The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism.

María Paulette Castro-Gil, Julia Esperanza Torres-Mena, Rosa M Salgado, Said A Muñoz-Montero, José Michael Martínez-Garcés, Carlos David López-Torres, Alfredo Mendoza-Vargas, Nayeli Belem Gabiño-López, Saúl Villa-Treviño, Luis Del Pozo-Yauner, Jaime Arellanes-Robledo, Edgar Krötzsch, Julio Isael Pérez-Carreón

Journal: Genomics 2022;114(1):72-83

PMID: 34861383

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Abstract

Hepatocellular carcinoma expressing hepatobiliary progenitor markers, is considered of poor prognosis. By using a hepatocarcinogenesis model, laser capture microdissection, and RNA-Sequencing analysis, we identified an expression profile in GGT/KRT19-positive experimental tumors; 438 differentially expressed genes were found in early and late nodules along with increased collagen deposition. Dysregulated genes were involved in Fatty Acid Metabolism, RXR function, and Hepatic Stellate Cells Activation. Downregulation of Slc27a5, Acsl1, and Cyp2e1, demonstrated that Retinoid X Receptor α (RXRα) function is compromised in GGT/KRT19-positive nodules. Since RXRα controls NRF2 pathway activation, we determined the expression of NRF2 targeted genes; Akr1b8, Akr7a3, Gstp1, Abcc3, Ptgr1, and Txnrd1 were upregulated, indicating NRF2 pathway activation. A comparative analysis in human HCC showed that SLC27A5, ACSL1, CYP2E1, and RXRα gene expression is mutually exclusive with KRT19 gene expression. Our results indicate that the downregulation of Slc27a5, Acsl1, Rxrα, and Cyp2e1 genes is an early event within GGT/KRT19-positive HCC.

Address: Laboratory of Liver Diseases, National Institute of Genomic Medicine, CDMX, Mexico.; Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", CDMX, Mexico.; Department of Computational Genomics, National Institute of Genomic Medicine, CDMX, Mexico.; National Institute of Genomic Medicine, CDMX, Mexico.; Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, CDMX, Mexico.; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Laboratory of Liver Diseases, National Institute of Genomic Medicine, CDMX, Mexico; Directorate of Cátedras, National Council of Science and Technology, CDMX, Mexico.; Laboratory of Liver Diseases, National Institute of Genomic Medicine, CDMX, Mexico. Electronic address: [email protected].

DOI: 10.1016/j.ygeno.2021.11.035