Citrullination enhances the tumor-suppressor function of p53 by redirecting its gene target selectivity.

Circulating tumour DNA (ctDNA) methylation analysis, a noninvasive liquid biopsy technique, has shown great potential in cancer diagnosis and treatment. This article reviews the progress of research in ctDNA methylation detection. It summarises the advantages and potential of ctDNA methylation analysis, suggesting that it holds the key to unlocking new chapters in cancer diagnosis and therapy.

Intronic PolyAdenylation (IPA) is an important post-transcriptional mechanism that can alter transcript coding potential by truncating translation regions, thereby increasing transcriptome and proteome diversity. This process generates novel protein isoforms with altered peptide sequences, some of which are implicated in disease progression, including cancer. Truncated proteins may lose tumor-suppressive functions, contributing to oncogenesis. Despite advancements in Alternative PolyAdenylation (APA) analysis using RNA-seq, detecting and quantifying novel IPA events remains challenging. To address this, we developed IPScan, a computational pipeline for precise IPA event identification, quantification, and visualization. IPScan has been benchmarked against existing methods using simulated data, different human and mouse cell lines, and TCGA (The Cancer Genome Atlas) breast cancer datasets. Differential IPA events under different biological conditions were quantified and validated via qPCR.

Inflammation is associated with sickness behavior symptoms in patients receiving chemotherapy. However, its impact on symptom burden (i.e., higher number of concurrent symptoms) requires evaluation. Study purposes were to evaluate for differentially perturbed immune and/or inflammatory pathways between outpatients receiving chemotherapy with Low (i.e., 0-8) versus High (i.e., 16-38) symptom burden and identify common immune and/or inflammatory pathways among symptom burden and single sickness behavior symptoms.

The mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in tumorigenesis and immune regulation. However, its prognostic significance in lung adenocarcinoma (LUAD) remains poorly defined. This study aimed to construct a robust MAPK-related gene (MRG) signature by integrating multi-omics data to enhance risk stratification and therapeutic guidance in LUAD.

Long non-coding RNAs (lncRNAs) play important roles in the occurrence and development of multiple cancers, but the role of lncRNAs in breast cancer has not been fully elucidated. We integrated data mining, bioinformatics analysis, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to pinpoint key lncRNAs that modulate breast cancer development. In vitro functional assays evaluated the impact of lncRNA 11β-hydroxysteroid dehydrogenase type 1-antisense RNA 1 (HSD11B1-AS1) on breast cancer cells proliferation, migration, and invasion. Interactions between HSD11B1-AS1 and Glyoxylate Reductase 1 Homolog (GLYR1) within breast cancer cells were confirmed through bioinformatics prediction, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. Rescue experiments substantiated the involvement of GLYR1 in breast cancer advancement through the regulation of HSD11B1-AS1. HSD11B1-AS1 is markedly downregulated in breast cancer tissues and cell lines, correlating with an unfavorable prognosis for patients. Functional assays revealed that the suppression of HSD11B1-AS1 notably amplified the proliferation, migration, and invasive capabilities of breast cancer cells. Conversely, the overexpression of HSD11B1-AS1 significantly curtailed the proliferation, migration, and invasion of breast cancer cells. Mechanistically, GLYR1 directly binds to the HSD11B1-AS1 promoter and repressess its transcription, thereby enhancing the malignant behaviors of breast cancer cells, including proliferation, migration, and invasion. GLYR1-mediated suppression of HSD11B1-AS1 drives breast cancer progression. The GLYR1/HSD11B1-AS1 axis may represent a promising avenue for diagnostic biomarkers and therapeutic intervention in breast cancer.

Accumulating evidence indicates that circular RNAs (circRNAs) play a pivotal role in tumor initiation and progression. However, their expression profiles and functional roles in serum exosomes from nasopharyngeal carcinoma (NPC) remain undefined. This study aims to explore the expression patterns, biological functions, and potential prognostic significance of circRNAs in serum exosomes of NPC. CircRNA expression profiles in serum exosomes were analyzed using a circRNA microarray, along with mRNA and miRNA data from RNA sequencing and the Gene Expression Omnibus (GEO). Initially, the competitive endogenous RNA (ceRNA) regulatory network was established by integrating multiple online databases and bioinformatics tools. Subsequently, LASSO and COX regression analyses were used to construct and validate the prognostic model. Additionally, the immunological characteristics analysis was conducted using CIBERSORT. qRT-PCR was performed to further validate the expression levels of circRNAs. Finally, a total of 314 differentially expressed circRNAs were identified in NPC serum exosomes, and a ceRNA regulatory network was constructed for three of them. The prognostic risk model effectively predicts outcomes for NPC patients. Immune cell infiltration analysis revealed a significant increase in M1-type macrophages in the high-risk group, whereas the low-risk group exhibited elevated levels of resting mast cells and activated CD4 memory T cells. Additionally, immune checkpoint gene analysis revealed significantly higher expression of CD276 and ICOSLG in the high-risk group compared to the low-risk group. Our findings suggest that serum exosomal circRNAs may be promising prognostic biomarkers in NPC, warranting further functional and clinical validation.

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, with peritoneal metastasis commonly seen in advanced cases. Based on RNA-sequencing data from GEO dataset, we focused on the role of SMOC2, SPARC-related modular calcium-binding protein 2, in regulating GC progression and peritoneal metastasis. Our analysis revealed that high SMOC2 expression was associated with poor survival in the population with peritoneal metastases. Functional assays demonstrated that SMOC2 promotes the migration and invasion of GC cells in vitro. In vivo experiments using a mouse peritoneal metastasis model showed that SMOC2 promoted the peritoneal metastasis of GC cells. Additionally, in a co-culture system of GC cells and endothelial cells, SMOC2 overexpression in GC cells promoted the proliferation, migration, and tube formation capability of endothelial cells. Mechanistically, SMOC2 knockdown reduced GSK-3β phosphorylation and nuclear β-catenin levels, accompanied by decreased expression of downstream target genes. These results indicate that SMOC2 promotes GC peritoneal metastasis involving Wnt/β-catenin pathway modulation. In conclusion, our findings highlight SMOC2's significant role in GC progression, potentially involving Wnt/β-catenin pathway modulation and angiogenesis. These results position SMOC2 as a potential prognostic biomarker and therapeutic target for GC peritoneal metastasis.

This study aimed to identify key genes regulating plasma cell (PC) infiltration in kidney renal clear cell carcinoma (KIRC) and construct a novel prognostic model for predicting KIRC. Clear cell renal cell carcinoma is the most common malignant tumor type of the kidney, with an increasing incidence rate and low survival rates in advanced patients. Plasma cells (PCs), as terminally differentiated B cells, produce highly specific antibodies that effectively target and kill tumors through the antibody-dependent cellular cytotoxicity (ADCC) mechanism. Growing evidence has shown that PC infiltration is closely associated with the progression of various malignant tumors, including ccRCC. Therefore, identifying PC infiltration-related biomarkers is of great significance for the prognosis and treatment of ccRCC patients. Machine learning was used to determine PC-related key genes in KIRC patients. A prognostic model termed PC score was developed using TCGA and ArrayExpress data and validated in external cohorts. The molecular background, immune characteristics, and drug sensitivity of the high PC score group were evaluated. Single-cell sequencing was employed to assess the expression of hub genes in KIRC patients. We identified 9 hub genes associated with PC infiltration, including 3 risk genes (ADAM8, KCNN4, and TCIRG1) and 6 protective genes (RAG1, ATPEV1D, CDKL2, RUNDC3B, SLC30A9, and PPARGC1A), and constructed a PC score based on these key genes. Older age, advanced TNM stage, and higher PC score were independent predictors of shorter overall survival. A nomogram model integrating age, stage, and PC score showed significantly higher predictive value than staging alone (P < 0.01). The high PC score group exhibited a higher abundance of immune cells (e.g., activated B cells, activated CD8 + T cells) in the tumor microenvironment. Drug sensitivity analysis revealed that tyrosine kinase inhibitors (e.g., ceritinib, imatinib) potently inhibited cancer cell lines in the high PC score group, while inhibitors like acalabrutinib were effective in the low PC score group. Patients with higher risk scores showed greater sensitivity to ofloxacin and cortivazol (a cortisol hormone). Expression of hub genes in KIRC patients was validated using a local cohort and single-cell sequencing. We identified key genes regulating PC infiltration in KIRC and proposed a predictive model that effectively identifies high-risk KIRC patients.

CD151 belongs to the tetraspanin family and is a transmembrane glycoprotein that forms a complex with integrins. The complex is involved in cancer cell adhesion, growth, migration, and metastasis. Previous studies have shown that CD151 plays distinctly different roles in different types of cancer. Concerning this, we attempted to elucidate the roles that the N-glycosylation of CD151 plays in cell behavior. The expression of CD151 was diverse in different types of cancer cells and was very low in the human breast cancer cell line MCF-7. To clarify the roles of N-glycosylation, we established wild-type CD151 (CD151/WT)-expressing cells and CD151-non-glycosylation mutant (CD151/NQ)-expressing cells in MCF-7 cells, and we found that the tumor growth of CD151/WT was increased, while the invasion activity of CD151/NQ cells was dramatically enhanced without an increment of the cell-surface expression of integrin β1. We also analyzed the glycan structure of CD151 and found that the N-glycan structure of CD151/WT was rich in oligomannose, which is potentially involved in the interaction with integrins according to 3D structural models. In addition, gene expression analyses using public genomics data sets showed that invasive breast cancers exhibit low expression levels of the STT3B gene. STT3B is a key player in the production and modification of N-glycans, and a low level of STT3B therefore results in a predominant expression of non-glycosylated CD151 and in the accumulation of oligomannose-type glycans in CD151. The results suggest that the expression of the non-glycosylated form of CD151 confers an invasive phenotype to cancer cells, and as such, it could be a therapeutic target to block metastasis in breast cancer.

Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer (ESCA). ESCC is one of the malignancies with high incidence and mortality rates. Studies have found that laminin subunit alpha 3 (LAMA3) functions as an oncogene in a variety of cancers. SPI1 is highly expressed in ESCC, but whether LAMA3 and SPI1 regulate the development of ESCC is still unclear. In this study, bioinformatics analysis tools were used to predict the expression of LAMA3 and SPI1 in ESCA. Subsequently, the levels of mRNA and protein were respectively detected by RT-qPCR and WB. Then, the cell biological behaviors were measured by CCK-8, colony formation, EdU, and tube formation assays. To investigate the in vivo effects of LAMA3 knockdown on ESCC, a xenograft tumor model was established, followed by IHC analysis. Additionally, glucose consumption, lactate production, ROS, and Fe2+ levels were determined by the corresponding kits. Besides, the interaction of LAMA3 and SPI1 was examined by ChIP and dual luciferase reporter assays. LAMA3 was highly expressed in ESCC and silencing it could curb the viability and proliferation of ESCC cells, tumor growth in vivo, tube formation of HUVECs, and induce oxidative stress and ferroptosis of ESCC cells. SPI1 was highly expressed in ESCC and could bind to the promoter of LAMA3 to jointly regulate the progression of ESCC. This study elucidated that SPI1 aggravated ESCC by binding to the promoter of LAMA3, thereby stimulating the growth and proliferation of ESCC cells and suppressing oxidative stress and ferroptosis.

Endometrial cancer (EC) is one of the most prevalent gynecologic malignancies, and long non-coding RNA (lncRNA) SOX9-AS1 has been identified as being upregulated in various cancers, indicating its potential role in driving carcinogenesis. However, the involvement and mechanism of SOX9-AS1 in EC have not been thoroughly investigated. The expression of SOX9-AS1 was assessed using qRT-PCR. The impact of molecular intervention on EC cells was evaluated through cell viability, migration, and invasion assays. Survival probability was analyzed using the Kaplan-Meier method. Bioinformatics predictions, dual-luciferase reporter assays, and rescue experiments were conducted to elucidate the specific competitive endogenous RNA (ceRNA) mechanism of the SOX9-AS1/miR-497-5p/E2F3 axis. SOX9-AS1 expression was significantly upregulated in EC tissues and cells, correlating with poor prognosis in EC patients. Knockdown of SOX9-AS1 inhibited the proliferation, migration, invasion, and glycolysis of EC cells. Mechanistically, miR-497-5p suppressed the proliferation, migration, invasion, and glycolysis of EC by targeting E2F3. Molecular interaction analysis indicate that SOX9-AS1 functions as a molecular sponge for miR-497-5p, thereby increasing E2F3 expression. Our work unveiled a novel mechanism by which SOX9-AS1 promotes EC development, suggesting that targeting the SOX9-AS1/miR-497-5p/E2F3 axis may represent a potential therapeutic strategy for EC.

Over the past decade, multiple research studies have focused on using miRNA expression in colorectal cancer (CRC) pathogenesis.

Objective. The insulin receptor substrate 2 (IRS2) is phosphorylated by the tyrosine kinase activity of the insulin receptor and the insulin-like growth factor I (IGF-1) receptor upon receptor stimulation. It mediates insulin signaling controlling metabolism as well as cell proliferation and invasion in tumors. Hypoxia and endoplasmic reticulum (ER) stress are significant factors in regulating the growth of malignant tumors including glioblastoma. The present study aims to investigate the regulation of the IRS2 gene expression in normal human astrocytes and U87MG glioblastoma cells by hypoxia and ER stress in the context of the native stress hormone hydrocortisone, which is widely used for the co-treatment of glioblastoma. Methods. The normal human astrocytes (line NHA/TS) and U87MG glioblastoma cells were used. Hypoxia was introduced by the HIF1A prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG), which mimics the effects of hypoxia under normoxic conditions. Tunicamycin and thapsigargin were used for the induction of ER stress. Hydrocortisone-water soluble BioReagent, suitable for cell culture (cyclodextrin-encapsulated hydrocortisone) was used. Cells were treated with DMOG, tunicamycin, thapsigargin, and hydrocortisone for 4 h. RNA was extracted with TRIzol reagent. IRS2 gene expression was examined by quantitative real-time RT-PCR and normalized to beta-actin mRNA. Results. It was found that hypoxia decreased the IRS2 gene expression in normal human astrocytes, but upregulated it in glioblastoma cells. At the same time, hydrocortisone did not significantly change the expression of this gene in both normal astrocytes and glioblastoma cells. However, hypoxia in combination with hydrocortisone strongly increased IRS2 gene expression in both cell types. Tunicamycin decreased the expression of the IRS2 gene in normal astrocytes, but increased it in glioblastoma cells and this effect of tunicamycin was not significantly altered by hypoxia in both cell types. At the same time, thapsigargin did not significantly alter the expression of the IRS2 gene in normal astrocytes, but it strongly upregulated it in glioblastoma cells. Hypoxia modified the effect of thapsigargin on this gene expression in both cell types, but by different ways: decreased in normal astrocytes and increased in glioblastoma cells. In addition, the impact of tunicamycin and thapsigargin on IRS2 gene expression was significantly upregulated by hydrocortisone in normal astrocytes and especially in glioblastoma cells. At the same time, the combined effect of hypoxia and hydrocortisone enhanced the expression of the IRS2 gene in tunicamycintreated normal astrocytes, especially in the glioblastoma cells. Hydrocortisone also increased the effect of hypoxia on this gene expression in thapsigargin-treated normal astrocytes and decreased it in glioblastoma cells. Conclusion. Our findings provide evidence that hypoxic regulation of IRS2 gene expression is modified by inducers of ER stress and hydrocortisone, but differently in normal astrocytes and glioblastoma cells and that the combined effect of hypoxia with ER stress and hydrocortisone greatly enhanced this gene expression in both cell types, especially in the glioblastoma cells.

Polygenic risk scores (PRS), a measure that sums multiple common genetic susceptibility variants into a single burden measure, can help identify individuals at higher risk for colorectal cancer (CRC). Consequently, there is growing interest in its potential use to guide screening practices, despite the current lack of evidence-based guidelines on the clinical utility of PRS models. Therefore, there is a need to understand the potential challenges and factors associated with PRS use in primary care settings. This qualitative study explores the perceptions of healthcare providers with PRS information to guide CRC screening decisions in the primary care setting. Using an exploratory approach, we conducted semi-structured interviews with 10 healthcare providers. The socioecological model guided the development of the interview questions. Transcripts were coded based on emergent themes. A total of seven themes were identified in this study, and each was organized using the socioecological model at the individual, interpersonal, community, and organizational levels. One key finding was the limited knowledge of PRS and the distinction between PRS and genetic testing for high-penetrant germline mutations. Providers shared the need for training, education, and comprehensive clinical guidelines for the use of PRS. This study provides insights to better optimize genetic education, testing, access, and care for improved CRC screening in at-risk individuals.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition characterized by highly variable presentation, making reproductive decision-making and pregnancy care particularly complex. While previous research has focused largely on clinical outcomes, little is known about how healthcare professionals (HCPs) provide care and communicate with patients during this process. This qualitative study explores the views and experiences of HCPs in providing reproductive and pregnancy-related care for individuals with NF1. Fifteen semi-structured interviews were conducted with genetic counselors, NF specialist nurses, and clinical geneticists in the UK. Reflexive thematic analysis was used to analyze the data. HCPs described supporting informed reproductive choices as central to their role, but this was often complicated by the unpredictable nature of NF1 and varying levels of patient understanding. They emphasized the importance of discussing reproductive choices early, yet found it particularly difficult to offer clear guidance when patients had mild symptoms themselves or drew on diverse family experiences to interpret risk. These challenges were further compounded by systemic barriers, such as limited consultation time, lack of standardized communication tools, and insufficient training. This study highlights the need for more structured and consistent communication practices to support patients with NF1 during reproductive and pregnancy care. A simplified, context-specific visual tool informed by the theoretical domains framework (TDF) may enhance counseling practice.

Polymerase theta (Pol θ) is a DNA repair factor that has drawn much recent interest as a target for cancer therapy, since its inhibition is well-tolerated in most cells but is lethal in cancers deficient in breast cancer-associated (BRCA) genes ("synthetic lethality"). Its normal biological functions, as well as how these functions change in BRCA-deficient cancers, are only recently becoming clear, however. We review here recent progress in our understanding of the cellular regulatory mechanisms at work in determining if Pol θ sees DNA damage. At the molecular scale Pol θ then must notably see and repair diverse classes of damage, including (at least) conventional double strand breaks (made by e.g. ionizing radiation), as well as several types of damage associated with replication stress. We speculate on the mechanisms that could explain this flexibility.

Esophageal squamous cell carcinoma (ESCC) imposes a heavy disease burden in China, accounting for over 50% of global cases and approximately 301,000 annual deaths. Current prognostic markers inadequately predict recurrence in early-stage patients. This study investigates microRNA-107 (miR-107) as a novel prognostic biomarker for ESCC.

AT-rich interaction domain 1A (ARID1A), is frequently mutated in cancer, leading to loss-of-function and posing challenges to therapeutic targeting. This study aimed to systematically explore epigenetic regulation of ARID1A, specifically promoter hypermethylation, in gastric cancer (GC) and its functional/immunological consequences.

Non-small cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths all over the world. N-acetyltransferase 10 (NAT10) has been reported to regulate N4-acetylcytidine (ac4C) modification of downstream mRNAs through certain pathways, thereby promoting the progression of diverse tumors, including lung cancer. However, the role and potential mechanism of NAT10 on NSCLC development is still unclear. In this study, GEPIA and TNMplot databases were applied to analyze Forkhead box A1 (FOXA1) expression in lung cancer patients. FOXA1 and NAT10 expression were determined using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell viability, proliferation, apoptosis, invasion, migration, and stemness were detected using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, Transwell, wound healing, and sphere formation assays. The abundance of ac4C on FOXA1 mRNA was measured using acRIP-qPCR. Their interaction was verified using RIP and dual-luciferase reporter assays. After JASPAR analysis, the binding between FOXA1 and NAT10 promoter was predicted and then verified using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. FOXA1 expression was increased in NSCLC tissues and cells, and its knockdown repressed NSCLC cell viability, proliferation, migration, invasion, stemness, and induced apoptosis in vitro. In mechanism, NAT10 maintained FOXA1 mRNA stability in an ac4C-dependent manner. Moreover, FOXA1 was also a transcription factor of NAT10 and increased the transcriptional activity of NAT10 via binding to its promoter region. These findings created a positive feedback cycle to facilitate NSCLC progression. This study elucidated the pivotal role of abnormal activation of the FOXA1/NAT10 positive feedback loop in the malignant progression of NSCLC, thereby uncovering novel prognostic factors and therapeutic targets in NSCLC.