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
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
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
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.