Arechederra, M. (María)

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    Pilot multi-omic analysis of human bile from benign and malignant biliary strictures: A machine-learning approach
    (MDPI AG, 2020) Latasa, M.U. (María Ujué); Banales, J.M. (Jesús M.); Carrascosa, J. (Juan); González, B. (Belén); Corrales, F.J. (Fernando José); Macias, R.I.R. (Rocío I. R.); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Pineda-Lucena, A. (Antonio); Bolado, F. (Federico); Urman, J.M. (Jesús M.); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Gil, I. (Iñigo); Alonso, C. (Cristina); Rullán, M. (María); Purroy, A. (A.); Iruarrizaga-Lejarreta, M. (Marta); Sangro, B. (Bruno); Fernandez-Urien, I. (Ignacio); Monte, M.J. (María J.); Herranz, J.M. (José M.); Iraburu-Elizalde, M. (María); Vila, J.J. (Juan J.); Álvarez-Sola, G. (Gloria); Oyón, D. (Daniel); Colyn, L. (Leticia); Romero, M. (Marta); Puchades-Carrasco, L. (Leonor); Cubero, F.J. (Francisco Javier); Zabalza, L. (Lucía); Martinez-Chantar, M.L. (María Luz); Marin, J.J.G (Jose J.G.); Carmona, L. (Lorena)
    Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy
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    Fibroblast growth factors 19 and 21 in acute liver damage
    (AME Publishing, 2018) Berasain, C. (Carmen); Arechederra, M. (María); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Ju, C. (Cynthia); Álvarez-Sola, G. (Gloria); Shan, Z. (Zhao); García-Fernández-de-Barrena, M. (Maite)
    Currently there are very few pharmacological options available to treat acute liver injury. Because its natural exposure to noxious stimuli the liver has developed a strong endogenous hepatoprotective capacity. Indeed, experimental evidence exposed a variety of endogenous hepatic and systemic responses naturally activated to protect the hepatic parenchyma and to foster liver regeneration, therefore preserving individual’s survival. The fibroblast growth factor (FGF) family encompasses a range of polypeptides with important effects on cellular differentiation, growth survival and metabolic regulation in adult organisms. Among these FGFs, FGF19 and FGF21 are endocrine hormones that profoundly influence systemic metabolism but also exert important hepatoprotective activities. In this review, we revisit the biology of these factors and highlight their potential application for the clinical management of acute liver injury
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    SLU7: a new hub of gene expression regulation-from epigenetics to protein stability in health and disease
    (2022) Berasain, C. (Carmen); Arechederra, M. (María); Avila, M.A. (Matías Antonio); Recalde, M. (Miriam); Gárate-Rascón, M. (María); García-Fernández-de-Barrena, M. (Maite); Rojo-González, C. (Carla)
    SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3 ' splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.
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    Epigenetics in liver fibrosis: could HDACs be a therapeutic target?
    (MDPI AG, 2020) Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Urman, J.M. (Jesús M.); Avila, M.A. (Matías Antonio); Colyn, L. (Leticia); Claveria-Cabello, A. (Alex)
    Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.
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    C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation
    (2020) Sánchez, A. (Aránzazu); Porras, A. (Almudena); Arechederra, M. (María); Gutiérrez-Uzquiza, A. (Alvaro); Bragado, P. (Paloma); Maina, F. (Flavio); Guerrero, C. (Carmen); Sequera, C. (Celia); Richelme, S. (Sylvie); Manzano, S. (Sara)
    The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.
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    Loss of liver function in chronic liver disease: An identity crisis
    (Elsevier, 2023) Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Avila, M.A. (Matías Antonio); Argemí, J. (Josepmaria)
    Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.
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    Splicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4α degradation, preserving hepatic differentiation and protecting from liver damage
    (Wiley, 2021) Latasa, M.U. (María Ujué); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Pineda-Lucena, A. (Antonio); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); García-Ruiz, C. (Carmen); Azkona, M.T. (María Teresa); Sangro, B. (Bruno); Fernández-Checa, J.C. (José C.); Esquivel, A. (Argitxu); Raquel; Recalde, M. (Miriam); Gárate-Rascón, M. (María); García-Fernández-de-Barrena, M. (Maite); Elizalde, M. (María); Bilbao, I. (Idoia); Jiménez-Andrés, M. (Maddalen)
    Background and aims: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and results: Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7+/- ) mice undergoing chronic (CCl4 ) and acute (acetaminophen) injury. SLU7 expression was restored in CCl4 -injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7+/- mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell's antioxidant machinery. Conclusions: Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
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    Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis
    (2020) Latasa, M.U. (María Ujué); Banales, J.M. (Jesús M.); Berasain, C. (Carmen); Arechederra, M. (María); Alvarez-Asiain, L. (Laura); Urman, J.M. (Jesús M.); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Sangro, B. (Bruno); Oyarzabal, J. (Julen); Herranz, J.M. (José M.); Rombouts, K. (Krista); Colyn, L. (Leticia); García-Fernández-de-Barrena, M. (Maite); Claveria-Cabello, A. (Alex); Martinez-Chantar, M.L. (María Luz); Marin, J.J.G (Jose J.G.)
    Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.
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    Activation of the unfolded protein response (UPR) is associated with cholangiocellular injury, fibrosis and carcinogenesis in an experimental model of fibropolycystic liver disease
    (2022) Latasa, M.U. (María Ujué); Bañares, R. (Rafael); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Nevzorova, Y. (Yulia); Peligros, M.I. (María Isabel); Nelson, L.J. (Leonard J.); Avila, M.A. (Matías Antonio); Davis, R.J. (Roger J.); Tortajada, A. (Agustín); Wu, H. (Hanghang); Vidal, A. (August); Rodriguez-Perales, S. (Sandra); Ye, H. (Hui); Reissing, J. (Johanna); Mohamed, M.R. (Mohamed Ramadan); Iraburu-Elizalde, M. (María); Lujambio, A. (Amaya); Martínez-Naves, E. (Eduardo); Trautwein, C. (Christian); Villanueva, A. (Alberto); Vaquero, J. (Javier); Colyn, L. (Leticia); Torres-Ruiz, R. (Raúl); Zheng, K. (Kang); Bruns, T. (Tony); Cubero, F.J. (Francisco Javier); Chen, C. (Chaobo)
    Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development.
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    Comprehensive analysis of epigenetic and epitranscriptomic genes’ expression in human NAFLD
    (Springer, 2023) Latasa, M.U. (María Ujué); Lopez-Pascual, A. (Amaya); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Uriarte, I. (Iker); Irigaray-Miramon, A. (Ainara); Avila, M.A. (Matías Antonio); Sangro, B. (Bruno); Herranz, J.M. (José M.); Adán-Villaescusa, E. (Elena); Castelló-Uribe, B. (Borja); Claveria-Cabello, A. (Alex)
    Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes’ expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.