Dataset Information

Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ER? and HNF1?.

ABSTRACT: Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1? on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ER?. HNF1? mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype.

SUBMITTER: Villemain L

PROVIDER: S-EPMC7464972 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α.

Villemain Laure L Prigent Sylvie S Abou-Lovergne Aurélie A Pelletier Laura L Chiral Magali M Pontoglio Marco M Foufelle Fabienne F Caruso Stefano S Pineau Raphael R Rebouissou Sandra S Chevet Eric E Zucman-Rossi Jessica J Combettes Laurent L

Cancers 20200807 8

Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenom ...[more]

PMID: 32784704

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Project description:Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1a (HNF1a), were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative RT-PCR, western-blotting and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong dowregulation of L-FABP suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1a-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1a-mutated HCA. In theses tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through SREBP-1 and ChREBP that were repressed. We conclude that steatosis in HNF1a-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1a inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies. Keywords: Disease state analysis In a first experiment, microarray analyses were applied to 8 HNF1-alpha mutated HCA and their corresponding non-tumor livers using cDNA in-house manufactured arrays following a randomized and blinded unbalanced design. RNA labelling, hybridization and analysis of fluorescence was carried out, as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501], considering that uneven numbers of samples were randomly allocated to each of the engineers who were not aware of sample phenotypes. To assess data reproducibility and minimize dye bias effects, each of the samples was measured four times, twice with Cy3 and twice with Cy5. To ensure robustness and flexibility in data analysis, a reference design was used with a universal reference sample (Stratagene, USA) serving as a baseline for the comparisons of tumor samples. Hybridizations were performed onto an 11K human array (11K_VJF-ARRAY, GPL3282), which provides a genome-wide coverage of functional pathways. Raw data were obtained using the ArrayVisionM-bM-^DM-" 7.0 software (Imaging Research Inc., USA); the resulting 3.2x106 hybridization data points collected from 32 arrays were stored in a MIAME-compliant database and pre-processed for normalization and filtering as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501]. In a second experiment, HG-U133A Affymetrix GeneChipTM arrays were used to compare the expression profiles of 5 HNF1-alpha mutated HCA and 4 non related non-tumor livers. RNA labelling, hybridization and analysis were carried out following the manufacturerM-bM-^@M-^Ys instructions(Affymetrix, Santa Clara, CA). Raw data were obtained by using Microarray Suite 5.0 (MAS5) software, embedded in the Affymetrix GeneChip Operating Software (Santa Clara, USA); the resulting raw numerical data (CEL files) - available as supplementary files - collected from 9 Affymetrix GeneChips were pre-processed for normalization and filtering as described in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603]. A platform-dependant statistical comparison was performed considering HNF1 alpha-mutated HCA versus non tumor liver tissues, using multiple testing procedures to evaluate statistical significance for differentially expressed genes, as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501] and in the supplemental experimental procedures in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603]. Thus, a combined cross-platform analysis was done considering the UGCluster Identifiants as a common primary key (Unigene Build184-June05). Additional information on the procedures is provided in the supplemental experimental procedures in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603].

Dataset Information

Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ER? and HNF1?.

Publications

Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α.

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