Overcoming resistance to poly (ADP-ribose) polymerase (PARP) inhibitors is an urgent challenge for ovarian cancer treatment. Here, we investigated RECQL1, a RecQ helicase involved in homologous recombination repair, as a potential target for overcoming PARP inhibitor resistance in this disease. Patients with platinum-sensitive recurrent ovarian cancer treated with the PARP inhibitor olaparib between March 2018 and December 2021 were included. Immunohistochemistry assays were conducted to assess RECQL1 protein expression patterns in surgically resected ovarian cancer tissues. The effect of RECQL1 knockdown on olaparib resistance was evaluated in vitro using ovarian cancer cells transfected with an anti-RECQL1 siRNA. Among 44 patients, those with no response to olaparib had significantly higher RECQL1 expression levels compared with responders (P = 0.020). Kaplan-Meier curves showed significantly shorter overall survival in the high RECQL1 expression group than in the low expression group (median, 26.0 months vs. not reached; P = 0.027). Multivariate analysis revealed high RECQL1 expression to be a significant prognostic factor for shorter overall survival (P = 0.036). RECQL1 knockdown significantly enhanced the sensitivity to olaparib in two ovarian cancer cell lines. Overall, RECQL1 plays a critical role in PARP inhibitor resistance and is a promising therapeutic target to improve ovarian cancer patient outcomes.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Despite its high mortality rate, the development of effective targeted therapies remains challenging due to an incomplete understanding of their underlying molecular mechanisms. Here, we highlight a pivotal role for IL27/IL27RA signalling in driving HCC progression. Our findings reveal that IL27RA is significantly upregulated in HCC. Both in vitro and in vivo experiments demonstrated that IL27RA knockdown markedly inhibited the proliferation and metastasis of HCC cells. Mechanistic investigations show that IL27RA promotes HCC progression through activation of the STAT3/TGF-β signalling pathway. Specifically, STAT3 enhances TGFβR1 protein stability by increasing the transcription of USP15. Notably, IL27RA regulates the proliferation and metastatic potential of liver cancer cells in a TGFβR1-dependent manner. In summary, these results underscore the critical role of IL27RA in HCC progression, identifying it as a promising therapeutic target for HCC treatment.

Approximately half of high-grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination deficiency (HRD) with characteristic genomic rearrangements. However, the impact of HRD on centromeres and transposable elements remains largely unexplored in HGSOC since conventional short-read sequencing is unable to interrogate these repetitive regions. We employed Oxford Nanopore long-read sequencing (LRS) to investigate genomic and epigenetic alterations in these regions. Pre-treatment archival cryopreserved tumor and matched blood samples were obtained for six patients with HGSOC. High-molecular-weight DNA was sequenced using Oxford Nanopore R10.4 flow cells and aligned to both the GRCh38 and the telomere-to-telomere T2T-CHM13 reference genome. Pathogenic gene mutations, allele-specific copy number variations, structural variants, and CpG methylation were analyzed. All six tumors had pathogenic TP53 mutations. Two carried germline BRCA1 mutations, while three showed CCNE1 amplifications. HRD scores and mutational signatures associated with HRD were elevated in the BRCA1-mutated tumors. Centromeric regions were significantly hypomethylated in tumors and their methylation profiles distinctly separated HRD tumors from non-HRD tumors. LINE1 and ERV transposable elements showed marked hypomethylation in tumors without germline BRCA1 mutations. Chromosome arm-specific telomere lengths were significantly shortened in tumors. Allele-specific hypermethylation in the TERT hypermethylated oncological region was detected in three tumors. LRS uncovered HRD-related genomic and epigenomic alterations in previously inaccessible repetitive regions of HGSOC, including centromeric and transposable element hypomethylation. These findings highlight the potential of such abnormalities as novel biomarkers for HGSOC and warrant further application of the methods to larger cohorts in future studies.

Glycolysis is crucial for maintaining cancer stemness. This study demonstrated the role of the glycolytic enzyme alpha-enolase (ENO1) in glycolysis and stemness in gastric cancer (GC). High ENO1 expression was associated with poor prognosis and promoted malignant phenotypes and stem-like characteristics in patients with GC. Mechanistically, ENO1 directly stimulates lactate and ATP production by regulating glycolysis, affecting lactate homeostasis and intracellular ATP pools, and coregulating the AMPK/mTOR and PI3K/AKT signaling pathways. This ultimately drives GC stemness, epithelial‒mesenchymal transition (EMT)-related marker expression, self-renewal, migration, and invasion. Notably, the increase in the intracellular ATP pool can directly activate the PI3K/AKT pathway in a concentration-dependent manner, thereby further stimulating glycolysis to form a positive feedback loop. The functional role of lactate depends on the simultaneous presence of glycolysis-derived ATP to synergistically activate the PI3K/AKT pathway. Lactate homeostasis can also promote tumor stemness by increasing overall plactylation levels. Furthermore, pharmacological studies revealed that metformin combined with copanlisib significantly inhibited tumors by blocking the energy metabolism pathways PI3K/AKT and AMPK/mTOR. Our findings are the first to reveal the multifaceted role of ENO1 in mediating intracellular signaling and metabolic regulation to enhance stemness in GC. By establishing cell models with varying metabolite concentrations, we identified differential regulation of the PI3K/AKT and AMPK/mTOR pathways through lactate homeostasis and intracellular ATP pools, further confirming the metabolic crosstalk mechanism. Rationally, targeting multiple nodes along the ENO1-ATP/lactate-AMPK/PI3K/AKT-mTOR axis may be effective for GC treatment, as indicated by the significant suppression of tumor growth by metformin (which inhibits ATP production) plus syrosingopine (which disrupts lactate homeostasis). In conclusion, the complex interplay between metabolism and tumor stemness offers novel therapeutic directions and potential treatment strategies for GC.

Chromatin remodelers are vital for cellular functions like transcription by modulating nucleosome accessibility. Although biological condensates regulate these processes, the contribution of chromatin remodelers to condensation mechanisms remains poorly understood. Here, we examine the role of the E1321 frameshift mutation in CHD1, a chromatin remodeler, which is often targeted in cancers. This mutation truncates CHD1's C-terminus, leading to an oncogenic transcriptome and promoting tumorigenesis. This is due to the loss of an intrinsically disordered region (IDR) crucial for forming CHD1 condensates. These condensates are facilitated by the presence of H3K4me3-modified nucleosomes and RNA, guided to active promoters to regulate gene expression. Furthermore, CHD1 condensates contain long noncoding RNA and histone-modifying proteins, revealing an integral role for CHD1 condensates in epigenetic regulation. Among these components, MLL mutations frequently co-occur with CHD1 mutations in various cancers, suggesting a shared pathway in cancer development. These findings underscore the importance of chromatin remodeler condensation as a regulatory hub in various cellular processes and tumor suppression.

Pre-transcriptional regulation through alternative promoter usage is a critical yet underexplored mechanism influencing gene expression in Triple-Negative Breast Cancer (TNBC), a highly aggressive and heterogeneous breast cancer subtype. While short-read RNA sequencing data are widely available, they offer limited resolution in accurately capturing transcript-level diversity. To overcome this, we focused on promoter-level quantification to infer active promoter usage and investigate transcriptional regulation dynamics in TNBC. Using RNA-seq data from 360 TNBC tumors and 88 adjacent normal tissues, we identified TNBC-specific and subtype-enriched Active Alternative Promoters (AAPs). Integration with H3K4me3 and H3K27ac ChIP-seq data confirmed a key promoter switching event in the HDAC9 gene: the promoter pr1077 was downregulated while another promoter pr1079 was specifically activated in TNBCs. This switch was epigenetically supported by differential enrichment of histone marks, implicating HDAC9 promoter switching as a tumor-specific regulatory mechanism. Further, we identified subtype-specific alternative promoters in TNBC, including basal subtype-enriched activity of SEC31A and reduced promoter usage of AKAP9, which were not reflected at the gene expression level but were evident through promoter-level analysis. Next, we identified alternative promoters of HUWE1 and FTX as independent predictors of relapse-free survival (RFS) in TNBC. Their prognostic value remained significant after adjusting for copy number alterations and transcriptomic subtypes. A 4-feature model integrating these two promoter activities with two clinical variables (Tumor size, Ki67 index) achieved an AUROC of 0.73 and improved patient risk stratification, with a Net Reclassification Improvement (NRI) of 0.40-0.48 over the clinical-only model, underscoring the potential of promoter activity as a biomarker in TNBC.

Pseudouridine (Ψ) is a widespread RNA modification in various RNA species, including rRNA, tRNA, snRNA and mRNA. Ψ plays a crucial role in RNA metabolism, where it regulates pre-mRNA splicing and affects protein translation. Whether and how Ψ may regulate transcription have not been adequately studied. Here, we report that pseudouridine synthase 7 (PUS7) can mediate pseudouridylation of 7SK small nuclear RNA (snRNA), a regulator of RNA polymerase II (Pol II) promoter-proximal pausing. PUS7 loss leads to hypo-pseudouridylation of 7SK, which promotes dissociation of the positive transcription elongation factor b (P-TEFb) complex from 7SK. The release of P-TEFb from 7SK increases serine 2 phosphorylation (Ser2P) in the RNA Pol II C-terminal domain and enhances transcription elongation. In colorectal cancer (CRC) cells, the Ψ level of 7SK can be modulated by PUS7, or by site-specifically targeted pseudouridylation through dCas13b-guided system. Hypo-pseudouridylation on 7SK upon PUS7 depletion promotes KLF6/DDIT3-mediated cell apoptosis and sensitizes CRC cells to 5-FU.

Single-cell studies have discovered abundant cancer-associated genetic/phenotypic changes in non-cancerous cells, strikingly contrasting with the infrequency of cancer. Epidemiological data have revealed decades-long plateaus of breast cancer incidence in the contralateral breast and twins/relatives following the first/proband's diagnosis, unlike the well-known continuous increase of population-level incidence with age, the latter ostensibly attributable to the successive accumulation of multiple genetic/epigenetic changes necessary for transformation. Here, we explain these contradicting observations by differentiating cell-level, individual-level, and population-level evidence. First, we show the same decades-long incidence plateau for renal-cell carcinoma in the contralateral kidney following the first diagnosis, expanding the individual-level evidence from breast cancer. We then consider somatic evolution and cell competition in stem-cell compartments and their bounded nature in ageing as a hypothesized mechanism for the abundant cancer-associated cell-level changes and the prolonged constancy of individual-level incidence. Individual-specific propensity with heritable/familial components underlies this process, with which we show congruence between individual-level's constant incidence vs. population-level's increasing incidence. The resulting postulate, an extension of one by Peto and Mack 25 years ago, distinguishes the last multistage "hit" as the critically rate-limiting event in carcinogenesis. Its supporting evidence calls for a reappraisal of the precise nature of multistage carcinogenesis in cancer biology.

Cancer diagnosis at an early stage is crucial for improving overall health outcomes. However, existing cancer diagnostic techniques are mostly invasive and tend to identify the disease only in its advanced stages. MicroRNAs (miRNAs), which are small non-coding RNAs involved in gene expression regulation, are stable in serum as circulating miRNAs and have potential as non-invasive biomarkers. However, their application in pan-cancer diagnostics and therapeutics is still largely unexplored. We developed Serum-MiR-CanPred, a deep learning framework using a multi-layer perceptron (MLP) trained on serum miRNA expression data from 20,271 samples across 12 cancer types and healthy controls from GEO databases. The model achieves robust pan-cancer classification (AUC = 96.87%, accuracy = 96%) with a consensus set of 88 miRNAs. Validation using external datasets demonstrated its generalizability and clinical potential. SHapley Additive exPlanations (SHAP) identified hsa-miR-5100 as a key biomarker, dysregulated in cancers including lung, bladder, and gastric carcinomas. Pathway analysis linked these miRNAs to cancer-related processes like VEGFA-VEGFR2 signalling. Molecular docking of pre-mir-5100 with rDock, identified AC1MMYR2 as a potential high-affinity ligand, with binding stability confirmed by molecular dynamics simulations using GROMACS In conclusion, Serum-MiR-CanPred integrates explainable AI with molecular modelling, advancing miRNA-based diagnostics and drug discovery for precision oncology.

Pediatric diffuse midline gliomas with the Histone 3 lysine 27-to-methionine mutation (H3K27M-pDMG) are aggressive brain tumors characterized by intrinsic resistance to radiation therapy, the current standard of care. These tumors exhibit significant intratumoral heterogeneity, with distinct subclonal populations likely contributing to therapy resistance. Emerging evidence suggests that small extracellular vesicles (sEV) mediate oncogenic signaling within glioma stem cell populations, yet their role under radiation-induced stress remains poorly understood. In this study, we characterized sEV uptake dynamics among H3K27M-pDMG tumor cells, identified key sEV surface proteins, and demonstrated that sEVs derived from radioresistant (RR) H3K27M-pDMG cells confer radioprotective effects on radiosensitive tumor cells. Molecular profiling revealed that RR-sEVs carry proteins, microRNAs (miRNAs) and metabolites associated with glycolysis, oxidative phosphorylation and DNA repair. Upon uptake, RR-sEVs reprogrammed recipient cells by altering gene expression and metabolic pathways, and enhancing DNA repair and survival following radiation exposure. These findings provide insights into the role of sEV-mediated intratumoral communication as a contributor to radiation resistance in H3K27M-pDMG and suggest potential therapeutic strategies to disrupt this process and enhance radiation efficacy.

Tumour-derived extracellular vesicles (TEVs) play a crucial role in cancer progression, metastasis and therapy resistance but their distinct profiles across different cancer stages and molecular subtypes remain underexplored. This study initially analysed TEVs from all CMS subtypes in colorectal cancer (CRC) cells and continued focusing on the epithelial (CMS2) and mesenchymal (CMS4) subtypes using six cell lines and clinical samples. Investigation of the cargo of vesicles secreted by the two subtypes revealed significant differences in mRNA, miRNA, and protein profiles between the two subtypes. Notably, CMS2 predominantly secreted smaller, Tetraspanin-8 (TSPAN8) enriched EVs, while CMS4 produced both larger and smaller EVs, enriched in TSPAN4. This underscores the complexity of vesicle heterogeneity between these subtypes. Additionally, we assessed miRNA profiles from plasma-derived bulk TEVs in CRC patients. Our integrative analysis identified a subtype-specific miRNA signature, indicating that TEVs from CMS2 and CMS4 cells can be detected in circulation and may serve as potential diagnostic tool for CRC.

RNA modifications play critical roles in cellular homeostasis and development by regulating gene expression, RNA metabolism, and translation. Their dysregulation contributes to the development of human diseases, including cancer. 3-methylcytidine (m3C) primarily occurs in transfer RNA, where it regulates translation, stem cell pluripotency, and mitochondrial function. m3C has also been detected in polyadenylated (poly[A]) RNA by mass spectrometric analysis; however, its transcriptome-wide distribution and functions remain unknown because of its low abundance and technical challenges. Here, we show that METTL2A, an m3C writer, is upregulated and associated with poor prognosis in pancreatic cancer tumors, while also being essential for pancreatic cancer cell proliferation. Using comparative nanopore direct RNA sequencing, we identify potential METTL2A-mediated m3C sites in poly(A) RNA. These m3C sites are mapped in both messenger RNA and mitochondrial RNA and are enriched in the CC motif and coding sequences. METTL2A knockdown alters expression of S100A4 mRNA isoforms, which contains METTL2A-mediated m3C sites. Notably, many transcripts with METTL2A-mediated m3C sites are upregulated upon METTL2A knockdown. We reveal the transcriptome-wide presence of m3C sites in poly(A) RNA and suggest their potential roles in regulating gene expression.

The epidermal growth factor receptor (EGFR) is a key driver in bladder cancer progression. This study investigated the tumor-suppressive role of miR-124-3p and its regulatory effect on EGFR.

The adverse side effects associated with chemotherapeutic agents have prompted the exploration of natural compounds as adjuvants to chemotherapy, offering more effective therapeutic alternatives. Licoricidin, a bioactive constituent of licorice, possesses diverse pharmacological properties. However, the antitumor mechanisms underlying the therapeutic effects of Licoricidin combined with paclitaxel in cervical cancer remain unclear and further investigations are warranted.

Non-small cell lung cancer (NSCLC) accounts for most lung cancer cases and has high mortality, especially in advanced stages. MicroRNAs (miRNAs) and immunoregulatory genes such as suppressor of cytokine signaling 3 (SOCS3) play critical roles in cancer progression and immune evasion. miR-30d-5p is known to act as a tumor suppressor by down-regulating oncogenic pathways, while SOCS3 modulates immune responses and tumor microenvironment interactions. This study aimed to evaluate the clinical relevance of circulating miR-30d-5p and serum SOCS3 protein levels in patients with NSCLC versus healthy controls and to assess their potential as diagnostic and prognostic biomarkers.

This study investigated the prognostic impact of human epidermal growth factor-2 receptor (HER2) status on the survival of patients with metastatic triple-negative breast cancer (TNBC).

Zinc finger CCCH-type containing 12A (ZC3H12A), also known as monocyte chemotactic protein-induced protein 1, has emerged as having a potential role in the landscape of some human cancer types, contributing to anti-tumorigenesis through signaling pathways of inflammation, apoptosis, autophagy and angiogenesis. However, its specific impact on the prognosis of oral squamous cell carcinoma (OSCC) remains to be investigated.

Mixed histological lung cancers, such as combined small-cell carcinoma (SCLC) and adenocarcinoma, are rare and often present diagnostic and therapeutic challenges due to intratumoral heterogeneity. In such cases, conventional tissue biopsies may fail to detect key genetic alterations, especially when sampling is limited or affected by tumor evolution. Liquid biopsy has emerged as a complementary approach capable of capturing broader genomic information in a non-invasive manner.

Aging results in diminished physiological functions and reduced stem cell activity, driving research into cellular mechanisms and natural compounds that support tissue regeneration and improve skin health. Marine algae, particularly Caulerpa lentillifera (sea grape), are rich in sulfated polysaccharides and widely used in the food and cosmetics industries due to their diverse biological properties, including UV protection, anti-inflammatory effects, and hydration.

Sideroflexin 4 (SFXN4) is important for mitochondrial function and relatively unstudied in relation to cancer. The aim of the study was to examine the SFXN4 gene and protein expression in patients with colorectal cancer (CRC) to identify associations with various clinicopathological parameters and evaluate the diagnostic and prognostic significance.