Goñi, S. (Saioa)
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- Impairment of pre-mRNA splicing in liver disease: mechanisms and consequences(Baishideng Publishing Group, 2010) Latasa, M.U. (María Ujué); Berasain, C. (Carmen); Avila, M.A. (Matías Antonio); Castillo, J. (Josefa); Goñi, S. (Saioa); Prieto, J. (Jesús)Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal of introns and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention of intronic sequences and the generation of exonic se- quences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing de- fects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulate pre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumori- genesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the develop- ment of new effective therapies.
- Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice(Public Library of Science, 2010) Latasa, M.U. (María Ujué); Banales, J.M. (Jesús M.); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Gil-Puig, C. (Carmen); Avila, M.A. (Matías Antonio); Rodriguez-Ortigosa, C.M. (Carlos M.); Goñi, S. (Saioa); Recio, J.A. (Juan A.); Lotersztajn, S. (Sophie); Raquel; Prieto, J. (Jesús); Juanarena, N. (Nerea); García-Fernández-de-Barrena, M. (Maite); Mendez, M. (Miriam); Lecanda, J. (Jon); Arcelus, S. (Sara)BACKGROUND: Inflammation and fibrogenesis are directly related to chronic liver disease progression, including hepatocellular carcinoma (HCC) development. Currently there are few therapeutic options available to inhibit liver fibrosis. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 5'-methylthioadenosine (MTA) in Mdr2(-/-) mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development. METHODOLOGY: MTA was administered daily by gavage to wild type and Mdr2(-/-) mice for three weeks. MTA anti-inflammatory and anti-fibrotic effects and potential mechanisms of action were examined in the liver of Mdr2(-/-) mice with ongoing fibrogenesis and in cultured liver fibrogenic cells (myofibroblasts). PRINCIPAL FINDINGS: MTA treatment reduced hepatomegaly and liver injury. α-Smooth muscle actin immunoreactivity and collagen deposition were also significantly decreased. Inflammatory infiltrate, the expression of the cytokines IL6 and Mcp-1, pro-fibrogenic factors like TGFβ2 and tenascin-C, as well as pro-fibrogenic intracellular signalling pathways were reduced by MTA in vivo. MTA inhibited the activation and proliferation of isolated myofibroblasts and down-regulated cyclin D1 gene expression at the transcriptional level. The expression of JunD, a key transcription factor in liver fibrogenesis, was also reduced by MTA in activated myofibroblasts. CONCLUSIONS/SIGNIFICANCE: Oral MTA administration was well tolerated and proved its efficacy in reducing liver inflammation and fibrosis. MTA may have multiple molecular and cellular targets. These include the inhibition of inflammatory and pro-fibrogenic cytokines, as well as the attenuation of myofibroblast activation and proliferation. Downregulation of JunD and cyclin D1 expression in myofibroblasts may be important regarding the mechanism of action of MTA. This compound could be a good candidate to be tested for the treatment of (biliary) liver fibrosis.
- Splicing regulator SLU7 is essential for maintaining liver homeostasis(2014) Latasa, M.U. (María Ujué); Berasain, C. (Carmen); Collantes, M. (María); García-Irigoyen, O. (Oihane); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Azkona, M.T. (María Teresa); Goñi, S. (Saioa); Raquel; Prieto, J. (Jesús); Lujambio, A. (Amaya); Elizalde, M. (María); Segura, V. (Víctor); Scala, M. (Marianna) DiA precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype. Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation, including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence.
- Impaired LXRa phosphorylation attenuates progression of fatty liver disease(Elsevier BV, 2019) Roberg-Larsen, H. (Hanne); Becares, N. (Natalia); Diaz-Zuccarini, V. (Vanessa); Louie, R. (Rikah); Voisin, M. (Maud); Shrestha, E. (Elina); Garabedian, M.J. (Michael J.); Treuter, E. (Eckardt); Liang, N. (Ning); Pourcet, B. (Benoit); Pineda-Torra, I. (Inés); Goñi, S. (Saioa); Gage, M.C. (Matthew C.); Steffensen, K.R. (Knut R. ); Rombouts, K. (Krista); O’Brien, A. (Alastair); Luong, T.V. (Tu Vinh); Martin-Gutierrez, L. (Lucina); Pello, O.M. (Oscar M.); Pichardo-Almarza, C. (Cesar)Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target.
- Epidermal growth factor receptor ligands in murine models for erythropoietic protoporphyria: potential novel players in the progression of liver injury(C.M.B. Association, 2009) Latasa, M.U. (María Ujué); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Matscheko, N. (N.); Avila, M.A. (Matías Antonio); Unzu, C. (Carmen); Goñi, S. (Saioa); Prieto, J. (Jesús); Enriquez-de-Salamanca, R. (Rafael); Fontanellas-Romá, A. (Antonio); Sampedro, A. (Ana); Garcia-Bravo, M. (M.); Mauleon, I. (Itsaso)Activation of the epidermal growth factor receptor (EGFR) plays an important role in liver regeneration and resistance to acute injury. However its chronic activation participates in the progression of liver disease, including fibrogenesis and malignant transformation. Hepatobiliary disease represents a constant feature in the clinically relevant Fechm1pas/Fechm1pas genetic model of erythropoietic protoporphyria (EPP). Similarly, chronic administration of griseofulvin to mice induces pathological changes similar to those found in patients with EPP-associated liver injury. We investigated the hepatic expression of the EGFR and its seven most relevant ligands in Fechm1pas/Fechm1pas mice bred in three different backgrounds, and in griseofulvin-induced protoporphyria. We observed that the expression of amphiregulin, betacellulin and epiregulin was significantly increased in young EPP mice when compared to aged-matched controls in all genetic backgrounds. The expression of these ligands was also tested in older (11 months) BALB/cJ EPP mice, and it was found to remain induced, while that of the EGFR was downregulated. Griseofulvin feeding also increased the expression of amphiregulin, betacellulin and epiregulin. Interestingly, protoporphyrin accumulation in cultured hepatic AML-12 cells readily elicited the expression of these three EGFR ligands. Our findings suggest that protoporphyrin could directly induce the hepatic expression of EGFR ligands, and that their chronic upregulation might participate in the pathogenesis of EPP-associated liver disease.
- Omics approaches in pancreatic adenocarcinoma(MDPI AG, 2019) Sayar, O. (Onintza); García, E. (Estefania); Arévalo, S. (Sara); Viudez, A. (Antonio); Zarate, R. (Ruth); Gonzalez, I. (Iranzu); Hernández-García, I. (Irene); Fernandez-Irigoyen, J. (Joaquín); Goñi, S. (Saioa); Arrazubi, V. (Virginia); Sala-Elarre, P. (Pablo); Pérez-Sanz, J. (Jairo); Oyaga-Iriarte, E. (Esther); Santamaria, E. (Enrique); Vera, R. (Ruth)Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.