This study aims to explore the impact of NFIC and its regulated signaling factors on epithelial ovarian cancer, providing new insights for the treatment of ovarian epithelial cancer. Bioinformatics methods were applied to predict and analyze NFIC and its downstream signaling factors. In vivo experiments involved dividing 27 purchased female nude mice into three groups: NC group, NFIC-OE group, and NFIC-OE + TBX2-OE group, to observe tumor growth in each group. In vitro experiments involved dividing the human epithelial ovarian cancer cell line SKOV3, OVCAR-3 and A2780 into five groups with different stimuli, using Western blot to observe protein expression, CCK-8 assay to observe cell proliferation, scratch assay to observe cell migration, transwell assay to observe cell invasion, Annexin V/PI assay to study apoptosis and Co-Immunoprecipitation experiment were used to study NFIC action. Bioinformatics revealed that NFIC promotes PTEN and TGFβ1, with TGFβ1 promoting the expression of TBX3 and EGR1, which in turn inhibit TBX2. Additionally, TBX2 inhibits PTEN and promotes MMPs. BRD4 promotes H3K27AC, which leads to TGFβ1 expression, while H3K27me3 inhibits TGFβ1 expression. EZH2 promotes H3K27me3, thereby inhibiting TGFβ1 and TBX3, and SP1 promotes the action of EZH2. In vivo, NFIC alleviated ovarian epithelial cancer, while TBX2 inhibited the effect of NFIC. In vitro, NFIC inhibited the expression of TBX2, nucleus SP1, EZH2, and MMPs, and promoted the expression of PTEN, nucleus BRD4, TGFβ1, and TBX3; TBX2 promoted MMPs expression. NFIC inhibited the migration and proliferation of SKOV3 cells, while TBX2 promoted it; NFIC functioned through TGFβ1 and PTEN, and their inhibition promoted the migration and proliferation of SKOV3 cells. NFIC inhibits the progression of epithelial ovarian cancer by regulating the balance of PTEN/TGFβ1/EGR1/BRD4 and SP1/EZH2 to suppress the TBX2/MMPs signaling pathway.

Transcriptional and post-transcriptional regulation mediated by RNA binding proteins (RBPs) have essential influence on the progression of colorectal cancer (CRC), while the underlying mechanisms need to be clarified. In this study, we focused on RBP-RBM47 and overexpressed its expression in HCT116 cells to evaluate its influence on cellular phenotypes and performed transcriptome sequencing (RNA-seq) to identify the downstream targets. After RBM47 overexpression (RBM47-OE), we found the proliferation level was decreased while apoptosis level was increased. Meanwhile, the invasion and migration ability of HCT116 was also significantly inhibited by RBM47-OE. We identified 216 up and 97 down differentially expressed genes (DEGs) by RBM47-OE, and found they were significantly enriched in immune response, apoptosis, TNF signaling, and autophagy pathways. RBM47-OE can also regulate the splicing pattern of 2541 alternative splicing (AS) events. The regulated AS genes were enriched in cell cycle, DNA damage and repair, mRNA splicing, and cell division associated pathways. To validate the regulation on gene expression and AS, we selected several DEGs and AS events to perform RT-qPCR experiment. The results showed that the expression level of CASP3, CCN1, and ATF5, and the splicing pattern of CD44 and MDM2, were significantly regulated by RBM47-OE in HCT116 cells. In summary, our results demonstrated the anti-tumor function and the globally downstream targets of RBM47 in CRC cells. We extend the cellular and molecular cognition of RBM47 in tumor. The identified molecular targets can also be served as potential targets for CRC treatment in future.

Tongue Squamous Cell Carcinoma (TSCC) represents a significant subtype of malignant oral cancer, characterized by a heterogeneous tumor microenvironment (TME). The tongue, a complex muscular organ, naturally presents an initial microenvironment that is largely inhospitable to the initiation and progression of TSCC. However, advanced-stage TSCC exhibits a pronounced accumulation of cancer-associated fibroblasts (CAFs), indicative of a drastic microenvironmental transformation. In this study, through comprehensive analysis combining cell model assessments and single-cell RNA sequencing data from a 4-NQO-induced TSCC mouse model, along with a lineage tracing-in-transplant assay, we elucidate and confirm the process of transdifferentiation whereby tongue muscle cells (TMCs) convert into CAFs in the TSCC context. Furthermore, we demonstrate that targeting TSCC with an IL-17a inhibitor offers a viable strategy to inhibit the reprogramming of TMCs into CAFs. Additionally, our research also identifies four critical marker genes involved in the transdifferentiation of TMCs to CAFs, Thbs1, Crabp1, Ifi205, and Cxcl5. Collectively, these findings delineate a mechanism through which TSCC cells induce the transdifferentiation of TMCs into CAFs, thereby transforming the cancer-suppressive microenvironment of the tongue into one that is conducive to TSCC progression.

Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we develop a zebrafish model in which all melanocytes experience CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only develops from melanocytes lining internal organs, analogous to the location of patient MM. We find that zebrafish MMs have a unique chromatin landscape from cutaneous melanomas. Internal melanocytes are labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes share a gene expression signature with MMs. Patient and zebrafish MMs show increased migratory neural crest and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests that the cell state of the originating melanocyte influences the behavior of derived melanomas. Our animal model phenotypically and transcriptionally mimics patient tumors, allowing this model to be used for MM therapeutic discovery. As this is a non-MAPK driven genetically engineered model of melanoma, our work also has implications for the 15% of cutaneous melanoma patients who lack MAPK-driving mutations.

MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis. In this study, we conducted high-throughput drug screenings using cell line and ex vivo cell model harboring, respectively, MEF2D::HNRNPUL1(MH) and MEF2D::BCL9(MB), the two major MEF2D fusions. We identified CUDC-907 as a highly potent dual-target inhibitor of PI3K/HDAC, demonstrating remarkable efficacy in inducing robust lethality while maintaining selectivity for MEF2D fusion-expressing cells. CUDC-907 effectively induced apoptosis and promoted the down-regulation of pre-BCR signaling. We discovered that the hyperactivation of the PI3K-AKT signaling pathway, HDAC9, and BCL2 contributed to the sustained state of MEF2D fusion (+) BCP-ALL. Importantly, CUDC-907 exerted dual regulatory function by targeting the integrative pathways of MEF2D fusions. It suppressed the PI3K-CREB pathway and fusion gene expression, while simultaneously inhibited transcriptional activity regulated by the MEF2D fusion-HDAC axis. CUDC-907 demonstrated remarkable efficacy in patient samples carrying distinct MEF2D fusion variants in vitro. Furthermore, this compound's effectiveness and safety were confirmed in both MH/NRAS^G12D BCP-ALL mouse model and MB patient-derived xenograft (PDX) model, outperforming conventional therapies. These results support the therapeutic potential of dual-pathway inhibition in MEF2D fusion (+) BCP-ALL and suggest CUDC-907 as a promising candidate for precision treatment in fusion-driven leukemias with similar molecular dependencies.

Osteosarcomas (OS) are aggressive bone tumors known for their extensive structural variations and rare recurrent oncogenic driver mutations. In this study, we identify ectopic expression of the oncohistone-mimic EZHIP in 20% of patients across two independent OS cohorts. We demonstrate that reduced deposition of the repressive H3K27me3 mark correlates with poor histological response to neoadjuvant therapy, serving as a predictor of patient outcomes. Through gain- and loss-of-function experiments, we provide functional evidence of the oncogenic activity of EZHIP in enhancing the aggressive characteristics of OS both in vitro and in vivo. EZHIP-induced epigenetic reprogramming reactivates developmental pathways and impedes the differentiation of mesenchymal progenitors, pushing them towards smooth muscle lineage commitment at the cost of other fates. Targeting residual H3K27me3 with EZH2 inhibitors may offer therapeutic benefit in EZHIP-expressing OS. Our findings highlight EZHIP expression as a prevalent driver in OS, offering insights into its pathogenic mechanisms and potential therapeutic strategies for this debilitating cancer.

This study describes mutations of genes that stimulate and regulate cell growth, programmed cell death, DNA repair, and cell growth suppression in a boy with osteosarcoma.

We report a case of bone sarcoma in a 9-year-old boy with possible familial predisposition. In our patient, only a subset of tumor cells expressed the ATRX protein, which is known to control the expression of several genome regions. The function of the p53 protein, which acts as a transcription factor that regulates the DNA damage repair response, cell cycle progression, and apoptosis pathways, is lost in 40-50% of malignant cells. Retinoblastoma was positive in the predominant subset of tumor cells. Deletion is found on chromosome 9, cytoband 9p21.3, where the genes for CDKN2A and CDKN2B are located. Neoplastic cells were SATB2-positive in a substantial subset, with nuclear staining. The SATB2 protein is a DNA-binding protein involved in transcriptional regulation and chromatin remodeling. Chromosomal losses of 8p and 19q11-q13.43 were also found. These regions contain several tumor suppressor genes, including NKX3.1, whose reduced expression correlates with 8p loss in high-grade tumors. Although there was no known cancer syndrome in the family, the maternal grandfather had a similar tumor requiring amputation.

Chromosomal instability is a hallmark of osteosarcoma and is characterized by heterogeneous and extensive genetic complexity. Various numerical and structural genomic rearrangements have been described in cancer cells. However, there is little consistent genetic change to understand the etiopathogenesis of this aggressive tumor.

Objective: To investigate the effect of miR-1-3p on mitophagy in human esophageal squamous cell carcinoma (ESCC) cells and the related mechanisms. Methods: The differentially expressed miRNAs in ESCC were screened using the GEO database. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure miR-1-3p expression in normal esophageal epithelial cells (HET-1A) and ESCC cell lines (TE1, KYSE30, KYSE150, KYSE410, Eca109). Bioinformatics tools were utilized to predict target genes of miR-1-3p, subcellular localization was confirmed by fluorescence in situ hybridization. The targeting relationship between miR-1-3p and SLC7A11 was validated using dual-luciferase reporter assay. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Furthermore, experimental validation demonstrated that overexpression of SLC7A11 rescued the presence of the miR-1-3p/SLC7A11 axis. Confocal microscopy was used to detect changes in mitochondrial autophagic lysosomes, while transmission electron microscopy was employed to observe mitophagy and morphological alterations. Western blot was conducted to evaluate the expression of autophagy-related proteins LC3 and P62. Flow cytometry was used to measure mitochondrial membrane potential and reactive oxygen species (ROS). Immunohistochemistry was applied to assess SLC7A11 expression in 133 ESCC patient tissues and 115 normal esophageal epithelial tissues. The correlation between SLC7A11 expression level and clinicopathological features was analyzed. Survival analysis was performed using the Kaplan-Meier method, and Cox proportional hazard regression models were used for multivariate analysis. Results: The expression of miR-1-3p in ESCC cells was significantly lower than that in HET-1A cells (P＜0.05). SLC7A11 was a target gene of miR-1-3p. Transfection of miR-1-3p mimic inhibited the proliferation of ESCC cells. CCK-8 assay results showed that the proliferative capacity of KYSE30 and KYSE410 cells in the miR-1-3p mimic group (absorbance values: 2.88±0.24 and 2.88±0.18, respectively) was significantly lower than that in the miRNA mimic negative control (NC) group (3.94±0.27, P＜0.001; 4.20±0.21, P＜0.001). Meanwhile, the proliferative capacity of KYSE30 and KYSE410 cells in the miR-1-3p mimic+SLC7A11-overexpression (OE) group (absorbance values: 3.57±0.15 and 3.60±0.13, respectively) was significantly higher than that in the miR-1-3p mimic +empty vector (EV) group (2.54±0.10, P＜0.001, 2.36±0.16, P＜0.001). Additionally, transfection of miR-1-3p mimic promoted apoptosis. Flow cytometry results demonstrated that the apoptosis rates of KYSE30 and KYSE410 cells in the miR-1-3p mimic group [(9.22±0.05)% and (6.55±0.37)%, respectively] were significantly higher than those in the miRNA mimic NC group [(0.81±0.17)%,P＜0.001); (1.04±0.12)%, P＜0.001]. Conversely, the apoptosis rates of KYSE30 and KYSE410 cells in the miR-1-3p mimic + SLC7A11-OE group [(0.73±0.04)% and (1.19±0.05)%, respectively] were significantly lower than those in the miR-1-3p mimic+EV group [(9.83±0.41)%, P＜0.001); (6.09±0.17)%, P＜0.00)]. MiR-1-3p mimic downregulated SLC7A11 protein expression and the LC3Ⅱ/LC3I ratio (P＜0.05), upregulated P62 protein expression (P＜0.05), this phenomenon can be rescued by overexpressing SLC7A11 (P＜0.05). Additionally, miR-1-3p mimic increased ROS levels and decreased mitochondrial membrane potential (JC-1 aggregate/monomer ratio), this phenomenon can be rescued by overexpressing SLC7A11 (P＜0.05). SLC7A11 expression was higher in ESCC tissues compared to normal esophageal epithelial tissues (P＜0.001), and SLC7A11 serves as an independent prognostic factor in ESCC (HR=2.15, 95% CI: 1.27-3.65, P=0.004). Conclusion: miR-1-3p inhibits mitophagy in esophageal squamous cell carcinoma by targeting SLC7A11.

Asia bears a disproportionate and rapidly rising burden of colorectal cancer (CRC). However, the incidence and mortality trends vary significantly between Asian countries, mainly due to the diversity of socioeconomic factors and the implementation of screening programs. This study aimed to report the contemporary distribution, socioeconomic correlates, and projections for future trends of CRC across Asia. The Global Cancer Observatory (GLOBOCAN) for the year 2020 was used to obtain data on prevalence, incidence, and mortality rates of CRC. We calculated mortality-to-incidence ratios (MIRs), age-standardized incidence and mortality rates (ASIR and ASMR), crude rates, numbers, and 5-year prevalent cases and rates by age, sex, and subregions of Asia. We assessed the correlation between indicators and human development index (HDI) and the ratio of current health expenditure (CHE) to gross domestic product (GDP) using Pearson's correlation coefficient. Estimated incidence or mortality rates between 2025 and 2040 were calculated by multiplying age-specific rates for 2020 by the estimated population between 2025 and 2040. In Asia, the 5-year prevalence rate, ASIR, and ASMR of CRC were 55.60, 17.30, and 8.40 per 100,000, respectively. The highest crude incidence and mortality rates were in the 70 + age group. Males had higher ASIRs than females (20.80 vs. 14.00 per 100,000) in Asia. MIRs for men and women were 0.49 globally and 0.50 and 0.51 in Asia, respectively. A positive significant correlation was observed between HDI and both the ASIR and ASMR. A strong negative correlation was observed between HDI and MIR. The number of incident and mortality cases are estimated to increase by 71.10% and 85.10% in 2040, respectively. CRC is a significant public health concern in Asia, with substantially high incidence and mortality rates in East Asia and lower quality of care and survival in less developed regions of the continent. Resource allocation prioritizing population-based screenings alongside capacity building around specialized care centers is crucial across the Asian countries.

Healthcare workers' (HCW) health and wellbeing directly affect patient care, yet little is known about their health-related quality of life (HRQoL) in the United Kingdom (UK). Using data from a nationwide study conducted during the COVID-19 pandemic in the UK (December 2020 to March 2021), we evaluated self-reported HRQoL among HCWs and its variation by sociodemographic characteristics.

HRQoL was measured using the five-dimension-five-level EuroQoL (EQ-5D-5L) questionnaire, covering five health dimensions. We explored differences in reported HRQoL by age, sex, Index of Multiple Deprivation (IMD) quintile, ethnicity, migration status and occupational group. Each HRQoL dimension was collapsed into a binary outcome (any problems versus none) and associations analysed using logistic regression. We also examined EQ-5D-5L visual analogue scale (VAS) scores using linear regression.

Among 12,026 HCWs, 75.9% were female, 26.7% overseas-born and 29.9% from non-White ethnic groups. HCWs reported high levels of pain/discomfort and anxiety/depression (43.7% and 46.1% reporting at least slight problems, respectively). Women were more likely than men to report problems across all EQ-5D-5L dimensions. Reporting health problems increased with increased deprivation. Asian overseas-born and Black HCWs were less likely than White UK-born HCWs to report anxiety/depression. Compared to the Medical group, other HCW types reported more problems with pain/discomfort (32.2% Medical, 55.4% Nursing, 45.4% Allied Health Professionals, 49.8% Ambulance groups) and anxiety/depression (36.8% Medical, 52.9% Nursing, 50.5% Ambulance groups). Nurses and ambulance workers showed particularly high rates of pain/discomfort. Overall, all HCWs reported more problems with anxiety/depression, usual activities and pain/discomfort than the Medical group. Similar associations were demonstrated in a parallel analysis of VAS scores.

In the largest study of HRQoL in HCWs to date, EQ-5D-5L VAS scores were lower than those reported elsewhere for the general UK population (for ages up 45 years), with high levels of anxiety/depression and pain/discomfort and substantial heterogeneities across EQ-5D-5L dimensions by sex, occupation and deprivation level. However, HCWs' circumstances during the COVID-19 pandemic may have influenced their reporting of HRQoL. Our findings highlight the need for further research to understand the causes of lower HRQoL, particularly among women and certain occupational groups, and to inform targeted interventions.