[This corrects the article DOI: 10.3389/fdgth.2025.1645233.].

YY1 is a multifunctional transcription factor whose regulation spans transcriptional, post-transcriptional, and post-translational layers, conferring remarkable context-dependent plasticity. Several studies carried out in YY1-deficient mouse models highlight its essential roles in embryogenesis, organogenesis, and cellular homeostasis, while its deregulation in adulthood predisposes to multiple chronic diseases. In cancer, YY1 displays a bidirectional function, acting as either oncogene or tumor suppressor depending on cellular context and tumor type, and reshaping transcriptional and epigenetic networks. Emerging evidence further identifies YY1 as a clock-controlled gene and architectural regulator of circadian transcription, bridging together enhancer-promoter communication, chromatin state, and the temporal dimension of gene expression. In this context, its deregulation links circadian misalignment with oncogenic signaling, underscoring its key role as a diagnostic and prognostic biomarker, as well as a therapeutic target, thus highlighting its relevance in precision oncology.

511 Background: Low quality diets and physical inactivity are two modifiable lifestyle factors that together with vitamin D deficiency have been associated with unfavorable breast cancer (BC) outcomes and cardiometabolic health. We therefore tested the effect of a lifestyle program on BC recurrence and cardiometabolic risk factors on a background of vitamin D sufficiency. Methods: Women aged 30-74 years were enrolled in a phase III trial (NCT02786875) within 12 months of their primary BC diagnosis (stages I-III) in 7 oncologic centres in Italy. Consenting participants were randomized to one of two lifestyle treatments lasting 33 months: 1) positive control (n = 249), standard advice on a Mediterranean diet (MedDiet) and avoidance of sedentary behavior; 2) intervention (n = 243), high intensity advice on low-glycemic index MedDiet and 30-minute additional daily brisk walking. Oral vitamin D3 was administered throughout. Data were collected quarterly on health status, anthropometry, 7-day food records, daily steps, serum 25(OH)D concentrations and metabolic syndrome parameters. The primary outcome was BC recurrence (intention to treat analysis) at 33 months, with cardiometabolic risk factors as secondary outcomes. Hazard ratios (HR) and 95% confidence intervals (CI) for BC recurrence were computed using Cox proportional hazards models adjusted for recruitment center. One-year changes in treatment variables and cardiometabolic risk factors were tested by paired Student’s t-test within each treatment arm and by analysis of covariance between treatment arms, adjusted for baseline values. Results: Approximately 58% of patients were aged ≥50 years, 94% were postmenopausal, 86% had stages I-IIB and 75% hormone-positive BC. A total of 37 recurrences were observed with no differences between arms (HR = 0.94, 95%CI: 0.49-1.79). Independently of randomization arm, women with hormone-positive BC who were more adherent to the intervention program (41%), showed 76% lower risk of BC recurrence (HR = 0.24, 95% CI: 0.06-0.95). Weight loss of 3 kg, representing a 4.2% drop of initial body weight, was significantly greater in the test arm compared to 1.7 kg or 2.4% in the control arm (p = 0.0034). This translated in reductions of body mass index from 27.5±5.7 to 26.3±5.4 kg/m 2 in the intervention arm and from 27.2±5.1 to 26.6±5.1 kg/m 2 in controls (p = 0.0032). The presence of metabolic syndrome dropped by 65% in the intervention arm and 34% in controls (p = 0.008). The probability of metabolic syndrome remission was 2.5-fold higher in the intervention arm. Conclusions: A safe and low-cost lifestyle program with low-glycemic index MedDiet, daily brisk walking and oral vitamin D supplementation resulted in weight loss, reduced metabolic syndrome prevalence and was significantly associated with lower recurrences in women with hormone-positive BC. Clinical trial information: NCT02786875 .

Abstract Despite significant advances in systemic therapies for colorectal cancer (CRC), this tumor remains the second leading cause of cancer-related mortality worldwide. Among the chemotherapeutic agents most widely used in CRC, oxaliplatin (OX) represents a cornerstone of both single-agent and combination regimens. However, the acquisition of drug resistance mechanisms leads to the failure of these treatments, underscoring the need to elucidate the molecular determinants underlying chemoresistance. Therefore, this study aimed to identify the molecular determinants associated with resistance to OX-based therapies through integrated genomic and transcriptomic approaches performed on drug-sensitive and OX-resistant CRC patient-derived tumor organoids (PDTOs). OX- and FOLFOX-resistant CRC PDTOs (5.24-fold increment of drug resistance) were generated through the administration of increasing and sublethal doses of the drug for at least 90 days and integrated transcriptomic and exomic profiling were performed to characterize the molecular mechanisms sustaining chemoresistance. RNA-sequencing analyses revealed profound dysregulation of pathways involved in cytoskeletal regulation, extracellular space and cell death in both OX and FOLFOX-resistant models, while whole-exome sequencing identified newly acquired variants affecting genes related primarily to cell adhesion and extracellular matrix organization, with notable alterations affecting LARGE1 and Thrombospondin Type-1 Domain-Containing Protein 7B (THSD7B), both genes potentially implicated in OX resistance. Particularly, the presence of the THSD7B NM_001080427.1:c.465dup, p.(Pro156ThrfsTer6) frameshift variant was first confirmed in OX-resistant PDTOs by droplet digital PCR (VAF=20.9%). RT-qPCR analyses performed in drug-sensitive and OX and FOLFOX-resistant PDTOs revealed markedly reduced THSD7B transcript levels in resistant models. Functional silencing of THSD7B using small interfering RNAs performed on Caco2, HT29, and HCT116 CRC cell lines led to a significant downregulation of THSD7B expression (from 27% to 90% reduction) and resulted in increased OX resistance, particularly in the more differentiated lines (Caco2 and HT29), whereas no substantial effect was observed in the undifferentiated HCT116 line. Overall, our data show for the first time that THSD7B loss mediates OX resistance in CRC. Intriguingly, this evidence has been recently associated with platinum resistance also in lung cancer; therefore, the evaluation of THSD7B status may represent a valuable strategy for the early identification of platinum-resistant patients to avoid the administration of ineffective and potentially harmful treatments. Citation Format: Graziana Spoto, Luca Falzone, Marco Fichera, Massimo Libra. THSD7B loss is associated with oxaliplatin resistance in colorectal cancer patient-derived tumor organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3402.

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and one of the leading causes of cancer death worldwide. Despite diagnostic and therapeutic advances, CRC mortality remains high, especially in industrialized countries. Numerous studies have highlighted the pathogenetic role of altered microRNA (miRNA) expression among the various factors contributing to the development and progression of colorectal cancer (CRC). However, the data regarding specific miRNAs involved in CRC pathogenesis remain inconsistent, and no miRNAs have been recognized so far as reliable or effective biomarkers for the diagnosis of this tumor type. To identify novel miRNA biomarkers in CRC, this study validated the expression levels of a four-miRNA signature predicted to be involved in CRC by analyzing both tissue and liquid biopsy samples. Our experimental and bioinformatics results highlighted the diagnostic potential of hsa-miR-21-5p, hsa-miR-503-5p, and hsa-miR-375, as well as the potential prognostic value of hsa-miR-497-5p overexpression and hsa-miR-375-3p downregulation. Overall, the results obtained suggest the diagnostic and prognostic significance of this four-miRNA signature in CRC.

Raf kinase inhibitor protein (RKIP), also known as Phosphatidyl Ethanolamine Binding Protein (PEBP1), is a pivotal modulator of multiple intracellular signaling cascades involved in tumorigenesis, progression, metastasis, and cancer therapy resistance. In recent years, increasing evidence has highlighted the regulatory role of non-coding RNAs, particularly microRNAs (miRNAs), in modulating RKIP expression and activity across various types of cancer. This review aims to comprehensively summarize current knowledge on the post-transcriptional regulation of RKIP by miRNAs, elucidating their impact on tumor biology.For this purpose, a systematic analysis of published experimental studies was conducted, focusing on both solid and hematological malignancies. The review discusses how miRNAs, such as miR-23a, miR-27a, miR-224, miR-181a, and others, directly or indirectly suppress RKIP, contributing to enhanced proliferation, invasion, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) traits, and radioresistance. Additionally, long non-coding RNAs (lncRNAs) like XIST and PEBP1P2 were identified as factors able to modulate RKIP suppression by acting as molecular sponges for miRNAs or stabilizing RKIP transcripts.All the data presented in the manuscript are supported by diverse experimental approaches, including transcriptional analyses, functional in vitro assays (migration, invasion, apoptosis), gain- and loss-of-function experiments, luciferase reporter assays, and in vivo xenograft models, further validating the miRNA-RKIP axis involved in the progression of multiple tumors.In conclusion, this review provides an integrated view of the complex post-transcriptional network governing RKIP regulation in cancer, underscoring the potential of targeting RKIP-associated non-coding RNA axes for innovative therapeutic strategies aimed at halting tumor progression and overcoming treatment resistance.

The oral microbiota plays a pivotal role in maintaining oral health, but its dysbiosis has been increasingly implicated in the development of systemic diseases, including cancer. Emerging evidence highlights the potential contribution of oral microorganisms to carcinogenesis in the oral cavity and distant organs, such as the lungs, pancreas, and genitourinary tract. This review explores the mechanisms through which the oral microbiota influences cancer development and treatment response, mainly driven by microbial translocation, systemic inflammation, immune modulation, and the release of carcinogenic metabolites. Additionally, the review discusses how oral microbiota perturbations interact with host factors, such as diet, systemic diseases, genetics, and cancer therapies, to influence tumor initiation, progression, and response to treatment. A critical analysis of past and emerging literature shows that specific microbial taxa potentially influence tumor progression and immune responses, including Fusobacterium, Porphyromonas, Aggregatibacter and Treponema. The detection of these microorganisms and the study of oral microbiome profiling in cancer care may offer new diagnostic and therapeutic strategies; however, further studies with homogeneous patient populations are needed to fully understand the contributions of oral dysbiosis in cancer development and treatment responses.

Vitamin D plays a key role in immune modulation, cell proliferation, and hormone regulation. Dysregulated testosterone may contribute to breast cancer progression. We investigated whether long-term vitamin D supplementation affects serum testosterone levels in breast cancer survivors. Complete data at baseline, 12, and 24 months were derived from 253 women with early-stage breast cancer participating in the DEDiCa trial and randomized to receive either a high-dose vitamin D to maintain serum 25(OH)D at 60 ng/mL (group A) or a standard dose to maintain serum levels at 30 ng/mL (group B). Serum 25(OH)D levels significantly increased in both groups (p < 0.001). No significant changes in testosterone concentrations were observed between treatment groups over the 24 month treatment period (A: 0.125 to 0.140 ng/mL; B: 0.162 to 0.193 ng/mL; p = 0.682). Baseline serum testosterone levels emerged as the most significant predictor of testosterone trajectories, possibly modulated by hormone-suppressive therapy. These results are reassuring that vitamin D supplementation did not adversely affect testosterone levels in this population of breast cancer survivors and may partially concur with a healthy lifestyle to equilibrate testosterone levels.

Background: Plant-based diets are recommended in guidelines for the prevention of cancer and cardiometabolic diseases, which remain major causes of death in breast cancer survivors (BCS). Since not all plant foods are healthy, we calculated the plant-based dietary index (PDI), healthy (hPDI) and unhealthy (uPDI), and their associations with cardiometabolic targets in BCS. Methods: Baseline dietary and cardiometabolic data were derived from 492 (median age 51, IQR 46–59) female BCS participating in a multicentric lifestyle trial conducted in Italy. Dietary data were collected with 7-day food records. PDI, hPDI, and uPDI were calculated by assigning positive scores to all plant foods, healthy plant foods or less healthy plant foods, respectively, as defined by the literature (scores ranged from 18 to 90). Using logistic or multinomial regression models, we estimated the odds ratios (OR) and the corresponding 95% confidence intervals (CI) between PDIs and cardiometabolic risk factors. Results: The OR of being obese (BMI ≥ 30 Kg/m2) was 0.47 (95%CI: 0.29–0.77), 0.37 (95%CI: 0.22–0.61) and 1.38 (95%CI: 0.83–2.28) with higher PDI, hPDI and uPDI, respectively. The OR of having a large waist circumference (≥88 cm) was 0.64 (95%CI: 0.42–1.00) with higher hPDI. The OR for hypercholesterolemia (≥200 mg/dL) was 1.80 (95%CI: 1.16–2.78) with higher uPDI. The ORs of hypertriglyceridemia (≥150 mg/dL) and metabolic syndrome were 0.38 (95%CI: 0.20–0.71) and 0.59 (95%CI: 0.35–0.97), respectively, with higher PDI. No other significant association was observed. Conclusions: Maintaining cardiometabolic risk factors within normal ranges is clinically relevant in BCS, and this may be more likely when a plant-based diet is consumed, especially if low in unhealthy plant foods.

In a relatively brief period, the mRNA COVID-19 vaccines have saved millions of lives and have considerably contributed to return to normality after the pandemic. More broadly, the development of RNA-based drugs represents a real paradigm shift with promising therapeutic applications. Besides their safety and efficacy, RNA-based drugs are essentially easy to design and manufactured and may therefore be cost effective. At the pharmacological level, the development of RNA-based drugs marks a breakthrough because these drugs can reach previously "undruggable" pharmacological targets. This clearly represents a step toward the possible establishment of personalized treatments for several difficult-to-treat diseases. This review provides an updated, critical, and comprehensive pharmacological analysis of the current RNA therapeutics landscape, including both approved RNA-based drugs and key investigational candidates. We summarize the state of clinical progress, highlighting pharmacological mechanisms, challenges in drug delivery, tolerability, and clinical outcomes. Our comprehensive overview emphasizes the versatility of RNA-based drugs, illustrating their therapeutic application across various diseases such as cancer, neurodegenerative, cardiovascular, metabolic, rare genetic, and infectious diseases. Also, we uniquely explore the concept of RNA-based drugs repurposing, which may leverage shared pathophysiological mechanisms across diseases to accelerate clinical impact.

Recent advances in screening programs and the development of innovative therapeutic strategies have significantly improved the clinical outcomes of cancer patients. However, many patients still experience treatment failure, primarily due to inherent or acquired drug resistance mechanisms. This challenge underscores the urgent need for novel therapeutic targets for the effective treatment of malignancies, as well as cancer-specific biomarkers to enhance early diagnosis and guide interventions. Epigenetic mechanisms, including DNA methylation, have recently garnered growing interest as key regulators of gene expression under both physiological and pathological conditions. Although epigenetic dysregulations are reliable tumor hallmarks, DNA methylation is still not routinely integrated into clinical practice, highlighting the need for further research to translate preclinical findings from the bench to the bedside. On these bases, the present review aims to illustrate the state of the art regarding the role of DNA methylation in cancer, describing the technologies currently available for DNA methylation profiling. Furthermore, the latest evidence on the application of DNA methylation hotspots in cancer diagnosis and prognosis, as well as the impact of epidrugs in cancer care, is discussed to provide a comprehensive overview of the potential clinical relevance of DNA methylation in advancing personalized medicine.

The disruption of the epigenetic patterns and its impact on gene expression is recognized as a critical factor in the initiation and progression of cancer. Altered patterns of DNA methylation, histone modifications, and non-coding RNA expression are distinctive features of tumorigenesis. These dynamic shifts in the epigenetic landscape during oncogenic transformation are intricately linked to tumor heterogeneity, the sustained capacity for self-renewal, and the ability to undergo multi-lineage differentiation. The abnormal reprogramming of cancer stem cells presents a formidable challenge in cancer treatment and drug resistance. However, the reversible nature of epigenetic modifications holds significant potential for developing novel cancer treatments through the targeted inhibition of epigenetic modifiers. Utilizing this approach as a standalone therapy or combined with other anticancer treatments has yielded promising outcomes. In this review, we emphasize the central role of epigenetic dysregulation in cancer pathogenesis, epigenetic changes in the cancer genome, and the latest advancements in cancer therapy, particularly the potential of epigenetic factors as biomarkers for early detection and their application in current cancer treatment modalities.

One of the leading causes of cancer-related death in women is breast cancer (BC). BC is a heterogeneous tumor. Although tissue biopsy is the gold standard for the diagnosis of BC, often tissue specimens are not informative enough about the tumor heterogeneity. The concept of "Liquid Biopsy" has recently emerged as a powerful clinical tool capable of better identifying mutations associated with the presence of primary or metastatic tumors. This article focuses on the clinical applications of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in breast cancer progression, relapse, diagnosis, and treatment response. The most important molecules analyzed in Liquid Biopsy are cfDNA, ctDNA, and CTCs. All these factors may be considered as non-invasive biomarkers for the early diagnosis of BC or to predict the progression and prognosis of patients, including BC recurrence and patients' treatment response. However, the clinical utility of ctDNA analysis and CTCs requires further investigation through better-designed studies to ensure their precision and diagnostic performance. In conclusion, liquid biopsy and ctDNA analysis demonstrate the potential to transform breast cancer management, with applications in screening, monitoring tumor progression, or response to treatment.

MicroRNAs (miRNAs) are important regulators of gene expression and their dysregulation is involved in various diseases, including tumors. Among these, colorectal cancer (CRC) is the result of both genetic and epigenetic alterations with miRNAs playing a key pathogenetic role. Although numerous studies have investigated the most frequently dysregulated miRNAs in CRC, there is still no consensus on the specific role of individual miRNAs in the mechanisms leading to tumorigenesis, tumor progression, and the development of chemoresistance. This lack of clarity highlights the need for a deeper understanding of miRNA functions in CRC. Therefore, this review aims to clarify the role of miRNAs in CRC by examining their involvement in major oncogenic pathways, highlighting key miRNAs implicated in the disease, and exploring their potential as diagnostic biomarkers and therapeutic targets. By providing a comprehensive overview, we hope to shed light on the complex and multifaceted roles of miRNAs in CRC, which could pave the way for more effective CRC monitoring and the development of miRNA-guided therapeutic strategies.

IntroductionHealthy lifestyle behaviors and improved quality of life have been associated with better prognoses in breast cancer survivors. However, sustaining behavioral changes remains challenging; therefore, identifying effective components of lifestyle education programs is essential to enhance adherence, improve quality of life, and facilitate their integration into clinical practice. This study aimed to predict patient adherence to a lifestyle intervention of diet, physical activity, and vitamin D supplementation and to forecast the most frequent Health-Related Quality of Life over the subsequent three measurements.MethodsA total of 316 breast cancer survivors were included in the analysis. Adherence was modeled as a multi-label time series classification task, with compliance recorded on a three-point scale for each treatment component at quarterly intervals over one year. Health-Related Quality of Life was predicted by evaluating first-year adherence data to estimate the mean score over the subsequent three measurements.ResultsThe dataset was split into 70% for training and 30% for evaluation. Random forest classifiers were employed for adherence prediction, achieving accuracy of up to 81%. An XGBoost regressor was used for Health-Related quality of life prediction, and it was compared to a baseline linear regression model. XGBoost demonstrated superior predictive performance, achieving an R-squared value of 0.62.DiscussionOur findings highlight the promise of machine learning techniques in supporting personalized medicine. Advanced predictive models may aid in identifying patients at risk of non-adherence, enabling early interventions, and improving long-term outcomes through tailored lifestyle strategies for breast cancer survivors.

Glioblastoma (GBM) represents an aggressive brain tumor, characterized by intra- and inter-tumoral heterogeneity and therapy resistance, leading to unfavourable prognosis. An increasing number of studies pays attention on the regulation of ferroptosis, an iron-dependent cell death, as a strategy to reverse drug resistance in cancer. However, the debate on whether this strategy may have important implications for the treatment of GBM is still ongoing. In the present study, we used ferric ammonium citrate and erastin to evaluate ferroptosis induction effects on two human GBM cell lines, U-251 MG, with proneural characteristics, and T98-G, with a mesenchymal profile. The response to ferroptosis induction was markedly different between cell lines, indeed T98-G cells showed an enhanced antioxidant defence, with increased glutathione levels, as compared to U-251 MG cells. Moreover, using bioinformatic approaches and analysing publicly available datasets from patients’ biopsies, we found that GBM with a mesenchymal phenotype showed an up-regulation of several genes involved in antioxidant mechanisms as compared to proneural subtype. Thus, our results suggest that GBM subtypes differently respond to ferroptosis induction, emphasizing the significance of further molecular studies on GBM to better discriminate between various tumor subtypes and progressively move towards personalized therapy.

BACKGROUND:Cancer onset and progression are driven by genetic and epigenetic alterations leading to oncogene activation and the silencing of tumor suppressor genes. Among epigenetic mechanisms, DNA methylation (methDNA) is gaining growing interest in cancer. Promoter hypomethylation is associated with oncogene activation while intragenic methDNA can be involved in transcriptional elongation, alternative spicing, and the activation of cryptic start sites. Several genes involved in the modulation of the tumor microenvironment are regulated by methDNA, including the Solute Carrier Family 22 Member 17 (SLC22A17), which is involved in iron trafficking and extracellular matrix remodeling cooperating with the Gelatinase-Associated Lipocalin (NGAL) ligand. However, the exact role of intragenic methDNA in cancer has not been fully investigated. Therefore, the aim of the present study is to explore the role of methDNA in the regulation of SLC22A17 in cutaneous melanoma (CM), used as a tumor model. METHODS:Correlation and differential analyses between SLC22A17 expression and methDNA were performed using the data contained in The Cancer Genome Atlas and Gene Expression Omnibus databases. Functional studies on melanoma cell lines treated with 5-Azacytidine (5-Aza) were conducted to assess the correlation between methDNA and SLC22A17 expression. A validation study on the diagnostic potential of the in silico-identified SLC22A17 methDNA hotspot was finally performed by analyzing tissue samples obtained from CM patients and healthy controls. RESULTS:The computational analyses revealed that SLC22A17 was significantly downregulated in CM, and its expression was related to promoter hypomethylation and intragenic hypermethylation. Moreover, SLC22A17 overexpression and hypermethylation of two intragenic methDNA hotspots were associated with a better clinical outcome in CM patients. The correlation between SLC22A17 methDNA and expression was confirmed in 5-Aza-treated cells. In agreement with in silico analyses, the SLC22A17 promoter methylation hotspot showed higher methDNA levels in CM samples compared to nevi. In addition, the methDNA levels of this hotspot were positively correlated with advanced CM. CONCLUSIONS:The SLC22A17 methDNA hotspot could represent a promising biomarker for CM, highlighting the regulatory role of methDNA on SLC22A17 expression. These results pave the way for the identification of novel epigenetic biomarkers and therapeutic targets for the management of CM patients.