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

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...

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Published inGenomics (San Diego, Calif.) Vol. 114; no. 1; pp. 72 - 83
Main Authors Castro-Gil, María Paulette, Torres-Mena, Julia Esperanza, Salgado, Rosa M., Muñoz-Montero, Said A., Martínez-Garcés, José Michael, López-Torres, Carlos David, Mendoza-Vargas, Alfredo, Gabiño-López, Nayeli Belem, Villa-Treviño, Saúl, del Pozo-Yauner, Luis, Arellanes-Robledo, Jaime, Krötzsch, Edgar, Pérez-Carreón, Julio Isael
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.01.2022
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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. [Display omitted] •Hepatic Stellate Cells activation is dysregulated in GGT/KRT19-positive HCC nodules.•RXR function is compromised in early and late GGT/KRT19-positive HCC nodules.•Downregulation of Slc27a5, Acsl1 and Cyp2e1 is an early event in GGT/KRT19 HCC development.•NRF2 pathway is activated in GGT/KRT19-positive nodules where RXR function is compromised.
AbstractList 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.
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. [Display omitted] •Hepatic Stellate Cells activation is dysregulated in GGT/KRT19-positive HCC nodules.•RXR function is compromised in early and late GGT/KRT19-positive HCC nodules.•Downregulation of Slc27a5, Acsl1 and Cyp2e1 is an early event in GGT/KRT19 HCC development.•NRF2 pathway is activated in GGT/KRT19-positive nodules where RXR function is compromised.
Author Martínez-Garcés, José Michael
Pérez-Carreón, Julio Isael
Castro-Gil, María Paulette
López-Torres, Carlos David
Krötzsch, Edgar
Arellanes-Robledo, Jaime
Torres-Mena, Julia Esperanza
Muñoz-Montero, Said A.
Gabiño-López, Nayeli Belem
del Pozo-Yauner, Luis
Mendoza-Vargas, Alfredo
Salgado, Rosa M.
Villa-Treviño, Saúl
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Issue 1
Keywords RNA-sequencing
Liver cancer
RXRα function
Laser capture microdissection
Dysplastic nodules
NRF2 activation
Language English
License This is an open access article under the CC BY-NC-ND license.
Copyright © 2021. Published by Elsevier Inc.
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Snippet Hepatocellular carcinoma expressing hepatobiliary progenitor markers, is considered of poor prognosis. By using a hepatocarcinogenesis model, laser capture...
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SubjectTerms Carcinoma, Hepatocellular - metabolism
Dysplastic nodules
Fatty Acids
Humans
Laser capture microdissection
Liver cancer
Liver Neoplasms - metabolism
NRF2 activation
Retinoid X Receptor alpha - genetics
Retinoid X Receptor alpha - metabolism
RNA-sequencing
RXRα function
Transcriptome
Title The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism
URI https://dx.doi.org/10.1016/j.ygeno.2021.11.035
https://www.ncbi.nlm.nih.gov/pubmed/34861383
https://search.proquest.com/docview/2606925124
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