched for relationships of ACE2 and TMPRSS2 mRNA expression levels with hepatocellular carcinoma (HCC) aggressiveness
Whereas ACE2 mRNA expression was 1.7-fold higher in non-tumors livers than in HCCs, TMPRSS2 expression did not differ between both groups (Supplementary Fig. 2b)

Summary

Introduction

Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19). Abbreviations ACE2 Angiotensin-converting enzyme 2 Ang Angiotensin CLEC4M C-Type Lectin Domain Family 4 Member M DPP4 Dipeptidyl Peptidase 4 COVID-19 Coronavirus disease 2019 CTNNB1 β-Catenin HCC Hepatocellular carcinoma LSECs, MERS-CoV Middle East Respiratory Syndrome Coronavirus SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 TCGA The Cancer Genome Atlas TMPRSS2 Transmembrane serine protease 2. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID19)[1,2,3]. ~ 80% of SARS-CoV-2-infected individuals develop asymptomatic self-limited upper airway forms of COVID-19, approximately 15% need hospitalization and 5% develop severe disease with acute respiratory distress syndrome, immune dysregulation and a “cytokine storm” with disseminated intravascular c oagulation[1,3,4]. Crown-like viral particles with complete envelope and typical spikes have been observed in lung, k idney[16,17] and in hepatocytes[14] suggesting multiorgan targeting of COVID-19

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