Intestinal diseases are highly prevalent, affecting millions worldwide and significantly contributing to global morbidity. The treatment of complex disorders, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), remains challenging due to multifactorial etiologies, diverse patient responses, and the limitations of current therapeutic strategies. Although the gut microbiota clearly plays a role in regulating the onset of intestinal diseases, few studies have explored the epigenetic factors by which the microbiota contributes to disease development. Here, the latest insights into the molecular mechanisms underlying the bidirectional influence between gut microbiota and epigenetic modifications are discussed, including DNA methylation, histone modifications, non-coding RNAs, and N6-methyladenosine (m6A). Importantly, mechanistic studies based on animal models or human cells have demonstrated that the gut microbiota, and other environmental factors, influence targeted gene expression and activate immune pathways through host epigenetic dysregulation, which are closely associated with the development of IBD and CRC. Furthermore, potential microbiome interventions, including probiotics, prebiotics and postbiotics, fecal microbiota transplantation (FMT), dietary modifications, and phage therapy, have been proposed as innovative therapeutic strategies to correct these abnormal epigenetic patterns associated with the diseases. Overall, addressing microbiome dysbiosis and its epigenetic consequences presents a promising frontier in the treatment of intestinal diseases, offering the potential to not only restore microbial balance but also provide more targeted and personalized therapeutic strategies for better patient outcomes.

Lung cancer is the primary cause of cancer-related mortality, but the molecular mechanisms behind this malignancy remain unclear.

Frequent drug resistance seriously limits the therapeutic efficacy of sorafenib in advanced hepatocellular carcinoma (HCC). Strategies to increase the response to sorafenib are limited, and the underlying mechanism to facilitate such an increase is not entirely understood. Homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) expression is high in HCC, promoting the occurrence and progression of HCC. In this study, we explored the mechanism through which HOTAIR knockdown affects the response of HCC cells to the chemotherapeutic sorafenib.

Radiotherapy is crucial for managing esophageal squamous cell carcinoma (ESCC). This research explored the potential and mechanism of enhancing ESCC radiosensitivity through targeting phosphoglycerate kinase 1 (PGK1).

Obesity induces chronic inflammation and hormonal imbalances that contribute to tumor growth. This study explores the less understood dynamics of tumor-related macrophages under a high-fat diet and its consequent impact on tumor growth, with a focus on elucidating the role of high-fat diets on macrophage behavior in liver cancer.

Significant advancements have been achieved over recent decades in deciphering the molecular mechanisms driving malignant tumor development. Despite this progress, the precise roles of individual genes, their interactions, and the associated signaling pathways involved in tumor proliferation remain insufficiently characterized. Among these pathways, the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK)1/2 and p38, which regulate essential cellular functions such as growth, differentiation, and apoptosis, have garnered considerable research attention. Building on recent insights into MAPK signaling, we identified components closely linked to ERK1/2 and p38 activity and examined changes in their behavior during tumorigenesis. Furthermore, we developed quantifiable metrics to assess ERK1/2 and p38 activity, including the ERK/p38 ratio, a key indicator of tumor cell proliferative or quiescent states, along with activation levels of these signaling pathways. Our findings underscore the potential of ERK and p38-related gene expression and pathway dynamics as biomarkers for predicting clinical outcomes and informing tailored therapeutic approaches.

Murine double minute 2 (MDM2) is an oncogene that plays a crucial role in regulating the activity of the tumor suppressor protein p53. By binding to p53, MDM2 promotes its degradation, thus promoting the malignant proliferation. The MDM2-p53 interaction has thus generated interest as a therapeutic target, particularly in some sarcomas characterized by the amplification of the MDM2 gene. In this manuscript, we provide an overview of the current and emerging targeted therapies for MDM2-amplified sarcomas.

Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.

Lung squamous cell carcinoma (LUSC) remains a major clinical challenge due to its aggressive nature and poor prognosis. Enhancer of zeste homolog 2 (EZH2), a key epigenetic regulator within the polycomb repressive complex 2 (PRC2), has emerged as a critical player in cancer progression. This study investigates the dual role of EZH2 in driving tumor proliferation and modulating the immune microenvironment in LUSC. Bioinformatics analysis revealed significant upregulation of EZH2 in LUSC tissues compared with normal counterparts, with high EZH2 expression correlating with improved overall survival in early-stage patients. Functional assays in EZH2 knockout LUSC cell lines demonstrated reduced tumor cell proliferation, migration, and invasion alongside enhanced apoptosis and cell cycle arrest. Furthermore, in vivo studies using an EZH2 knockout mouse model showed decreased tumor growth and increased immune cell infiltration, including CD8+ T cells, macrophages, and neutrophils. These findings highlight the pivotal role of EZH2 in promoting tumor progression and orchestrating immune evasion mechanisms in LUSC. Given its multifaceted influence on tumor biology and the immune landscape, EZH2 represents a promising therapeutic target for improving outcomes in LUSC patients. Future studies should explore the therapeutic potential of targeting EZH2 to enhance immune responses and overcome resistance to current treatments.

AMBRA1 is associated with a variety of pathological processes in cancer cells, but may have different functions in different tumour microenvironments or genetic backgrounds. In this study, the function and regulatory mechanisms of AMBRA1 were explored in the progression of non-small cell lung cancer (NSCLC). The abnormally expressed miRNAs in AMBRA1-overexpressed and differentially expressed genes in miR-1178-knockdown NSCLC cells were validated by RNA sequencing. Cell viability, proliferation, invasion, apoptosis, and cell cycle were tested through Cell Counting Kit-8 (CCK-8), EdU, colony formation, transwell, and flow cytometry. A mouse tumour xenograft model was conducted to assess the roles of the AMBRA1-miR-1178 axis on NSCLC progression in vivo. AMBRA1 overexpression suppressed NSCLC cell proliferation and invasion, while promoting apoptosis and G0/G1 phase cell cycle arrest in vitro, and inhibited tumour growth in vivo. RNA sequencing revealed miR-1178 as a target of AMBRA1. miR-1178 overexpression partially weakened the suppressive function of AMBRA1 on cell malignant biological behaviours. p53 and CDK2 were confirmed as the downstream targets of miR-1178. Silencing p53 or overexpressing CDK2 reversed the repressive effects of AMBRA1 on the development of NSCLC cells. AMBRA1 may suppress the malignant phenotype of NSCLC cells via regulating the miR-1178-p53-CDK2 signalling pathway.

Colorectal cancer (CRC) is one of the most common malignancies worldwide, and its complex pathogenesis and significant tumor cell heterogeneity remain major challenges. With the rapid development of single-cell sequencing technology, we can now delve deeper into the cellular composition and dynamic changes within the tumor microenvironment, revealing cellular interactions and their potential roles in tumorigenesis.

Programmed cell death (PCD) refers to a regulated and active process of cellular demise, initiated by specific biological signals. PCD plays a crucial role in the development, progression, and drug resistance of uterine corpus endometrial carcinoma (UCEC), making the exploration of its relationship with UCEC prognosis highly clinically relevant.

Succinylation, a key post-translational modification, plays a crucial role in metabolic regulation and tumor progression. However, its influence on the tumor immune microenvironment and its prognostic implications remain unclear. A systematic pan-cancer analysis of succinylation-related molecular activities is needed.

The role of gut microbiota, especially viruses, in colorectal cancer (CRC) pathogenesis remains unclear. This study investigated the interplay between gut microbiota and CRC development. We developed a viral/bacterial sequence analysis pipeline to reanalyze gut metagenomic datasets from eight CRC studies. A multisample co-occurrence network was constructed to delineate microbiota species interconnections. Our analysis confirmed dysbiosis in CRC patients and revealed enrichment of viral species, particularly those hosted by Lactococcus and Escherichia. These viruses were identified as central hubs in the multikingdom interaction network. We developed a network-based model using single sample networks (SSN) that distinguished CRC patients from controls with an area under the curve (AUC) of 0.93. Models combining relative abundance and SSN assessment achieved an AUC of 0.97, outperforming SSN-based models without viral data. This study highlights the crucial role of viruses in the gut microbiome network and their potential as targets for CRC prevention and intervention. Our approach offers a new perspective on noninvasive diagnostic criteria for CRC.

Despite rapid advances in HCC therapy, surgical resection is still the most effective treatment. However, postoperative relapse develops in a large population and the mechanism remains to be explored.

To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations.

BRCA2 is a causal gene for hereditary breast and ovarian cancer (HBOC) syndrome. However, its association with other cancers and interplay with polygenic scores (PGS) remains unclear.

Cutaneous squamous cell carcinoma (SCC) is known for its stepwise progression from healthy skin to premalignant actinic keratosis (AK), followed by a malignant transformation to SCC. Unfortunately, less attention has been paid to changes in gene expression in the tumour microenvironment during this process. We retrospectively selected early-stage cutaneous SCC tissue samples containing both invasive and premalignant portions and conducted a spatial transcriptomic experiment using a NanoString GeoMx Digital Spatial Profiler (DSP). First, we selected invasive and premalignant regions of interest (ROIs) for each tissue. We then compared the gene expression patterns between the two portions (invasive versus premalignant) of the three segments: tumour cells, immune cells and fibroblasts, in each ROI. As a result, early-stage cutaneous SCC tissue samples from 17 patients were selected for this study. We identified 29, 14 and 15 differentially expressed genes (DEGs) between the invasive and premalignant portions of the tumour cells, immune cells and fibroblasts, respectively. The top three genes with the highest absolute log2 fold-change were CCDC88C, GJD3 and COMP in tumour cells; SVEP1, TSLP and PPP2R5C in immune cells; and SPAG6, PPP1CA and CCDC68 in fibroblasts. Notably, several genes, such as COMP, SVEP1 and SPAG6, have been linked to the development and function of cancer-associated fibroblasts. Functional enrichment analysis revealed that several pathways were altered in tumour and immune cells. In conclusion, distinctive changes in gene expression patterns were observed as AK progressed to SCC.

Esophageal cancer (EC) is the ninth most common cancer worldwide that kills about 300,000 people each year. Esophageal squamous cell carcinoma (ESCC) is the main type of EC. Long non-coding RNAs (lncRNAs) have been proven to be severely dysregulated in EC, but the functions of more lncRNAs still need to be explored.

Between 5 and 8% of the general population carry a constitutional methylation of the BRCA1 promoter ("epimutation"). Several studies have suggested that these BRCA1 epimutations confer an increased risk of breast cancer, in particular triple-negative breast cancer (TNBC), with an earlier onset than in the general population. However, those studies relied on very few patients with early-onset TNBC. Using specific Methylation-Sensitive High-Resolution Melting, we assessed BRCA1 epimutation prevalence in a large cohort of 112 early-onset (≤ 30 years-old) TNBC patients with no genetic cancer-predisposing pathogenic variants (PVs). We compared this cohort to 87 early-onset TNBC patients carrying cancer-predisposing PVs and to 93 late-onset (≥ 70 years-old) TNBC with no cancer-predisposing PVs. We observed a high prevalence of BRCA1 epimutation in blood cells from early-onset TNBC patients with no cancer-predisposing PVs (38/112, 33.9% [95% confidence interval: 25.4-43.6%]) as compared to early-onset patients with cancer-predisposing PVs (1/87, 1.1% [0.1-7.1%], p value < 0.001) and late-onset patients (11/93, 11.8% [6.3-20.6%], p value < 0.001). These differences remained significant when restricting to epimutations with low variant epiallele frequencies (VEF under 1%). Our results highlight the role of constitutional BRCA1 epimutations in early-onset TNBC risk and call for their integration into multifactorial models used to compute personalized breast cancer risk.