Open Access
Circulating low density neutrophils are associated with resistance to anti-PD1 immunotherapy in squamous head and neck cancer
(Wiley, 2023) Arrazubi, Virginia; Goñi Irigoyen, Saioa; González Borja, Iranzu; Hernández García, Irene; Arasanz Esteban, Hugo; Pérez Sanz, Jairo; Bocanegra Gondán, Ana Isabel; Kochan, Grazyna; Escors Murugarren, David; Ruiz de Azúa, Yerani; Elizalde, Jesús María; Viúdez, Antonio; Vera García, Ruth; Ciencias de la Salud; Osasun Zientziak
Background: Identification of predictive biomarkers to Immune checkpoint inhibitors (ICIs) in head and neck cancer (HNSCC) is an unmet need. Methods: This was a prospective observational study including 25 patients with HNSCC treated with immunotherapy or chemotherapy after a prior platinum-based regimen. Low density neutrophils (LDNs) and serum markers were analyzed. Results: In the immunotherapy cohort, patients with high LDN levels had a shorter progression free survival (PFS) (1.8 months vs. 10.9 months; *p = 0.034). Also, progressors showed higher percentage of LDNs compared to non-progressors although significance was not reached (mean 20.68% vs. 4.095%, p = 0.0875). These findings were not replicated in patients treated with chemotherapy. High levels of interleukin-7 (IL7) were correlated with a significantly longer overall survival (OS) (13.47 months 3.51 vs. months, *p = 0.013). Conclusions: High baseline circulating LDNs and low IL7 could identify a subset of patients intrinsically refractory to ICIs as monotherapy in HNSCC.
Open Access
Deciphering CHFR role in pancreatic ductal adenocarcinoma
(Frontiers Media, 2021) González Borja, Iranzu; Alors-Pérez, Emilia; Amat Villegas, Irene; Alonso, Laura; Viyuela-García, Cristina; Goñi Irigoyen, Saioa; Reyes, José C.; Ceballos-Chávez, María; Hernández García, Irene; Sánchez-Frías, Marina E.; Santamaría Martínez, Enrique; Razquin, Socorro; Arjona Sánchez, Álvaro; Arrazubi, Virginia; Pérez Sanz, Jairo; Vera García, Ruth; Fernández Irigoyen, Joaquín; Castaño, Justo P.; Viúdez, Antonio; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Checkpoint with forkhead-associated and ring finger domains (CHFR) has been proposed as a predictive and prognosis biomarker for different tumor types, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The aim of this study was two-pronged: to review the role of CHFR in PDAC and evaluating CHFR as a potential predictive biomarker in this disease. For this purpose, we first explored the CHFR messenger (m)RNA expression and promoter methylation through the TCGA database. Secondly, the CHFR expression and promoter methylation were prospectively evaluated in a cohort of patients diagnosed with borderline (n = 19) or resectable (n = 16) PDAC by immunohistochemistry (IHC), methylation specific-PCR (MSP), and pyrosequencing. The results from the TCGA database showed significant differences in terms of progression-free survival (PFS) and overall survival (OS) based on the CHFR mRNA expression, which was likely independent from the promoter methylation. Importantly, our results showed that in primarily resected patients and also the entire cohort, a higher CHFR expression as indicated by the higher IHC staining intensity might identify patients with longer disease-free survival (DFS) and OS, respectively. Similarly, in the same cohorts, patients with lower methylation levels by pyrosequencing showed significantly longer OS than patients without this pattern. Both, the CHFR expression intensity and its promoter methylation were established as independent prognostic factors for PFS and OS in the entire cohort. In contrast, no significant differences were found between different methylation patterns for CHFR and the response to taxane-based neoadjuvant treatment. These results suggest the potential role of the higher expression of CHFR and the methylation pattern of its promoter as potential prognostic biomarkers in PDAC, thus warranting further comprehensive studies to extend and confirm our preliminary findings.
Open Access
Impairment of pre-mRNA splicing in liver disease: Mechanisms and consequences
(Baishideng Publishing Group, 2010) Berasain, Carmen; Goñi Irigoyen, Saioa; Castillo, Josefa; Latasa, Maria Ujue; Prieto, Jesús; Ávila, Matías A.; Ciencias de la Salud; Osasun Zientziak
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 sequences 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 defects 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 tumorigenesis, 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 development of new effective therapies.
Open Access
Impaired LXRα phosphorylation attenuates progression of fatty liver disease
(Cell Press, 2019) Bécares, Natalia; Gage, Matthew C.; Voisin, Maud; Shrestha, Elina; Martín-Gutiérrez, Lucía; Liang, Ning; Louie, Rikah; Pourcet, Benoît; Pello, Óscar M.; Luong, Tu Vinh; Goñi Irigoyen, Saioa; Pichardo-Almarza, César; Røberg-Larsen, Hanne; Díaz-Zuccarini, Vanessa; Steffensen, Knut R.; O’Brien, Alastair; Garabedian, Michael J.; Rombouts, Krista; Treuter, Eckardt; Pineda-Torra, Inés; Ciencias de la Salud; Osasun Zientziak
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.
Open Access
Cytokines and lymphoid populations as potential biomarkers in locally and borderline pancreatic adenocarcinoma
(MDPI, 2022) González Borja, Iranzu; Viúdez, Antonio; Alors-Pérez, Emilia; Goñi Irigoyen, Saioa; Amat Villegas, Irene; Ghanem, Ismael; Pazo-Cid, Roberto; Feliu, Jaime; Alonso, Laura; López López, Carlos; Arrazubi, Virginia; Gallego, Javier; Pérez Sanz, Jairo; Hernández García, Irene; Vera García, Ruth; Castaño, Justo P.; Fernández Irigoyen, Joaquín; Ciencias de la Salud; Osasun Zientziak
Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis of these patients, this research has been focused on the discovery of new biomarkers. For this purpose, patients with BL and resectable disease were recruited. Serum cytokines and growth factors were monitored at different time points using protein arrays. Immune cell populations were determined by flow cytometry in peripheral blood as well as by immunohistochemistry (IHC) in tumor tissues. Several cytokines were found to be differentially expressed between the study subgroups. In the BL disease setting, two different scores were proven to be independent prognostic factors for progression-free survival (PFS) (based on IL-10, MDC, MIF, and eotaxin-3) and OS (based on eotaxin-3, NT-3, FGF-9, and IP10). In the same context, CA19-9 was found to play a role as independent prognostic factor for OS. Eotaxin-3 and MDC cytokines for PFS, and eotaxin-3, NT-3, and CKβ8-1 for OS, were shown to be predictive biomarkers for nab-paclitaxel and gemcitabine regimen. Similarly, oncostatin, BDNF, and IP10 cytokines were proven to act as predictive biomarkers regarding PFS, for FOLFIRINOX regimen. In the resectable cohort, RANTES, TIMP-1, FGF-4, and IL-10 individually differentiated patients according to their cancer-associated survival. Regarding immune cell populations, baseline high levels of circulating B lymphocytes were related to a significantly longer OS, while these levels significantly decreased as progression occurred. Similarly, baseline high levels of helper lymphocytes (CD4+), low levels of cytotoxic lymphocytes (CD8+), and a high CD4/CD8 ratio, were related to a significantly longer PFS. Finally, high levels of CD4+ and CD8+ intratumoural infiltration was associated with significantly longer PFS. In conclusion, in this study we were able to identify several prognostic and predictive biomarker candidates in patients diagnosed of resectable or BL PDAC.
Open Access
Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα
(Nature Research, 2019) Liang, Ning; Damdimopoulos, Anastasius; Goñi Irigoyen, Saioa; Huang, Zhiqiang; Vedin, Lise-Lotte; Jakobsson, Tomas; Giudici, Marco; Ahmed, Osman; Pedrelli, Matteo; Barilla, Serena; Alzaid, Fawaz; Mendoza, Arturo; Schröder, Tarja; Kuiper, Raoul; Parini, Paolo; Hollenberg, Anthony; Lefebvre, Philippe; Francque, Sven; Van Gaal, Luc; Staels, Bart; Venteclef, Nicolas; Treuter, Eckardt; Fan, Rongrong; Ciencias de la Salud; Osasun Zientziak
Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.
Open Access
Epigenetic regulation of microRNAs in cancer: shortening the distance from bench to bedside
(MDPI, 2021) Pajares Villandiego, María Josefa; Alemany Cosme, Ester; Goñi Irigoyen, Saioa; Bandrés Elizalde, Eva; Palanca Ballester, Cora; Sandoval, Juan; Ciencias de la Salud; Osasun Zientziak
Cancer is a complex disease involving alterations of multiple processes, with both genetic and epigenetic features contributing as core factors to the disease. In recent years, it has become evident that non-coding RNAs (ncRNAs), an epigenetic factor, play a key role in the initiation and progression of cancer. MicroRNAs, the most studied non-coding RNAs subtype, are key controllers in a myriad of cellular processes, including proliferation, differentiation, and apoptosis. Furthermore, the expression of miRNAs is controlled, concomitantly, by other epigenetic factors, such as DNA methylation and histone modifications, resulting in aberrant patterns of expression upon the occurrence of cancer. In this sense, aberrant miRNA landscape evaluation has emerged as a promising strategy for cancer management. In this review, we have focused on the regulation (biogenesis, processing, and dysregulation) of miRNAs and their role as modulators of the epigenetic machinery. We have also highlighted their potential clinical value, such as validated diagnostic and prognostic biomarkers, and their relevant role as chromatin modifiers in cancer therapy.
Open Access
Epidermal growth factor receptor ligands in murine models for erythropoietic protoporphyria: potential novel players in the progression of liver injury
(CMB Association, 2009) Berasain, Carmen; Sampedro, Ana; Mauleón, I.; Goñi Irigoyen, Saioa; Latasa, Maria Ujue; Matscheko, N.; García-Bravo, M.; Unzu, Carmen; Corrales, Fernando J.; Enríquez de Salamanca, R.; Prieto, Jesús; Ávila, Matías A.; Fontanellas, Antonio; Ciencias de la Salud; Osasun Zientziak
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 EPPassociated liver disease.
Open Access
Pediococcus acidilactici pA1c® improves the beneficial effects of metformin treatment in type 2 diabetes by controlling glycaemia and modulating intestinal microbiota
(MDPI, 2023) Cabello Olmo, Miriam; Oneca Agurruza, María; Urtasun Alonso, Raquel; Pajares Villandiego, María Josefa; Goñi Irigoyen, Saioa; Riezu Boj, José I.; Milagro Yoldi, F. I.; Ayo, Josune; Encío Martínez, Ignacio; Barajas Vélez, Miguel Ángel; Araña Ciordia, Miriam; Ciencias de la Salud; Osasun Zientziak
Type 2 diabetes (T2D) is a complex metabolic disease, which involves maintained hyperglycemia, mainly due to the development of an insulin resistance process. Metformin administration is the most prescribed treatment for diabetic patients. In a previously published study, we demonstrated that Pediococcus acidilactici pA1c® (pA1c) protects from insulin resistance and body weight gain in HFD-induced diabetic mice. The present work aimed to evaluate the possible beneficial impact of a 16-week administration of pA1c, metformin, or the combination of pA1c and metformin in a T2D HFD-induced mice model. We found that the simultaneous administration of both products attenuated hyperglycemia, increased high-intensity insulin-positive areas in the pancreas and HOMA-β, decreased HOMA-IR and also provided more beneficial effects than metformin treatment (regarding HOMA-IR, serum C-peptide level, liver steatosis or hepatic Fasn expression), and pA1c treatment (regarding body weight or hepatic G6pase expression). The three treatments had a significant impact on fecal microbiota and led to differential composition of commensal bacterial populations. In conclusion, our findings suggest that P. acidilactici pA1c® administration improved metformin beneficial effects as a T2D treatment, and it would be a valuable therapeutic strategy to treat T2D.
Open Access
Omics approaches in pancreatic adenocarcinoma
(MDPI, 2019) González Borja, Iranzu; Viúdez, Antonio; Goñi Irigoyen, Saioa; Santamaría Martínez, Enrique; Carrasco García, Estefanía; Pérez Sanz, Jairo; Hernández García, Irene; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua, Ref. 008-2018
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.