Colorectal cancer (CRC) is the fourth-leading cause of cancer-related mortality worldwide. Semaphorin 6A (SEMA6A) is a member of the semaphorin family, and its specific biological function in CRC progression remains unclear. Bioinformatics analysis revealed that SEMA6A expression was downregulated in CRC tissues and that low expression of SEMA6A was associated with a poor prognosis. Compared with those in normal colorectal epithelial cells, SEMA6A expression levels were lower in CRC cell lines. CACO2 and SW48 cells were chosen to construct stable SEMA6A-knockdown and SEMA6A-overexpressing cell lines. SEMA6A knockdown promoted CACO2 proliferation. Conversely, SEMA6A overexpression inhibited the proliferation and promoted the apoptosis of SW48 cells. Transwell and wound healing assays demonstrated that SEMA6A overexpression inhibited the invasion and migration ability of SW48 cells. SEMA6A overexpression might impede CRC cell migration and invasion by inhibiting the epithelial-to-mesenchymal transition, as evidenced by the downregulation of N-cadherin expression and the upregulation of E-cadherin expression in SW48 cells. To further validate the role of SEMA6A in CRC progression in vivo, transplanted tumor and liver metastasis mouse models were constructed in nude mice by injecting stable SEMA6A-overexpressing SW48 cell lines. SEMA6A overexpression inhibited tumor growth in SW48 tumor-bearing mice and the expression of Ki-67 in tumor tissues. In addition, SEMA6A overexpression resulted in a marked decrease in liver metastasis of CRC cells, with decreased numbers of hepatic metastatic nodules and infiltration of cancer cells. In summary, SEMA6A overexpression alleviated CRC progression by inhibiting tumor growth and metastasis both in vivo and in vitro.

CXCL3, a member of the CXC chemokine family, has been increasingly implicated in the progression of various cancers, including hepatocellular carcinoma, due to its role in immune and inflammatory responses within the tumor microenvironment. This study aimed to investigate the expression and function of CXCL3 in liver cancer and to elucidate its underlying mechanisms. A combination of bioinformatics analysis, ELISA, RT-qPCR, immunohistochemistry, in vitro cell assays, and in vivo nude mouse models was employed to assess CXCL3 expression and function. The results showed that CXCL3 was significantly upregulated in hepatocellular carcinoma tissues and associated with reduced overall survival in patients. It promoted the proliferation, colony formation, and migration of liver cancer cells (Bel-7402, HepG2, and SMMC-7721) via exogenous, autocrine, and paracrine mechanisms, and recruited tumor-associated macrophages, neutrophils, and fibroblasts into the tumor microenvironment. Mechanistically, CXCL3 activated the PI3K/AKT/mTOR pathway by upregulating PI3K, p-PI3K, AKT, p-AKT, mTOR, and p-mTOR, while the mTOR inhibitor Torin 1 reversed these effects. Gene set enrichment analysis showed enrichment in immune-related pathways, including Toll-like receptor and chemokine signaling. In vivo, CXCL3 overexpression significantly promoted tumor growth in nude mice. These findings suggest CXCL3 facilitates liver cancer progression through tumor microenvironment modulation and PI3K/AKT/mTOR pathway activation.

Primary results of the CORIN trial indicated that, compared with chemotherapy, icotinib significantly improved 3-year disease-free survival (DFS) in patients with Epidermal Growth Factor Receptor (EGFR)-mutated stage IB non-small cell lung cancer (NSCLC). However, evidence regarding the outcomes of adjuvant icotinib in patients with high-risk factors remains limited. This retrospective study evaluated the efficacy and safety of adjuvant icotinib in patients with EGFR-mutated high-risk stage IB NSCLC. We enrolled 37 patients with completely resected EGFR-mutated high-risk stage IB NSCLC. The median follow-up time was 31 months, and the 3-year DFS rate was 91.4%. Two patients experienced disease recurrence and were successfully switched to osimertinib upon identification of an EGFR (T790M) mutation. Although overall survival (OS) and central nervous system (CNS)-DFS data were not mature, no deaths or central nervous system metastases were observed by the end of follow-up. 29 (78.4%) patients experienced grade 1-2 adverse events (AEs), no grade 3 or higher AEs occurred. This study suggests a potential DFS benefit and well-tolerated profile of adjuvant icotinib in patients with EGFR-mutated high-risk stage IB NSCLC. However, longer-term follow-up is necessary to assess the long-term outcomes.

Current evidence on circulating tumor DNA (ctDNA) in the adjuvant setting of early breast cancer (eBC) confirms its high prognostic value. CtDNA-positive patients without radiographic signs of relapse show reduced disease-free and overall survival. Secondary adjuvant treatment intervention studies represent a new appealing therapeutic option.

To investigate the mechanism by which heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) regulates the maturation of LncRNA MM2P to promote M2 polarization of macrophages in gastric cancer. In vitro experiments showed that hnRNPA2B1 could promote M2 polarization of iBMDM cells, enhance the maturation and expression of MM2P, and increase STAT6 phosphorylation levels. When MM2P was knocked out, hnRNPA2B1 could no longer further promote cell M2 polarization. iBMDM cells with hnRNPA2B1-induced M2 polarization could enhance the metastasis and invasion of MFC cells, improve clonogenic ability, and increase cell viability. In vivo experiments demonstrated that hnRNPA2B1 could promote the infiltration and polarization of CD206 cells and facilitate tumor growth. hnRNPA2B1 can regulate macrophage M2 polarization by promoting the maturation and expression of MM2P, thereby enhancing the malignant behavior of gastric cancer cells and tumor growth.

Nonsyndromic capillary malformations (CM) are seen predominantly in skin. In Sturge-Weber Syndrome (SWS), CMs occur in the skin, leptomeninges of the brain, and choroid of the eye. >90% of CM are caused by a somatic mutation-GNAQ p.R183Q, the gene encoding the G-protein subunit Gαq. Longitudinal MRI of the brain in one SWS patient suggests developing vascular permeability. We modeled this in a transendothelial electrical resistance assay and found endothelial cells with GNAQ p.R183Q (EC-R183Q) exhibited increased permeability compared to EC wild-type. Increased vascular permeability was confirmed in a Gnaq p.R183Q mouse model. Knockdown of elevated angiopoietin-2 (ANGPT2) in EC-R183Q partially restored the EC barrier, as did a MEK1,2 inhibitor, implicating MAPK/ERK signaling. The combination of ANGPT2 knockdown and trametinib further restored the EC barrier in an additive manner. indicating the two operate in separate pathways. In summary, we found that EC-R183Q exhibits increased permeability, reflecting the compromised endothelial barrier in CMs.

Ferroptosis has emerged as a promising therapeutic target for colorectal cancer (CRC) due to its ability to selectively eliminate cancer cells. By inducing ferroptosis, novel treatment strategies aim to overcome traditional challenges such as cancer recurrence and drug resistance. In this study, we screened cells with high LEF1 expression, knocked down LEF1, or simultaneously overexpressed SLC7A11 in these cells, and intervened with ferroptosis inducers and inhibitors to investigate the mechanism of LEF1 in inhibiting ferroptosis and promoting CRC cell growth. Dual-luciferase reporter assays and CHIP-qPCR were utilized to validate the effect of LEF1 on SLC7A11 transcription. Furthermore, a nude mouse subcutaneous xenograft model was established using CRC cells with stable LEF1 knockdown to verify the impact of LEF1 on CRC tumor growth in vivo. Our findings indicate that LEF1 knockdown inhibits CRC cell progression both in vitro and in vivo. Moreover, we discovered that the molecular mechanism underlying the role of LEF1 is the targeted activation of SLC7A11 transcription, which alleviates ferroptosis, ultimately leading to CRC progression. Our results suggest that LEF1 inhibits ferroptosis in CRC cells by promoting SLC7A11 transcription, potentially serving as a therapeutic target for CRC. This study reveals that the promotion of CRC by LEF1 is associated with activating SLC7A11 transcription and inhibiting cellular ferroptosis, providing a new direction for clinical targeted therapy of CRC.

Epigenetic rewiring modulates gene expression by reshaping chromatin architecture without altering the underlying DNA sequence. The eukaryotic genome is intricately folded within a dynamic three-dimensional nuclear architecture, which is vital for maintaining genomic integrity and ensuring spatially precise gene regulation. Long non-coding RNAs (lncRNAs), a class of regulatory transcripts, play a pivotal role in organizing nuclear structure, preserving cell identity, and sustaining complex regulatory networks. Through interactions with DNA, RNA, transcription factors, and chromatin-modifying complexes, lncRNAs influence the formation and maintenance of higher-order chromatin structures, including topologically associating domains (TADs), lamina-associated domains (LADs), and chromatin loops. These structural frameworks facilitate or constrain long-range genomic interactions, thereby governing transcriptional programs. Aberrant lncRNA expression disrupts this regulatory architecture and is increasingly recognized as a driving force in oncogenesis. Notable lncRNAs, such as XIST, HOTAIR, and MALAT1, modulate gene expression by recruiting epigenetic regulators, including Polycomb Repressive Complex 2 (PRC2), which alters histone modifications and DNA methylation landscapes, and rewires enhancer-promoter contacts. These mechanisms underlie profound transcriptional reprogramming in cancer cells. Technological advances in genome conformation capture methods (e.g., Hi-C, 3C) have enabled high-resolution mapping of these dynamic chromatin interactions, revealing the extent of lncRNA-mediated 3D genome remodeling in malignancy. This review synthesizes emerging evidence on the role of lncRNAs in shaping nuclear architecture and gene regulation, with a focus on their oncogenic and tumor-suppressive functions. By integrating insights into chromatin topology and epigenetic control, we underscore the potential of targeting lncRNAs and associated chromatin remodeling pathways as innovative diagnostic and therapeutic strategies in cancer and other complex diseases.

Metabolic reprogramming, especially lipid metabolism, is crucial in cancer progression and treatment resistance. Apolipoproteins are crucial targets for research as they regulate autophagy, oxidative stress, and chemoresistance. A systematic bibliometric and bioinformatics approach is necessary to identify trends and elucidate the molecular mechanisms linking apolipoproteins to cancer.

Aldehyde dehydrogenases (ALDHs) are responsible for the NAD(P)+-dependent oxidation of aldehydes into carboxylic acids, fulfilling key roles in detoxification, antioxidant defense, biosynthesis, and regulatory processes. Elevated expression and activity of ALDH isoenzymes have been documented in various human cancers, where they are linked to cancer recurrence. While the human genome encodes 19 functional ALDH genes, aldehyde dehydrogenase 1B1 (ALDH1B1) has emerged as a critical enzyme in diverse human pathologies. ALDH1B1 is a major mitochondrial enzyme involved in detoxifying lipid peroxidation by-products and metabolizing various aldehyde substrates. Notably, both low and high ALDH1B1 expression levels contribute to tumor progression and with marked variability observed across different tumor types. This review summarizes the essential functions and potential ALDH1B1 mechanisms in the tumor initiation, progression, metastasis, and therapeutic responses across cancer types. Our analysis indicates that ALDH1B1 is a potential therapeutic target for cancer therapy.

In vitro models of acute leukemia are crucial for understanding its biology and developing effective treatments. The authors have established and characterized a novel cell line, ICH-BCPALL-3, which expresses the TCF3::HLF fusion from B cell precursor acute lymphoblastic leukemia (BCP-ALL). The karyotype of the cultured cells is 46,XY, der(1)(1qter- > 1q11::1p32- > 1q11::4q21- > 4qter), der(4)t(1;4)(q11;p32), add(8)(q24), del(17)(q24). Analysis of the diagnostic sample revealed deletions in RB1, VPREB1, and NR3C1. The cell line showed additional deletions of VPREB1, NR3C1, and CDKN2A/2B, as well as a gain of AKT1. The loci for PAX5 and BTG1 were retained. Exome and Sanger sequencing identified nucleotide variants of ARID5B and NCOR1 in the diagnostic sample, as well as a KRAS variant (p.Lys117Asn) in the first recurrent sample and another KRAS variant (p.Asp119Gly) in the second recurrent sample and the cell line. Transcriptome analysis and RT-PCR confirmed that all examined samples contained a TCF3::HLF chimeric transcript. However, molecular cytogenetics did not verify the juxtaposition of TCF3 and HLF loci. Further long-range PCR analyses confirmed that genomic material containing HLF exon 4 was inserted into TCF3 intron 16. Using dimensional reduction techniques, we found that the current cell line shares an expression pattern with other TCF3::HLF-positive BCP-ALL cell lines. The cytotoxicity assay indicated that the cell line is sensitive to Aurora Kinase B inhibitor, but not to BCL2 inhibitor. This cell line is the first TCF3::HLF-positive BCP-ALL model without the t(17;19) translocation, facilitating research into leukemogenesis and the development of novel treatments for patients with poor prognosis associated with TCF3::HLF-positive BCP-ALL.

Various long non-coding RNAs (lncRNAs) have indicated their role in different regulatory processes and therapeutics in cervical cancer (CC). This study aims to assess the gene expression and methylation status of LINC00518 & MAFG-AS1 in CC patients. Methylation-specific PCR (MS-PCR) and quantitative real-time PCR (qRT-PCR) were performed on 81 patients. The association of the promoter methylation status of cancer tissues was studied with HPV infection and clinicopathological factors. The Kaplan-Meier curves were used from the GEPIA and TANRIC databases to analyze the overall survival of CC patients. The bioinformatics analysis of relative gene expression was carried out using the GEPIA database. The RNAinter database was also explored to find out the potential interacting partners. This is the first-ever research revealing that hypomethylation of the LINC00518 gene promoter may be relevant to its oncogenic behavior in CC (p < 0.05). However, no significant difference was observed between the MAFG-AS1 methylation status of cancerous and normal tissues. A notable association between the methylation status of LINC00518 promoter and clinicopathological factors, including age (p < 0.001), histological subtypes (p < 0.00001), and differentiation degree (p < 0.00001), has been observed, indicating its possible role in predicting the severity and prognosis of this disease. Overall survival analysis showed a significant value for LINC00518 using GEPIA (p < 0.05). Our findings about the gene expression of LINC00518 and its hypomethylated status in cancerous tissues suggest a potential mechanism that might contribute to its dysregulation in CC and could serve as a potential clinical biomarker.

Mitochondrial permeability transition (MPT)-driven necrosis is associated with kidney renal clear cell carcinoma (KIRC), but its role in prognosis remains unclear. This study develops a prognostic model for KIRC outcomes using MPT-driven necrosis-related genes (MPTDNRGs). Differentially expressed genes (DEGs) from TCGA-KIRC samples were analyzed and categorized based on MPTDNRGs scores. Three key genes-IL2RA, CD7, and CXCL13-were identified as significant prognostic markers and used to construct a risk model, validated through public datasets and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The risk score and age were the independent prognostic factors. A nomogram incorporating these factors demonstrated good clinical utility. The high-risk group was enriched in immune-related pathways, such as systemic lupus erythematosus, while the low-risk group showed enrichment in metabolism-related pathways, including butanoate metabolism. Significant differences in 25 immune cells were observed between the risk groups, with the high-risk group exhibiting higher TIDE scores, suggesting a greater likelihood of immune escape. Additionally, a ceRNA network revealed complex interactions, such as CXCL13-hsa-miR-670-5p-AL121985.1, and predicted 25 transcription factors for key MPTDNRGs. This study presents a novel prognostic model for KIRC based on three MPTDNRGs, offering valuable insights into KIRC prognosis and potential therapeutic targets.

Aberrant DNA methylation drives cancer development, yet current screening methods require substantial resources for targeted enrichment across multiple CpG-rich regions. Early cancer detection in cell-free DNA (cfDNA) presents additional challenges due to low circulating tumor DNA fractions (0.01-10%) that dilute cancer-specific signals. To address these limitations, we developed Restriction Enzyme-based CpG-methylated fragment AmPlification sequencing (RECAP-seq) to selectively enrich hypermethylated fragments from existing Enzymatic Methyl-seq (EM-seq) libraries. RECAP-seq combines EM-seq library preparation with BstUI restriction enzyme digestion to target CGCG motifs, achieving preferential enrichment of CpG islands. With spike-in experiments using cell line mixtures, RECAP-seq successfully distinguished samples as low as 0.001%. The method identified 7,091 hypermethylated markers, including ALX4 which showed progressive increases with colorectal cancer stage. Clinical validation using cfDNA from 35 healthy donors and 47 colorectal cancer patients demonstrated robust detection with an area under the curve (AUC) of 0.932, achieving 78.7% sensitivity at 95% specificity.

Ecotropic viral integration site 5 (EVI5), a member of the Tre-2/Bub2/Cdc16 (TBC) domain-containing protein family, has been implicated in the initiation of various cancers. However, its precise role in lung adenocarcinoma (LUAD) remains unclear. This study aimed to elucidate the function of EVI5 in LUAD, with a focus on its regulation of the immune checkpoint molecule PD-L1. In the present study, we found that EVI5, Rab11 and PD-L1 were significantly overexpressed in LUAD tissues compared to adjacent normal tissues. In vitro experiments demonstrated that EVI5 knockout suppressed the expression of Rab11 and PD-L1 in LUAD cells. Notably, EVI5 overexpression promotes the expression of Rab11 and PD-L1 in LUAD cells. EVI5 was also shown to interact with Rab11 to upregulate PD-L1 expression in LUAD cells. Mechanistically, our findings identify a novel EVI5-Rab11-PD-L1 axis and suggest that EVI5 is a potential regulator of the tumor immune microenvironment, which may have implications for the efficacy of immunotherapy.

Precision therapy for glioma remains a major challenge due to tumor heterogeneity. The Origin Recognition Complex Subunit 6 (ORC6) is a crucial regulator of DNA replication initiation. This study aims to investigate the expression of ORC6 in gliomas and its relationship with survival rates and malignancy, while screening potential drugs targeting its functional network. By integrating multiple bioinformatics approaches with structure-based virtual screening, retrospective RNA sequencing data analysis was performed using patients from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. A protein-protein interaction (PPI) network was constructed from ORC6-coexpressed genes to identify core hubs. Molecular docking was employed to screen a library of natural compounds and known drugs against these hub targets. Research has revealed that ORC6 is significantly upregulated in high-grade gliomas, with its elevated expression associated with poor survival outcomes and immune inflammatory responses. Network analysis identified five core hub genes (ORC1, ORC2, MCM2, MCM6, CDC45) central to DNA replication. Molecular docking revealed that several compounds, including the natural flavonoid Baicalein and the FDA-approved drug Palbociclib, exhibited high binding affinity to these hub targets. ORC6 represents a highly promising novel target for precision therapy in glioma. Potential approaches to target this pathway include disrupting the ORC6-replication axis using existing drugs (such as palbociclib) or natural products (such as baicalin).

Colorectal cancer (CRC) is the third most frequent cancer worldwide. It is the second leading cause of cancer-related death, affecting both men and women. It has been described that 20-25% of colorectal tumors have mutations in the PIK3CA gene, mainly in three hotspots: E542 and E545 and H1047. The aim of this study was to compare the prevalence of PIK3CA gene mutations in colorectal tumors based on a systematic review of a selection of studies. Nighty seven studies enrolling 48,446 patients were eligible for inclusion. Most studies were conducted in Asian (41.2%) and European countries (34.0%). The global prevalence ranged from 0 to 80%, with a mean prevalence of 13.7%. Fourteen studies reported a prevalence of less than 5%, 22 between 5 and 10%, 32 between 10 and 15% and 29 showed a prevalence of more than 15%. Mutations were more common in exon 9 than in exon 20 (9.5% vs. 4.7%). After discussing a number of possible reasons that could explain the differences in prevalence, it is very hard to deduce which is the main factor influencing the observed frequency.

Methyltransferase-like protein 3 (METTL3) functions as the primary "writer" of N6-methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes. Functionally, METTL3 regulates a broad spectrum of cellular processes, including cell cycle progression, proliferation, apoptosis, invasion, migration, and differentiation. In colorectal cancer, METTL3 expression is frequently upregulated and has been correlated with poor prognosis. Therefore, this review attempts to organize and describe the main molecular and cellular mechanisms through which METTL3 drives colorectal cancer. Mechanistically, METTL3 contributes to tumor growth, metastatic dissemination, and the development of resistance to chemotherapy and radiotherapy. Special emphasis is placed on the clinical relevance of METTL3, not only as a biomarker, but also as a potential therapeutic target. Less explored topics are also addressed, such as the interaction between METTL3 and gut microbiota. Altogether, this review underscores the multifaceted role of METTL3 in colorectal cancer and the importance of further investigation to translate these insights into clinical applications.

Fibroblast-driven deposition of extracellular matrix, particularly type III collagen, is linked to poor outcomes in patients with liver fibrosis, fibrotic solid tumors such as hepatocellular carcinoma and pancreatic cancer as well as in patients with other fibrotic diseases. The pro-peptide of type III collagen (PRO-C3) serves as a serum biomarker of active collagen formation. PRO-C3 is elevated and prognostic in patients with liver fibrosis and pancreatic cancer, suggesting that targeting mechanisms behind PRO-C3 elevation could benefit these individuals. In this study, we sought to identify genetic variants associated with circulating PRO-C3 levels as potential therapeutic targets for fibrotic diseases and cancer. A genome-wide association study (GWAS) of the PERF cohort (n = 4968) identified variants in the gene TGFBI (BIGH3/βigH3), a known risk factor for tumor fibrosis, as associated with elevated PRO-C3. Further analyses of serum samples from patients with pancreatic ductal adenocarcinoma and liver fibrosis confirmed significant correlations between PRO-C3 and BIGH3 levels. Functional studies in a fibroblast model demonstrated that BIGH3 induces PRO-C3 in a dose-dependent manner, which was blocked by an anti-BIGH3 antibody, indicating a causal role. BIGH3 expression was observed in macrophages and fibroblasts, especially under TGFβ stimulation, positioning BIGH3 as a downstream mediator of TGFβ-induced fibrosis. Finally, blocking BIGH3 in a TGFβ-induced fibrosis model led to reduced PRO-C3 levels, demonstrating that BIGH3 is local mediator of pathological TGFβ signaling. This highlights that BIGH3 may be implicated in TGFβ-induced fibrosis and underscore the potential for treatment of pathological fibrotic processes by inhibiting BIGH3 in patients with elevated PRO-C3 levels.

Cholangiocarcinoma is a very deadly epithelial cell cancer with poor clinical outcome. Cellular senescence plays a vital role in the oncogenesis and the aggressiveness of cholangiocarcinoma. Integrative machine learning procedure including 10 methods (random survival forest, elastic network, Lasso, Ridge, stepwise Cox, CoxBoost, partial least squares regression for Cox, supervised principal components, generalized boosted regression modelling, and survival support vector machine) was performed to construct a cellular senescence-related signature (CSS) for cholangiocarcinoma. Cellular experiment was used to verify the biological function of hub gene. The optimal prognostic CSS developed by Lasso method served as an independent risk factor and had a stable and powerful performance in predicting the overall survival rate in cholangiocarcinoma, with the AUC of 1-, 3-, and 5-year ROC curve being 0.957, 0.929 and 0.928 in TCGA cohort. Low CSS score indicated with a lower tumor immune dysfunction and exclusion score, lower tumor microsatellite instability score, lower immune escape score, lower MATH score, and higher tumor mutation burden score in cholangiocarcinoma. Down-regulation of EZH2 inhibited the proliferation, colony and promoted apoptosis of cholangiocarcinoma cell. Integrative machine learning analysis was performed to construct a novel CSS in cholangiocarcinoma. This CSS acted as an indicator for predicting the prognosis and immunotherapy benefits of cholangiocarcinoma patients.