C17orf75 plays an important role in LIHC progression by regulating cell cycle progression and EMT, and it may serve as a potential therapeutic target for LIHC.
Abstract
Background Chromosome 17 Open Reading Frame 75 (C17orf75) encodes the protein Njmu-R1 (Protein Njmu-R1),, which is involved in intracellular vesicle trafficking; however, its role in tumor progression remains largely unclear. Methods Public datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA) were analyzed to evaluate the expression profile, mutation landscape, and diagnostic and prognostic value of C17orf75. Bioinformatics analyses were subsequently performed to explore its associations with immune infiltration. In addition, functional assays were conducted on Hep3B and MHCC-97H cells, and immunohistochemistry (IHC) was performed on clinical liver hepatocellular carcinoma (LIHC) samples. Results C17orf75 was significantly upregulated in multiple cancer types, particularly in LIHC. Elevated C17orf75 expression was associated with unfavorable prognosis and advanced clinicopathological features in LIHC. Functional enrichment analyses indicated that C17orf75-related genes were involved in cell cycle regulation, DNA replication, and epithelial–mesenchymal transition (EMT). Furthermore, C17orf75 expression was closely correlated with immune infiltration, ferroptosis-related genes, and m6A regulators. Knockdown of C17orf75 inhibited the proliferation, migration, and invasion of LIHC cells. C17orf75 knockdown induced G2-phase arrest without significantly affecting apoptosis. Moreover, knockdown of C17orf75 suppressed EMT. Conclusion C17orf75 plays an important role in LIHC progression by regulating cell cycle progression and EMT, and it may serve as a potential therapeutic target for LIHC.
Background Hepatocellular carcinoma (HCC) is a highly aggressive cancer with high metabolic adaptability. TCF7L2, a transcription factor implicated in type 2 diabetes and cancer, is overexpressed in HCC. However, its specific role in HCC metabolic reprogramming is not well defined. We aimed to elucidate the previously unrecognized molecular mechanisms through which TCF7L2 impacts HCC progression. Methods To investigate the function of TCF7L2, a stable MHCC-97H cell line with TCF7L2 overexpression was established via lentiviral transduction. Cell viability and migration were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays. Transcriptomic profiling [RNA sequencing (RNA-seq)] was performed to identify differentially expressed genes (DEGs). Functional enrichment analysis [Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA)] and bioinformatics promoter analysis (the JASPAR CORE database) were conducted. Clinical correlations, survival analysis, and tumor microenvironment (TME) interrogation were performed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and single-cell datasets [Human Protein Atlas (HPA), CellChat]. Drug sensitivity was predicted via the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results TCF7L2 overexpression significantly promoted HCC cell proliferation and migration. Transcriptomic analysis revealed that TCF7L2 drives a profound metabolic shift, with key enrichments in lipid homeostasis, fatty acid β-oxidation, and the PI3K/Akt pathway. Mechanistically, TCF7L2 directly binds to the promoter of CPT1A, the rate-limiting enzyme of fatty acid oxidation, and indirectly upregulates the mitochondrial gene MT-ND4Lvia a strong positive correlation with the mitochondrial transcription factor TFAM. In clinical cohorts, TCF7L2 was overexpressed in HCC and its expression correlated positively with MT-ND4L, MKI67, and SNAI1, and served as a predictor of poor overall survival (OS). Furthermore, TCF7L2-high tumors were enriched in hepatic progenitor cell (HPC)-like niches, mediated by enhanced ANGPTL4 signaling. High TCF7L2 expression predicted increased sensitivity to PI3K/mTOR pathway inhibitors. Conclusions TCF7L2 acts as a master metabolic regulator in HCC, coordinating lipid catabolism and mitochondrial biogenesis to drive aggressive tumor behavior. It further remodels the TME towards an HPC-like state and predicts sensitivity to metabolic-targeted therapies. These findings identify TCF7L2 as a key prognostic biomarker and a promising therapeutic target.
Rong Chen, Wei-Jie Liu, Zi-Long Yang et al.· Translational Cancer Researc...· 0 citations
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high invasive-ness, limited therapeutic options, and unfavorable clinical outcomes. Ribosomal protein L5 (RPL5), a component of the large ribosomal subunit, has been implicated in ribosome biogenesis, translational regulation, and p53-associated cellular processes. This study investigated the immunohistochemical expression pattern of RPL5 in TNBC tissues and explored its potential biological significance through integrated transcriptomic analyses. Tumor tissues from 37 patients with TNBC and 7 adjacent non-tumorous breast tissues were collected from the Affiliated Tumor Hospital of Xinjiang Medical University between December 2017 and December 2023. RPL5 protein expression was evaluated by immunohistochemistry, and its association with clinicopathological characteristics was analyzed. Public transcriptomic datasets from TCGA-BRCA and GEO were further used to validate RPL5 expression patterns in TNBC. Co-expression analysis and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate potential biological functions and signaling pathways associated with RPL5. Immunohistochemical analysis demonstrated significantly lower RPL5 protein expression in TNBC tissues compared with adjacent normal breast tissues (p=0.001). In contrast, transcriptomic analyses revealed significantly higher RPL5 expression in TNBC compared with non-TNBC breast cancer subtypes (p<0.001). No significant associations were observed between RPL5 expression and clinicopathological parameters, including age, tumor size, menopausal status, TNM stage, histological grade, or lymph node metastasis (all p>0.05). Survival analysis showed no significant difference in overall survival between patients with high and low RPL5 expression. Functional enrichment analyses indicated that RPL5-related genes were predominantly involved in ribosome biogenesis, translational regulation, and p53-related signaling pathways. These findings suggest that abnormal RPL5 expression may be associated with TNBC biology through ribosome-related programs, although causal roles require functional validation. RPL5 may represent a potential histopathological and molecular indicator associated with TNBC biology, although its precise functional role requires further experimental validation.
Bing Zhao, Peiyuan Yu, Li Li et al.· European Journal of Histoche...· 0 citations
Objective To elucidate the role and molecular mechanism of the ERα36–SLC7A5/LAT1 signaling axis in the malignant progression of cervical cancer and its sensitivity to boron neutron capture therapy (BNCT). Methods Transcriptomic data from TCGA (n=296) and GTEx (n=10) were integrated to analyze SLC7A5 expression and its clinicopathological associations. Multiplex immunofluorescence staining was performed on a tissue microarray containing 99 cervical cancer specimens for spatial phenotyping. SiHa cell lines with stable ERα36 knockdown or overexpression were established using lentiviral transduction. CCK-8, flow cytometry, wound healing, Transwell, and colony formation assays were used to assess the effects of ERα36 on malignant phenotypes. Co-immunoprecipitation, Western blot, and qRT-PCR were employed to explore the interaction between ERα36 and LAT1 as well as downstream signaling changes. The impact of ERα36 on BNCT sensitivity was evaluated in both cellular and subcutaneous xenograft nude mouse models. Results SLC7A5 was significantly upregulated in cervical cancer tissues and correlated with M stage and poor prognosis. ERα36 and SLC7A5 exhibited robust spatial co-expression in the tumor microenvironment, and the double-positive phenotype was associated with shorter overall survival (P<0.05). ERα36 interacted with LAT1 and was associated with elevated CD98hc and EGFR expression. Knockdown of ERα36 suppressed proliferation, migration, and colony formation while promoting apoptosis; overexpression produced opposite effects. In BNCT simulation experiments, ERα36 knockdown markedly attenuated BNCT-induced cytotoxicity, as evidenced by increased colony formation, reduced apoptosis, and altered S-phase distribution. Both cellular and animal models consistently showed downregulation of ERα36 and LAT1 protein expression after BNCT. Conclusion The ERα36–SLC7A5/LAT1 axis associated with malignant phenotypes and BNCT sensitivity in cervical cancer. The ERα36+/SLC7A5+ spatial double-positive phenotype may represent a prognostic biomarker, and ERα36 may serve as a predictive marker for BNCT response.
Li-Li Zhang, Rui Quan, Hefa Huang et al.· Frontiers in Oncology· 0 citations
Regulator of G protein signaling 2 (RGS2), a negative regulator of G protein-coupled receptor signaling, is implicated in ovarian cancer. Given the disease's late-stage diagnosis and poor prognosis, identifying reliable molecular biomarkers is crucial. This study evaluated RGS2 gene expression in ovarian cancer and its clinicopathological and prognostic associations using public transcriptomic data. RNA-sequencing data from 419 The Cancer Genome Atlas (TCGA) tumor samples and 88 Genotype-Tissue Expression (GTEx) normal samples were compared using the Mann-Whitney U test. Additionally, 308 TCGA cases were analyzed for associations with tumor grade, clinical stage, and survival outcomes—including overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI), and disease-free interval (DFI) using the Kaplan-Meier method and log-rank tests based on median RGS2 expression. Results demonstrated that RGS2 was significantly down-regulated in ovarian cancer tissues compared to normal tissues (p<0,001). However, RGS2 expression showed no significant correlation with tumor grade, clinical stage, or any evaluated survival metrics (all p>0,05). In conclusion, while RGS2 is consistently down-regulated at the transcript level in ovarian cancer, it is not significantly associated with patient survival. These findings suggest that although reduced RGS2 expression is a common molecular feature of ovarian cancer, its utility as a standalone prognostic biomarker is limited in unstratified transcriptomic analyses.
A. A. Ghifari, M. Sianturi, Suyanto Suyanto et al.· Jurnal Ilmiah Kesehatan· 0 citations
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
Findings identify NTMT1 as a candidate regulatory node associated with MYC activation and downstream HLA-A suppression, warranting further mechanistic and in-vivo investigation, and highlighting NTMT1 as a promising candidate for future therapeutic investigation.
Jin-Ling Zhang, Chen Chen, Huibin Song et al.· Frontiers in Immunology· 0 citations
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