Aug 2026· Molecular and Cellular Probes· Vol 90, pp.
102082
· 0 citations· 30 references
Medicine
TL;DR
Integrative analyses and experimental validation suggest that DDX52 is a potential prognostic biomarker and therapeutic target in LIHC and its associations with immune features and multiple cancer-related pathways provide hypotheses for future mechanistic investigation.
Abstract
Background
The DExD/H-box (DDX) helicase family plays critical roles in RNA metabolism and has been implicated in tumorigenesis. However, the pan-cancer activities and prognostic potential of DDX52, especially in liver hepatocellular carcinoma (LIHC), are largely unknown.
Methods
We comprehensively analyzed DDX52 across pan-cancer using TCGA, GEO, HPA, and SpatialTME databases, assessing its differential expression, prognosis, genetic alterations, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), and immune microenvironment features. In LIHC, we performed functional enrichment, PPI network, single-cell sequencing, and drug sensitivity analyses. Molecular docking explore potential small-molecule inhibitors of DDX52. Finally, we validated DDX52 expression and function in LIHC.
Results
DDX52 mRNA and protein expression were significantly upregulated in multiple malignancies, including LIHC. Elevated DDX52 expression correlated with poor prognosis in LIHC. Genetic analysis revealed frequent copy number variations (CNV) and single-nucleotide variants (SNV) of DDX52, with significant positive correlations between DDX52 expression and both TMB and MSI across numerous cancer types. DDX52 expression was also significantly associated with immune cell infiltration, immune checkpoint molecules. In LIHC, DDX52 was predominantly expressed in B cells, proliferating T cells, malignant cells, and monocytes/macrophages. Functional enrichment analysis indicated DDX52 involvement in metabolic processes, histone modification, cell cycle regulation, and oncogenic signaling pathways. Pharmacologically, high DDX52 expression correlated with reduced drug sensitivity. Experimentally, DDX52 silencing significantly inhibited proliferation, colony formation, migration, and invasion in HepG2 and MHCC-97H cells.
Conclusions
Our integrative analyses and experimental validation suggest that DDX52 is a potential prognostic biomarker and therapeutic target in LIHC. Its associations with immune features and multiple cancer-related pathways provide hypotheses for future mechanistic investigation.
Background WD Repeat Domain 76 (WDR76) plays a potential role in cellular regulation; however, its comprehensive landscape across human malignancies and its specific biological function in hepatocellular carcinoma (HCC) remain largely unexplored. Methods We conducted a systematic pan-cancer analysis utilizing multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) atabases to evaluate WDR76 expression, subcellular localization, and its correlation with clinicopathologic features, genomic instability, and immune infiltration. Diagnostic and prognostic values were assessed via Receiver operating characteristic (ROC) and Kaplan-Meier analyses. Furthermore, the functional role of WDR76 in HCC was validated in vitro using Hep-3B and Huh7 cell lines through siRNA-mediated knockdown, followed by CCK-8, wound-healing, and transwell assays. Results WDR76 was significantly upregulated in the majority of tumor types, including LIHC, LUAD, and COAD, while exhibiting nuclear localization. Elevated WDR76 expression correlated with advanced tumor staging, metastasis, and poor clinical outcomes across multiple cohorts, particularly in ACC, KIRP, and LIHC. ROC analysis highlighted its exceptional diagnostic precision in cancers such as GBM and LIHC. Immunologically, WDR76 expression was intricately linked to immune cell infiltration, immune checkpoint markers, and genomic instability parameters, suggesting a role in shaping the tumor microenvironment. Drug sensitivity profiling revealed that high WDR76 levels correlate with resistance to specific chemotherapeutic agents. Experimentally, silencing WDR76 in HCC cells significantly suppressed cell proliferation, migration, and invasion capabilities. Conclusion Our study establishes WDR76 as a robust pan-cancer prognostic biomarker and a potential immunotherapeutic target. Specifically, we provide experimental evidence that WDR76 functions as an oncogenic driver in liver cancer, promoting malignant phenotypes and offering a novel avenue for targeted therapeutic intervention.
Yi-Fan Wang, Rong Zhou, Shen-Long Guo et al.· International Journal of Imm...· 0 citations
Collectively, m6A-related genes are dysregulated in breast cancer and correlate with patient outcomes, highlighting their biomarker potential, with YTHDF3 warranting in-depth investigation.
Pu Jin, Yue-Tsz Fan· Journal of Visualized Experi...· 0 citations
Long noncoding RNAs (lncRNAs) are emerging as critical regulators of tumor initiation and progression through transcriptional and posttranscriptional mechanisms. UPK1A antisense RNA 1 (UPK1A-AS1), a cancer‐associated lncRNA, has been reported to participate in oncogenic processes; however, its overall landscape across human malignancies and its biological role in therapy resistance remain poorly understood. Given the increasing importance of identifying functional lncRNAs with prognostic and therapeutic potential, this study presents a comprehensive multiomics characterization of UPK1A-AS1 and its experimental validation in hepatocellular carcinoma (HCC). We integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype‐Tissue Expression Project (GTEx), the cancer immunology data engine (CIDE), and the cBioPortal for cancer genomics (cBioPortal) to systematically assess its expression pattern, genomic alterations, clinical significance, and immunological associations. Our analyses revealed that UPK1A-AS1 is significantly upregulated in multiple tumor types, with copy‐number amplification as the predominant genomic alteration driving its overexpression. Elevated UPK1A-AS1 expression was correlated with advanced disease stage, poor differentiation, immune exclusion, and unfavorable prognosis, supporting its potential as a cancer type‐dependent biomarker. In parallel, functional studies demonstrated that hypoxia transcriptionally induces UPK1A-AS1 in HCC, where it promotes sorafenib resistance by suppressing apoptosis. Silencing UPK1A-AS1 restored apoptotic and enhanced sorafenib efficacy both in vitro and in vivo. Collectively, our findings suggest that UPK1A-AS1 is a hypoxia‐inducible oncogenic lncRNA that plays dual roles in cancer, with cancer type‐dependent associations with progression and immune modulation across malignancies and mechanistically mediating hypoxia‐associated drug resistance in HCC.
Ze-Kai Li, Min Luo, Shu-Sen Fang et al.· Analytical Cellular Patholog...· 0 citations
Background The ubiquitin domain‐containing protein 1 (UBTD1) is involved in protein homeostasis and cell cycle regulation, and emerging evidence suggests its role in tumor biology. However, its function in ovarian cancer (OC) remains unclear. OC is highly lethal due to late diagnosis, metastasis, and platinum resistance. This study is aimed at investigating the role of UBTD1 in OC by integrating single‐cell transcriptomics, mutation and HRD‐related analyses, tumor microenvironment evaluation, and experimental validation. Methods We examined UBTD1 expression, prognosis, somatic mutation features, and immune microenvironment characteristics utilizing public databases, such as the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Single‐cell RNA‐seq data were analyzed using Seurat, hdWGCNA, and CopyKAT to characterize UBTD1‐associated malignant‐cell states and inferred CNV burden. Based on the median UBTD1 expression, TCGA‐OV samples were divided into high and low expression groups to compare mutation spectra, DNA repair pathway activity, stromal scores, and immune cell infiltration. Functional assays were performed in A2780 and SK‐OV‐3 cell lines following lentiviral shRNAs‐mediated UBTD1 knockdown. RNA sequencing and rescue experiments were used to explore downstream pathways. Results Integrated single‐cell and TCGA‐OV analyses revealed that UBTD1‐low tumors were enriched for genomic instability–related features, including increased inferred CNV burden and higher tumor mutation burden. By comparison, UBTD1‐high tumors showed increased stromal scores and modest enrichment of selected immune‐cell populations, including macrophages and neutrophils. Experimentally, UBTD1 was upregulated in OC and associated with poor prognosis. UBTD1 knockdown inhibited malignant phenotypes, enhanced cisplatin sensitivity, promoted apoptosis, and suppressed TNF/AP‐1/FOS–related signaling. FOS overexpression partially reversed the effects of UBTD1 silencing. Conclusions UBTD1 expression defines distinct mutation and microenvironmental states in OC and functionally promotes malignant phenotypes, potentially through TNF/AP‐1/FOS–related signaling.
Ai-Xin Liu, Yan-Xia Chen, Xian Zhao et al.· Human Mutation· 0 citations
Background This study aims to systematically elucidate the clinical significance and biological function of the phospholipid phosphatase (PLPP) family member (PPAP2C) phosphatidic acid phosphatase type 2C in breast cancer, and to evaluate its potential as a prognostic biomarker and therapeutic target. Methods Gene expression data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases were integrated to characterize the expression profile of PLPP family members, focusing on PPAP2C in breast cancer. The prognostic value of PPAP2C, initially identified at the mRNA level (TCGA, (METABRIC) Molecular Taxonomy of Breast Cancer International Consortium, Gene Expression Omnibus (GEO)), was confirmed at the protein level by immunohistochemistry (IHC) on tissue microarrays (TMA). The oncogenic functions of PPAP2C were investigated in triple-negative breast cancer (TNBC) cells through CRISPR-Cas9-mediated knockout and ectopic overexpression, with assessment of key phenotypes including proliferation, colony formation, migration, and invasion. In vivo validation was subsequently performed using an MDA-MB-231 xenograft model. Results PPAP2C exhibits the most significant overexpression pattern across 33 cancer types (upregulated in 16 cancers, downregulated in only 3). Compared with normal tissues, PPAP2C showed specific overexpression in breast cancer tissues and was significantly associated with advanced clinical stages and aggressive subtypes (HER2+ and TNBC). Survival analysis demonstrated that high PPAP2C expression correlated with significantly shorter overall survival and disease-free survival, which was further validated in METABRIC and GEO cohorts. Tissue microarray analysis confirmed higher PPAP2C protein positivity in tumor tissues (94.7%) than in adjacent normal tissues (59.7%), with worse OS and RFS in high-expression groups. Multivariate analysis identified PPAP2C as an independent prognostic factor for OS. Functional experiments revealed that PPAP2C knockout (via 5-bp/1-bp frameshift mutations) suppressed TNBC cell proliferation, colony formation, migration, and invasion, while overexpression enhanced these phenotypes. In vivo studies further demonstrated complete tumor regression in MDA-MB-231 xenografts upon PPAP2C knockout. Conclusion This study identifies PPAP2C as a key oncogenic driver and a robust independent prognostic biomarker in breast cancer. The findings provide compelling evidence that PPAP2C represents a promising therapeutic target, offering a new strategic avenue for precision therapy, particularly for aggressive breast cancer subtypes.
Xiao-Xi Lin, Li-Hang Cen, Si-Hui Yue et al.· Frontiers in Pharmacology· 0 citations
The findings suggest that SLC5A6 may participate in glucose-deprivation-induced disulfide stress, while its direct role in regulating disulfidptotic cell death remains to be established.
Chong Fu, Ze-Min Fang, Yan-Ping Zhang et al.· Frontiers in Oncology· 0 citations
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