Jan 2026· Human Mutation· Vol 2026· 0 citations· 60 references
Medicine
TL;DR
The PTM‐related six‐gene model showed potential for prognostic stratification and characterization of immune‐related features in LUAD and demonstrated that the low‐risk group may be more likely to benefit from immunotherapy.
Abstract
Introduction Posttranslational modification (PTM) plays an important role in protein regulation and may influence tumor initiation and progression. However, the role of PTM‐related programs in lung adenocarcinoma (LUAD) remains incompletely understood. Materials and Methods Single‐cell RNA sequencing (scRNA‐seq) data were analyzed to quantify the activity of PTM‐related gene set using the AUCell algorithm and to characterize intercellular communication using CellChat. Molecular subtypes and differentially expressed genes (DEGs) were identified using ConsensusClusterPlus and limma packages, respectively, followed by functional enrichment analysis. Univariate Cox regression, LASSO regression with 10‐fold cross‐validation, and stepwise multivariable Cox regression based on the Akaike information criterion (AIC) were used to construct a prognostic model. Immune infiltration was evaluated using ESTIMATE, CIBERSORT, MCP‐counter, and TIMER algorithms, and drug sensitivity was predicted using oncoPredict package. The IMvigor210 cohort was used for exploratory assessment of immunotherapy response. Quantitative real‐time reverse transcription PCR (qRT‐PCR) was used to measure the expressions of the model genes. CCK‐8, wound‐healing, and Transwell assays were performed to evaluate the effects of CDKN3 knockdown on LUAD cells. Results Comparison between two PTM groups revealed that receptor ligands such as MIF‐(CD74+CXCR4) and MIF‐(CD74+CD44) had higher communication probabilities in the high–PTM‐score group. Two molecular subtypes were identified, and a six‐gene risk model for LUAD was established based on CDKN3, PKP2, ADM, MS4A1, FAM83A, and DKK1. The high‐risk group showed a lower immune score, and drugs such as Docetaxel_1007 may have therapeutic potential for LUAD. Immunotherapy response prediction further demonstrated that the low‐risk group may be more likely to benefit from immunotherapy. In vitro experiments demonstrated that CDKN3, PKP2, ADM, FAM83A, and DKK1 were upregulated, whereas MS4A1 was downregulated in A549 cells compared with BEAS‐2B cells. Additionally, knockdown of CDKN3 significantly suppressed the viability, migration, and invasion of LUAD cells. Conclusion The PTM‐related six‐gene model showed potential for prognostic stratification and characterization of immune‐related features in LUAD. However, further prospective and experimental validation is required before direct clinical application.
While several G2/M oncogenes are known to promote tumor progression, their coordinated tumor-suppressive networks antagonizing this axis and their regulatory and immunological contexts remain poorly defined.
We performed a multi-layered integrative analysis combining correlation profiling (UALCAN and ENCORI), multi-endpoint survival analysis (KM Plotter: OS, FPS, PPS across pan-lung, LUAD, and smoker cohorts), and transcriptomic refinement using TNMplot. A miRNA–mRNA regulatory network was constructed via miRNet, refined using UALCAN expression filtering, KM survival, and CancerMIRNome ROC analysis, followed by ENCORI-based miRNA–gene correlation. Direct miRNA–mRNA and lncRNA–miRNA binding affinities were assessed using IntaRNA. lncRNAs associated with the key miRNA were identified via Enrichr, filtered by expression, correlation, and survival, and validated by binding and gene correlation analyses. Finally, immune cell correlations were evaluated using GSCA, and an integrated ROC model was generated in R.
We identified a high-confidence panel of six tumor suppressors (CBX7, CD81, CRY2, CYBRD1, NR3C2, REEP5) and six G2/M oncogenes (AURKA, AURKB, BUB1, FOXM1, MELK, TTK) based on correlation, survival, and TNMplot criteria. hsa-let-7b-5p emerged as a central regulatory miRNA (AUC = 0.89) positively correlated with tumor suppressors and predicted to bind all six oncogenes. TMPO-AS1 was identified as an oncogenic lncRNA antagonizing hsa-let-7b-5p via strong binding (–15.85 kcal/mol) and negative correlation with tumor suppressors. An integrated lncRNA-miRNA-mRNA ROC model achieved an AUC ≈ 0.97. Immune analysis revealed reciprocal patterns: tumor suppressors correlated with MAIT, NKT, and Tfh cells and inversely with exhausted cells and nTregs, whereas oncogenes showed the opposite trend with the same.
This study defines a robust G2/M -associated regulatory framework in LUAD, characterized by reciprocal dysregulation of oncogenes and tumor suppressors and associated with the predicted TMPO-AS1–hsa-let-7b-5p regulatory network, which is linked to a less immunosuppressive tumor microenvironment, offering potential prognostic and therapeutic implications in LUAD.
Prerna Vats, B. Baweja, Chainsee Saini et al.· BMC Pulmonary Medicine· 0 citations
BACKGROUND
Bladder cancer (BCa) is a common urological malignancy with high recurrence rates and limited treatment options for advanced disease. Circular RNAs (circRNAs) are emerging as key regulators of cancer progression, but the roles of most circRNAs in BCa remain poorly understood.
OBJECTIVE
To investigate the expression, function and mechanism of circPCMTD1 (hsa_circ_0001801) in BCa, focusing on its m6A methylation and its role as a ceRNA regulating the miR-3681-5p/HPSE/PI3K/AKT axis.
METHODS
circPCMTD1 expression was analyzed in GEO datasets, 30 paired BCa tissues and cell lines by qRT-PCR. Circular structure and stability were confirmed by RNase R and actinomycin D assays. Subcellular localisation was determined by fractionation and FISH. Gain- and loss-of-function experiments assessed circPCMTD1 effects on BCa cell malignancy. A subcutaneous xenograft model was used for in vivo validation. m6A sites were predicted by SRAMP, and circPCMTD1-EIF4A3 interaction validated by RIP. Protein-protein docking predicted EIF4A3-METTL3 binding. miRNA targets were screened by ENCORI and confirmed by qRT-PCR and RNA-FISH. miR-3681-5p targets were identified by transcriptome sequencing and database analysis. Western blotting assessed HPSE, PI3K, AKT and p-AKT. Rescue experiments verified the circPCMTD1/miR-3681-5p/HPSE axis.
RESULTS
circPCMTD1 was upregulated in BCa tissues and cells, stable and cytoplasmic. Knockdown suppressed BCa proliferation, migration, invasion and Tumor growth in vivo, while overexpression promoted these phenotypes. circPCMTD1 contained nine predicted m6A sites, interacted with EIF4A3, and EIF4A3 docked with METTL3. circPCMTD1 overexpression increased METTL3, METTL14, FTO and YTHDF2. circPCMTD1 directly sponged miR-3681-5p. miR-3681-5p acted as a tumor-suppressive miRNA. HPSE was a direct target of miR-3681-5p and overexpressed in BCa. circPCMTD1 positively regulated HPSE, PI3K and p-AKT, whereas miR-3681-5p had opposite effects. Rescue experiments confirmed that circPCMTD1 promoted BCa through sponging miR-3681-5p and activating HPSE/PI3K/AKT.
CONCLUSIONS
EIF4A3 facilitates METTL3-mediated m6A methylation of circPCMTD1. Methylated circPCMTD1 acts as a ceRNA sponging miR-3681-5p, derepressing HPSE and activating PI3K/AKT to drive BCa progression. This study identifies a novel EIF4A3/m6A-circPCMTD1/miR-3681-5p/HPSE/PI3K/AKT axis and suggests potential therapeutic targets for BCa.
Lingbao Xiang, Yutong Li, Xuan Dong et al.· Cellular Signalling· 0 citations
A robust prognostic model based on four RhoGTPase-related prognostic genes was established, effectively stratifying LUAD patients and provides valuable insights into the heterogeneity of LUAD and has the potential to inform personalized therapeutic strategies.
Tianchuan Li, Danhong Wu, A. Yang et al.· Scientific Reports· 0 citations
BACKGROUND
Methyltransferase-like 9 (METTL9) has been implicated in tumor progression, yet its clinical significance, functional roles, and immunoregulatory functions in lung adenocarcinoma (LUAD) remain unclear. This study aimed to integrate multi-omics datasets and experimental evidence to systematically evaluate the expression profile, prognostic value, molecular mechanisms, and tumor microenvironment (TME)-related functions of METTL9 in LUAD.
METHODS
Transcriptome and clinical data for LUAD and METTL9 protein expression were obtained from public databases. Survival analysis was performed using Kaplan-Meier analysis and Cox proportional hazards models. METTL9-related differentially expressed genes (DEGs) were screened, followed by functional annotation and pathway enrichment analysis. A protein-protein interaction (PPI) network associated with METTL9 was constructed using STRING. METTL9 gene mutations and promoter methylation levels were analyzed via cBioPortal and UALCAN. Immune infiltration was evaluated through gene set variation analysis (GSVA) and the TIMER platform. The role of METTL9 depletion in regulating transforming growth factor-β (TGF-β)/Smad signaling, epithelial-mesenchymal transition (EMT), as well as the behavior of A549 and H1975 cells was investigated.
RESULTS
METTL9 was markedly elevated in LUAD, which was confirmed in external datasets and immunohistochemistry. Increased METTL9 expression showed a strong association with advanced TNM stage, unfavorable clinicopathological parameters, and poor survival outcomes in univariate analysis. Receiver operating characteristic (ROC) analysis indicated that METTL9 showed moderate diagnostic utility for LUAD, with an Area Under the Curve (AUC) of 0.704 (95% Confidence Interval [CI]: 0.650-0.758) in the The Cancer Genome Atlas (TCGA) dataset and 0.815 (95% CI: 0.758-0.872) in the GSE31210 dataset. Moreover, high METTL9 expression was significantly correlated with poor survival outcomes (Hazard Ratio [HR] = 1.349, 95% CI: 1.010-1.802, p = 0.043). METTL9 interacted with multiple oncogenic proteins in the PPI network and showed significant correlations with cuproptosis-related genes. Immune infiltration analysis further demonstrated that METTL9 expression showed significantly associated with immune cell infiltration and the tumor immune microenvironment in LUAD. METTL9 knockdown suppressed LUAD cell proliferation, migration, invasion, and EMT, while promoting apoptosis and reducing the expression of B-cell lymphoma 2 (Bcl-2), phosphorylated Smad2 (p-smad2), and phosphorylated Smad3 (p-smad3).
CONCLUSION
METTL9 is upregulated in LUAD and correlates with an unfavorable prognosis. Our results indicate that METTL9 may contribute to LUAD progression and EMT, potentially in relation to the TGF-β/Smad signaling pathway.
Chen Gong, Yuyan Chen, Yuchen Xie et al.· Frontiers in Bioscience· 0 citations
Background PTPRF interacting protein alpha 1 (PPFIA1), a cytoplasmic scaffold protein of the liprin family, modulates cell adhesion, signal transduction, and cytoskeletal dynamics. Its pan-cancer prognostic implications and functional roles, particularly in pancreatic cancer, remain underexplored. Methods Pan-cancer datasets including TCGA, GTEx and TISCH were integrated to assess PPFIA1 expression, genomic alterations, and pathway enrichment via Kaplan-Meier survival analysis, Cox regression, cBioPortal, and GSEA. In pancreatic cancer, external cohorts (e.g., GSE28735, GSE52452) were used for expression and prognosis validation. Besides, immunotherapy response was analyzed by using TIGER cohorts. Functional impacts were determined by using ShRNA-mediated knockdown in CFPAC-1, PANC-1 and Panc-02 cells and evaluating their proliferation, migration and invasion in vitro and in vivo. Results PPFIA1 exhibited differential expression across multiple cancer types, with overexpression in pancreatic adenocarcinoma (PAAD) versus non-tumor tissue at mRNA/protein levels, predominantly in malignant cells. High PPFIA1 correlated with adverse prognosis in PAAD across multiple endpoints. Genomic analyses revealed amplifications in head/neck cancers and mutations in endometrial carcinoma, clustering in SAM domains. GSEA enrichment analysis indicated pan-cancer activation of the mitotic spindle assembly pathway and Epithelial-Mesenchymal Transition (EMT) pathways in PAAD. Knockdown suppressed PAAD cell proliferation, colony formation, migration, invasion, and tumor growth in vivo. Notably, elevated PPFIA1 predicted superior responses to immunotherapy in pan-cancer cohorts rather than pancreatic cancer. Conclusions PPFIA1 emerges as a pan-cancer biomarker with prognostic significance and shows an oncogenic role in PAAD, potentially associating with EMT-related malignant phenotypes. Its association with immunotherapy efficacy suggests PPFIA1 warrants further investigation as a candidate biomarker and potential functional target for precision oncology.
Shu Li, Hailin Jiang, Xiaojia Li et al.· Frontiers in Oncology· 0 citations
INTRODUCTION
Sorafenib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical benefit is limited by significant interpatient variability in response. Identifying reliable candidate biomarkers associated with sorafenib treatment is critical for optimizing treatment strategies and improving patient outcomes.
METHODS
Samples in the GSE109211 dataset were divided into sorafenib-treated and control groups. Differentially expressed genes (DEGs) were screened using the limma package and filtered via LASSO and SVM-RFE algorithms to identify potential HCC biomarkers. CIBERSORT and ESTIMATE algorithms were used to evaluate immune infiltration and its correlation with candidate genes, followed by GSEA to explore enriched functional pathways. Regulatory networks were constructed using hTFtarget and ENCORI, and potential drugs were predicted by molecular docking. The expression and knockdown effects of RPS21 were validated in THLE-2 and HuH7 cells using qRTPCR, wound-healing, and Transwell assays.
RESULTS
Five sorafenib-treatment-associated candidate biomarkers were identified, including glutamic-oxaloacetic transaminase 1 (GOT1), out at first homolog (OAF), Xprolyl aminopeptidase 2 (XPNPEP2), cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2), and ribosomal protein S21 (RPS21). These genes were related to immune cell infiltration. In particular, the expression of OAF and CRISPLD2 was associated with immune scores. GSEA showed enrichment in pathways such as OXIDATIVE_ PHOSPHORYLATION and MYC_TARGETS. GOT1 stably bound to sorafenib, carbamazepine, and diclofenac. RPS21 was upregulated in HuH7 cells, and its knockdown impaired migration and invasion, validating its oncogenic role.
DISCUSSION
This study identified candidate biomarkers related to sorafenib treatment for HCC through computational analyses, experimentally validated the oncogenic function of RPS21, and predicted carbamazepine and diclofenac as potential combination therapies for precision treatment of HCC.
CONCLUSION
We identified HCC biomarkers associated with sorafenib treatment and the tumor immune microenvironment, predicted targeted drugs, and expanded the paradigm for precision therapy in HCC.
Mengru Zhan, Penghui Li, Wanyi Wang et al.· Current Medicinal Chemistry· 0 citations
Related blog posts
MIT News · Artificial Intelligence· news.mit.eduAug 27, 2026
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
