Volume 27, Issue 1

The increasing incidence of cancer highlights the urgency for a deeper understanding of its complex pathogenesis. Recent research has identified novel post-translational modifications (PTMs) as key contributors to cancer. This review examines the role of emerging PTMs, including lactylation, crotonylation, methacrylation, succinylation, sulfhydration, β-hydroxybutyrylation, and 2-hydroxyisobutyrylation, in cancer development. We provide a comprehensive review of these novel PTMs, and their impact on proteins involved in tumor progression. Additionally, we summarize the associated enzymes, proteins, and signaling pathways, showcase the latest preclinical studies on PTMs in cancer, and offer insights into future research directions. Investigating these modifications is expected to facilitate the development of innovative and patient-centric therapies, marking a significant advancement in cancer research.

Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) has emerged as a promising strategy in the treatment of various cancers, particularly gliomas. The biosynthesis of prodrug 5-ALA plays a pivotal role in the heme production pathway of Protoporphyrin IX (PpIX), and understanding this molecular process offers significant insights into cellular physiology and therapeutic potential. This review highlights the clinical applications of 5-ALA in PDT, underscoring the translational impact of foundational research on its biosynthesis. The search, performed on PubMed and Web of Science, included both in vivo clinical studies and in vitro preclinical studies. The findings of this review emphasize the expanding potential for novel therapeutic strategies, driven by an enhanced understanding of 5-ALA biosynthesis and its application in PDT, offering a promising future for medical advancements in cancer treatment.

Along with the continuous development of chromatin immunoprecipitation sequencing and its derivative technologies, as well as an increased understanding of epigenetic modification, the post-translational modification of histones has gradually been revealed, including their acetylation, methylation, phosphorylation, and ubiquitination, and their roles in diseases, especially cancer, have also been gradually explored. The role and regulation of histone methylation and acetylation in cancer and the mechanism of action of drugs have been thoroughly discussed. In particular, the review highlights recent advances in the development of epigenetic-targeted therapies and the challenges that remain in translating these findings into clinical applications. Research on epigenetic-targeted drugs is in its infancy, and more research in the fields of dominant biology, structural biology, and pharmacodynamics is needed. Through this review, the authors aim to provide theoretical guidance for the construction and clinical transformation of histone methylation and acetylation.

The CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6), a member of the chemokine-like factor superfamily, binds to programmed death-ligand 1 (PD-L1) on the cell membrane, thereby impeding PD-L1’s lysosomal degradation and sustaining its expression. In recent years, extensive studies on PD-L1 have provided insights into its function as an immunepoint inhibitor involved in tumor cell immune evasion. The specific interaction between CMTM6 and PD-L1 suggests a potential role in tumor cell immune evasion and suppression, potentially offering a novel therapeutic target for cancer immunotherapy. Currently, the research on CMTM6 and PD-L1 in diverse tumors and diseases is limited, but their significant roles are indicated. This article provides an overview of the impact of CMTM6 on the immune microenvironment in different types of cancer (such as lung cancer, breast cancer, and liver cancer), and summarizes the effects of CMTM6 on the occurrence and development of various tumors.

Objectives Oxabicycloheptene sulfonate (OBHS), a selective estrogen receptor modulator (SERM), demonstrates the potential to exert antineoplastic effects and modulate abnormal glycometabolism in BC cells. However, mono-chemotherapy therapy doesn’t always achieve full anticancer effects. Therefore, the present study aimed to evaluate the effect of combining OBHS with 2-deoxy- d -glucose (2-DG) or metformin on BC in an attempt to establish effective new combinations. Methods Impacts of OBHS alone and the combinations on cell cycle progression, cell viability, mitochondrial function, apoptosis, epithelial-mesenchymal transition (EMT)-associated gene levels, and the concentrations of glucose, lactate, and seven glycolysis kinases. Results Our findings demonstrate that both combinations involving OBHS significantly reduced BC cell viability and proliferation. Besides, the synergy of their combinations in MCF-7 cells (10 μmol/L OBHS and 20 μmol/L 2-DG or 10 μmol/L metformin) and T47D cells (30 μmol/L OBHS and 25 μmol/L 2-DG or 20 μmol/L metformin) on the loss of cell mitochondrial integrity, the triggering of mitochondria-mediated cell apoptosis, and potentially metabolic regulation were shown compared to each drug alone. Furthermore, in regulating tumor cell metastasis, the combination of OBHS and two antidiabetic drugs synergistically suppressed the expression of mesenchymal cell markers within BC cells in comparison with monotherapy. Conclusions Based on the findings, the synergistic effect of OBHS and 2-DG/metformin on cytotoxicity may be mediated through intrinsic mitochondria-mediated cell apoptosis to inhibit cell proliferation and reprogram the glycometabolism, which achieved the possible anticancer effect. This is an indication that OBHS combined with 2-DG/metformin was a potentially effective treatment strategy for estrogen receptor (ER)-positive BC.

Objectives Certain basic cell indices may possess prognostic significance in the treatment of multiple myeloma (MM). This study aims to evaluate the prognostic value of a combination of cell indices (CCI), comprising the percentage of bone marrow plasma cells (BMPCs), neutrophil-to-lymphocyte ratio (NLR), and platelet count, on progression-free survival (PFS) in MM patients. Methods This retrospective cohort study analyzed 111 patients with newly diagnosed MM. Patients were assigned 1 point for each of the following: high percentage of BMPCs (40 %), high NLR (2.065), and low platelet count (<150 × 10 9 /L). Based on these scores, the CCI was formulated. Patients were categorized into low-risk (0 points), intermediate-risk (1–2 points), and high-risk (3 points) groups. Results Univariate and multivariate analyses identified CCI as an independent prognostic factor for PFS (intermediate-risk group: Hazard ratio (HR) 3.538, 95 % CI: 1.592–7.860, high-risk group; HR 5.049, 95 % CI: 1.890–13.482, p<0.001). The PFS for the low-risk, intermediate-risk, and high-risk groups were 41.732, 27.758, and 16.600 months, respectively. Conclusions The CCI, incorporating the percentage of BMPCs, NLR, and platelet count, may serve as an independent prognostic factor for PFS in MM patients.

Objectives CXCL14, a member of the CXC chemokine family, plays a significant role in tumor development, progression, and metastasis, making it a potential target for cancer diagnosis and treatment. This study aims to investigate the impact of a point mutation in the ( 41 VSRYR 45 ) motif of CXCL14 on its anti-tumor activity. Methods Phylogenetic analysis, tertiary structure prediction, homology modeling, and cell culture experiments were employed to assess the effects of CXCL14 mutations on protein stability and anti-tumor activity. Phylogenetic analysis identified conserved regions critical for function, while computational tools predicted structural changes due to mutations. Homology modeling provided structural insights, and cell culture experiments involved transfecting HeLa cells with wild-type or mutant CXCL14 plasmids, assessing stability and anti-tumor effects. Additionally, in vivo, xenograft experiments using nude mice were conducted to evaluate the anti-tumor efficacy of CXCL14 variants. Results The conserved Y44 site within the ( 41 VSRYR 45 ) motif was identified as a key ubiquitination site. Mutations Y44V and Y44F enhanced CXCL14 stability, reducing HeLa cell proliferation and migration while increasing apoptosis. In vivo , tumor xenograft experiments confirmed the stronger inhibitory effect of these CXCL14 variants on tumor growth compared to the wild-type protein. Conclusion The Y44 site in CXCL14 is crucial for its stability and anti-tumor activity. Mutations Y44V and Y44F enhance CXCL14 stability and anti-tumor effects, suggesting that targeting this site could be a promising therapeutic strategy for cervical cancer.

Objectives Oxeiptosis could suppress the progression of breast cancer (BRCA). We aim to identify the prognostic factor associated with BRCA using oxeiptosis gene expression profiling and investigate its role in BRCA. Methods We extracted RNA sequencing data and clinical information on BRCA samples from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases using an oxeiptosis-related gene set. Prognosis-related genes for BRCA were screened from the TCGA dataset using bioinformatics analysis. Subsequently, we constructed a prognostic model for BRCA depending on the expression of this predictive factor and analyzed the associated function. The effects of Transcobalamin 1 (TCN1) on BRCA cell function and H 2 O 2 -induced oxeiptosis were validated in vitro . Results TCN1 was identified as the most strongly associated factor with BRCA prognosis among the differentially expressed genes in oxeiptosis. Patients with high TCN1 expression demonstrated a better prognosis in BRCA. In BRCA, TCN1 was enriched in response to the oxidative stress pathway. Additionally, TCN1 was associated with the expression of immune checkpoints and gene variations. Compared to normal human breast epithelial cells, TCN1 was downregulated in BRCA cells. Overexpression of TCN1 inhibited the proliferation, migration, and invasion of BRCA cells, and enhanced H 2 O 2 -induced oxeiptosis in BRCA cells. Conclusions Based on the oxeiptosis gene set, we identified TCN1 as a prognostic factor associated with BRCA. The findings highlight the potential of TCN1 as a therapeutic target and provide valuable insights into the development of personalized treatment strategies for BRCA.

Objectives Oral squamous cell carcinoma (OSCC) is characterized by the presence of cancer-associated fibroblasts (CAFs) in its tumor microenvironment. This study aimed to investigate factors associated with stromal CAFs and develop a CAF-based classifier for prognosis and treatment prediction in OSCC. Methods mRNA expression profiles of mRNA and clinical data from 245 patients with OSCC were sourced from TCGA. Additional datasets (GSE41613, GSE65858, and GSE30784) comprising 97, 83, and 167 OSCC patients were also included. Weighted gene co-expression network analysis revealed genes linked to stromal CAFs, and a CAF-based risk signature was established. Primary OSCC tumor tissues were obtained from Nanjing Stomatological Hospital, and CAFs were isolated from fresh tumor samples. Expression of POSTN was confirmed in fibroblast and OSCC cell lines using reverse transcription-quantitative PCR and western blotting. Results Enhanced infiltration of CAFs correlated with a worse prognosis in OSCC patients. A four-gene prognostic signature including POSTN, TGFB3, PDGFRB, and COL6A2 was identified. Patients were categorized into high and low CAF risk groups based on median risk scores, with the high-risk group showing a significantly worse prognosis (p<0.001). High-risk OSCC patients exhibited increased susceptibility to BMS-754807, GSK269962A, and JQ1 treatments, while the response to radiotherapy and immunotherapy did not significantly differ. Fibroblast cell lines exhibited higher POSTN expression compared to OSCC cell lines and normal fibroblasts. Conclusions This study links increased CAF infiltration to a negative prognosis in OSCC patients. The four-gene prognostic signature holds potential clinical value, and identified markers may serve as therapeutic targets for OSCC.

Objectives Esophageal squamous cell carcinoma (ESCA) is a challenging disease characterized by a high mortality rate. Understanding the prognostic relationship between G protein-coupled receptors (GPR) and ESCA is critical for improving patient outcomes, yet this connection remains to be fully explored. Methods In this study, we examined the roles of GPR genes and the tumor microenvironment (TME) in ESCA development and progression. Cox regression and Kaplan–Meier analysis demonstrated the predictive value of these genes. Our analysis of TME cell-cell communication revealed extensive interactions, particularly involving neutrophils. We also assessed the combined predictive value of GPR genes, TME score, and tumor mutation burden (TMB) for patient prognosis in ESCA, ultimately constructing a GPR-TME-TMB classifier for prognosis prediction. Results We identified significant differences in GPR gene expression between normal and tumor tissues, with four genes (GPER1, GPR82, FFAR2, and HCAR3) correlating with patient prognosis. Single-cell RNA sequencing analysis revealed 10 major cell types in the TME, with GPR gene expression highly enriched in neutrophils. Our findings indicate that the GPR-TME-TMB classifier is strongly associated with patient prognoses. Additionally, our results align with previous studies on the roles of GPR genes and the TME in ESCA. Conclusions Our results suggest that GPR-related genes play a role in ESCA progression and are strongly associated with TME in ESCA. We constructed a GPR-TME classifier for ESCA to provide new directions for the treatment and prognosis of ESCA patients.

Objectives The primary objectives of this research were to examine the prognostic significance of the albumin-to-fibrinogen ratio (AFR) in patients who have undergone surgery for esophageal squamous cell carcinoma (ESCC) and to develop an easily implementable predictive model with clinical utility. Methods The present study retrospectively analyzed the clinical data of 414 patients who underwent R0 resection after being diagnosed with stage I–III ESCC. The prognostic value of AFR was evaluated using Kaplan-Meier survival curves and COX proportional risk regression modeling, and the effectiveness of AFR compared with other inflammatory markers was evaluated. Additionally, a nomogram prediction model was developed, and its accuracy was evaluated using the receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves. Results AFR was significantly correlated with tumor length, T-stage, N-stage, pathological stage, and vascular infiltration (p<0.05 for all). The multivariate analysis results demonstrated that AFR was an independent prognostic factor that affected patient outcomes, whereas other inflammatory and nutritional biomarkers did not. Furthermore, the overall C-index of the nomogram risk prediction model was 0.737 (95 %-CI: 0.700–0.776). The calibration curves showed that the 3- and 5-year overall survival (OS) probabilities predicted by the nomogram were consistent with actual observations. Moreover, the DCA and ROC curves showed that our model had better clinical utility. Conclusions Preoperative AFR, a clinical indicator based on inflammation and nutrition, plays a clear role in the predictions of patient prognosis. The prognostic prediction model incorporating pathological factors and AFR demonstrates simplicity, efficacy, and exceptional accuracy.

Objectives Neutrophils play a crucial part in the proliferation, migration, and invasion of a variety of cancers. Multi-omics approach was applied to explore the role of neutrophils in lung adenocarcinoma (LUAD) and their influence on LUAD progression was characterized. Methods The Cancer Genome Atlas Program (TCGA) database was accessed to obtain relevant data, based on which neutrophil subsets were identified after cell clustering and annotation using FindNeighbors and FindClusters. Monocle2 was utilized for Pseudotime analysis. Transcription factor (TF) prediction analysis was performed by applying pySCENIC. Hub genes identified by WGCNA were intersected with the genes screened by Cox regression to select key genes for LUAD. In addition, the expression and potential biological functions of the screened genes in LUAD were verified by conducting quantitative reverse transcription polymerase chain reaction (qRT-PCR), wound healing, and transwell assays. Results This study identified four neutrophil subsets, namely, Neu0, Neu1, Neu2, and Neu3. Pseudotime results revealed that the cells had five states, and cell communication analysis demonstrated a correlation between neutrophils and tumor cells. WGCNA analysis screened 381 hub genes, which were further compressed to 15 key genes. In vitro experiments validated the potential of the top five genes ( P2RY13 , CYTIP , ZYX , KLRB1 , and HMOX1 ) to serve as biomarkers for LUAD. Knocking down HMOX1 effectively inhibited LUAD cell invasion and migration. Analysis of the prognostic models showed that the RiskScore and nomogram had strong prediction capabilities. Drug sensitivity analysis predicted vincristine as a potential drug for LUAD. Conclusions This study identified five neutrophil-related biomarkers ( P2RY13 , CYTIP , ZYX , KLRB1 , and HMOX1 ) for LUAD. Importantly, HMOX1 affected LUAD cell invasion and migration. The present findings improved the current understanding of the pathogenesis of LUAD.

Objectives Palmatine Hydrochloride (PaH), an isoquinoline alkaloid from Phellodendron amurense and Coptis chinensis , has analgesic, anti-inflammatory, and anticancer properties. This study aimed to assess PaH’s effectiveness against SW480 colorectal cancer (CRC) cells and explore its molecular mechanisms. Methods PaH’s effects on SW480 CRC cells were evaluated using MTT assays for proliferation, scratch assays for migration, and flow cytometry for apoptosis. Differentially expressed genes (DEGs) were identified through high-throughput sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses assessed DEG roles. Prognostic significance related to programmed cell death (PCD) was analyzed using R-Package with TCGA data. RT-qPCR validated key genes identified. Results PaH significantly inhibited SW480 cell growth, invasion, and apoptosis. The MTT assay showed inhibition rates increased from 5.49 % at 25 μg/mL to 52.48 % at 400 μg/mL. Scratch assays indicated reduced cell invasion over 24, 48, and 72 h. Apoptosis rose from 12.36 % in controls to 45.54 % at 400 μg/mL. Sequencing identified 3,385 significant DEGs, primarily in cancer pathways (p=0.004). Among 35 PCD-related DEGs, Lasso Cox regression highlighted 12 key genes, including TERT, TGFBR1, WNT4, and TP53. RT-qPCR confirmed TERT and TGFBR1 downregulation (0.614-fold, p=0.008; 0.41-fold, p<0.001) and TP53 and WNT4 upregulation (5.634-fold, p<0.001; 5.124-fold, p=0.002). Conclusions PaH inhibits CRC cell proliferation, migration, and invasion by modulating key PCD genes, suggesting its potential as a CRC therapeutic agent.