Cancer Genomics & Proteomics最新文献

Background/aim: Clear cell renal cell carcinoma (ccRCC) is among the 10 most common cancers diagnosed in the United States. Despite its severity and aggressive nature, biomarkers that can serve as prognostic and predictive factors for ccRCC are lacking. ABCD3, a peroxisomal long-chain fatty acid transporter, has been shown to serve as a prognostic factor in both prostate and colon cancers. Thus, this study aimed to ascertain if ABCD3, which is highly expressed in kidney tissues, may also serve as a biomarker for renal cancer.

Materials and methods: Bioinformatics and immunohistochemical staining were employed to systematically investigate the relationship between the ABCD3 gene and protein expression, the immune microenvironment, and survival outcomes in ccRCC. We extensively harnessed data from publicly available databases, including The Cancer Genome Atlas (TGCA), UALCAN, Gene Set Cancer Analysis, UCSC Xena, and various other databases.

Results: In silico analyses of the TCGA database revealed that ABCD3 transcripts and protein levels were significantly reduced (p<0.001) across all tumors and stages. Moreover, decreased ABCD3 expression was associated with poorer patient survival [hazard ratio=0.45 (0.33-0.61), p<0.001]. Immunohistochemical and CPTAC database analyses revealed that ABCD3 was significantly downregulated in ccRCC patients (p<0.05). Multivariate Cox regression analysis revealed that ABCD3 expression is an independent factor for overall survival [HR=0.4534 (0.2859-0.7189), p<0.001].

Conclusion: Our findings suggest that ABCD3 is a novel biomarker for ccRCC and that the downregulation of ABCD3 expression, and other members of the peroxisomal VLCFA oxidation pathway may represent a unique molecular feature of ccRCC.

Background/aim: Pregnancy-associated breast cancer (PABC) is one of the most frequently diagnosed pregnancy-related malignancies, characterized by a notably rising incidence. Data remain scarce in the literature regarding the molecular nature and pathophysiology of PABC. Proteomic analyses are known to reflect cellular functions more accurately when compared to genomic or transcriptomic studies.

Materials and methods: In the present study, two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were employed to identify differentially expressed serum proteins among five patients with PABC, five matched (according to age, histological type and stage) non-pregnant patients diagnosed with BC, and five healthy pregnant controls.

Results: A panel of 53 differentially expressed (>1.5-fold) proteins with diverse biological roles and various functional interactions was identified among the three groups examined in our study. Of the 53 differentially expressed proteins, 23 proteins were identified in the PABC group, 8 proteins in the non-PABC group, and 22 proteins in healthy pregnant controls. Many of the proteins differentially expressed in patients with PABC were involved in biological processes known to be deregulated in carcinogenesis, such as metabolism (e.g., apolipoprotein-E, and apolipoprotein-A1) and immune system regulation (e.g., complement factor B, and defensin-5).

Conclusion: Differential proteomic expression was detected in PABC-derived serum samples, implying distinct PABC molecular features that require further investigation. The identification of PABC proteomic signatures provides significant insight into PABC pathophysiology and offers novel targets for early diagnosis and optimal treatment.

Background/aim: Uveal melanoma (UVM) is the most prevalent primary intraocular malignancy, accounting for 3-5% of all melanomas. Despite its rarity, particularly in Japan (~2 cases per 100,000 individuals annually), UVM exhibits highly aggressive behavior, with nearly 50% of patients developing distant metastases. Once metastasized, the prognosis remains dismal, with a median survival of only 4-5 months. Identifying prognostic biomarkers and potential therapeutic targets is imperative to improve clinical outcomes. Stanniocalcin-1 (STC-1) is a glycoprotein hormone implicated in calcium and phosphate homeostasis. Recent studies have linked STC-1 overexpression to tumor progression, poor prognosis, and increased metastatic potential in various malignancies. However, the prognostic significance and mechanistic role of STC-1 in UVM remain unexplored.

Materials and methods: To elucidate the clinical relevance of STC-1 in UVM, we analyzed publicly available transcriptomic datasets using GEPIA2 and UALCAN, assessing STC-1 mRNA expression across disease stages and its correlation with patient survival. In parallel, single-cell RNA sequencing (scRNA-seq) datasets were utilized to identify the cellular sources of STC-1 within the UVM tumor microenvironment and to investigate its association with specific functional cellular states.

Results: STC-1 expression was significantly up-regulated in stage IV UVM tumors compared to stage III (n=4 and 36, respectively). Moreover, elevated STC-1 expression was inversely correlated with overall survival, suggesting its potential role in disease progression. scRNA-seq analysis revealed that STC-1 is expressed by both tumor cells and fibroblasts, indicating a possible cooperative mechanism that may drive tumor progression.

Conclusion: These findings suggest that STC-1 serves as a potential prognostic biomarker in UVM, providing novel insights into its role in tumor biology. Further investigation is warranted to explore its therapeutic implications and mechanistic contributions to UVM progression.

Background/aim: Noggin is a secreted antagonist of bone morphogenetic proteins (BMPs) and plays a key role in regulating various developmental and homeostatic biological processes. BMPs have been linked to the development of several types of cancers. However, the impact of Noggin on cellular functions and its role in pancreatic cancer remain unclear. This study aimed to investigate the role of Noggin in pancreatic cancer and its underlying molecular mechanisms.

Materials and methods: Noggin expression in both normal and cancerous pancreatic tissues was assessed using both quantitative and conventional PCR methods, alongside an analysis of publicly available gene expression array datasets. Correlations between Noggin expression and patient survival, TNM staging, tumor/stroma subtypes, and the expression of other cancer-related genes were examined. The influence of Noggin on cellular functions was evaluated in pancreatic cancer cell lines Mia PaCa-2 and PANC-1, which were genetically modified to overexpress Noggin.

Results: Noggin expression was found to be significantly higher in tumor tissues compared to normal pancreatic tissues. Elevated Noggin expression was associated with shorter overall survival in patients. Overexpression of Noggin led to increased proliferation of pancreatic cancer cells. Furthermore, elevated levels of EGFR and HER2 proteins were observed in the PANC-1 and Mia PaCa-2 cell lines, respectively. Treatment with EGFR and HER2 inhibitors reduced Noggin-induced proliferation in these cell lines.

Conclusion: Noggin is overexpressed in pancreatic cancer tissues and is linked to poor patient survival. Noggin promotes the proliferation of pancreatic cancer cells by up-regulating EGFR and HER2.

Background/aim: Tongue squamous cell carcinoma (TSCC), a highly aggressive subtype of head and neck cancers, is characterized by frequent lymphatic metastasis and poor prognosis. Recently, we showed that lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is involved in TSCC progression, yet the underlying molecular mechanisms remain unclear.

Materials and methods: CRISPR/Cas9 gene editing was employed to generate LYVE1 knockout (KO) TSCC cell lines. Single-cell clones were isolated, screened, and validated through sequencing and Inference of CRISPR Edits (ICE) analysis and qRT-PCR. RNA sequencing was performed on LYVE1 KO and wild-type (WT) cells to identify differentially expressed genes (DEGs). Bioinformatic analyses, including Gene Ontology (GO) enrichment and protein-protein interaction (PPI) network mapping, were conducted to explore affected pathways. Finally, network topology was examined using NetworkAnalyzer and cytoHubba plugins.

Results: Transcriptomic analysis revealed significant down-regulation of pro-metastatic pathways, including epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and immune modulation. DEG analysis identified 263 genes, with key down-regulated targets such as WNT5A, TGFB2, and MMP2, and up-regulation of tumor-suppressive genes including PTGS2. GO and PPI analyses highlighted LYVE1's pivotal role in regulating cell adhesion, migration, and immune response.

Conclusion: LYVE1 KO reduces TSCC invasive potential by disrupting EMT and tumor-stroma interactions, aligning with previous experimental findings. These results suggest LYVE1 as a critical driver of metastasis, highlighting its potential as a therapeutic target.

Background/aim: Particulate matter 2.5 (PM2.5) is known to adversely affect human health. While its involvement in lung cancer pathogenesis is recognized, its specific impact on metastasis-related behaviors of lung cancer cells remains largely unexplored.

Materials and methods: In this study, we employed cell culture models, proteomic analysis, and bioinformatic analysis. Target proteins and signaling pathways were validated using western blotting and immunofluorescence assay. Wound healing, transwell migration and phalloidin-rhodamine assays were used to determine the migratory activity.

Results: Proteomic analysis identified 3,795 proteins in both control and PM2.5-treated groups. Among these, proteins associated with metastasis, particularly those related to "cell migration" (GO: 0016477), were highlighted, identifying six key proteins involved in cancer metastasis. Protein-protein interaction analysis pinpointed fibroblast growth factor receptor 1 (FGFR1) as a central target influenced by PM2.5, which promoted cell migration via the Rap1 signaling pathway through integrin signaling. The enhanced migratory behavior of PM2.5-treated cells aligned with proteomic findings, demonstrating that PM2.5 exposure increases the motility of lung cancer cells. Western blotting and immunofluorescence confirmed that PM2.5 exposure led to up-regulation of FGFR1, integrin αV, β1, and activated p-Akt. Notably, PM2.5-treated cells exhibited significantly increased motility and a higher number of filopodia per cell.

Conclusion: These results indicate that FGFR1 is a crucial target in PM2.5-induced metastasis in lung cancer cells, operating through an FGFR1/integrin/Akt signaling axis. This study advances our understanding of the role of PM2.5 in lung cancer metastasis and suggests potential therapeutic strategies to mitigate cancer progression.

Background/aim: Prostate cancer remains a major global health burden, with treatment resistance posing a significant challenge. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a histone methyltransferase, is frequently overexpressed in prostate cancer, contributing to tumor progression and castration resistance. Clinical trials of EZH2 inhibitors may have therapeutic benefits. This study aimed to evaluate the impact of genetic variants in EZH2-related genes on survival outcomes in prostate cancer.

Patients and methods: We conducted a genetic association study evaluating 76 single nucleotide polymorphisms (SNPs) across 10 EZH2-related genes in 630 patients with prostate cancer undergoing androgen deprivation therapy (ADT). Functional analyses, including gene ontology and pathway enrichment assessments, were performed to elucidate the biological significance of key genes across multiple datasets.

Results: DNMT3A rs77993651 was significantly associated with both cancer-specific survival [hazard ratio (HR)=0.82, p=0.042] and overall survival (HR=0.80, p=0.011). Functional annotation indicated that rs77993651 resides within enhancer histone marks, potentially regulating DNMT3A expression. Elevated DNMT3A expression was observed in prostate tumor tissues and correlated with more aggressive features and shorter progression-free survival. Gene set enrichment analysis revealed that DNMT3A expression was strongly associated with cell cycle G₂/M checkpoint regulation, implicating a role in prostate cancer progression.

Conclusion: The prognostic significance of DNMT3A and its genetic variant rs77993651 in prostate cancer is herein highlighted. Targeting DNMT3A-mediated pathways may offer novel therapeutic strategies for prostate cancer management.

Background/aim: Recent advancements in omics analysis have significantly enhanced our understanding of the molecular pathology of malignant melanoma, leading to the development of novel therapeutic strategies that target specific vulnerabilities within the disease. Despite these improvements, the factors contributing to the poor prognosis of patients with malignant melanoma remain incompletely understood. The aim of this study was to investigate the role of C1orf50 (Chromosome 1 open reading frame 50), a gene previously of unknown function, as a prognostic biomarker in melanoma.

Materials and methods: We performed comprehensive transcriptome data analysis and subsequent functional validation of the human Skin Cutaneous Melanoma project from The Cancer Genome Atlas (TCGA).

Results: Elevated expression levels of C1orf50 correlated with worse survival outcomes. Mechanistically, we revealed that C1orf50 plays a significant role in the regulation of cell cycle processes and cancer cell stemness, providing a potential avenue for novel therapeutic interventions in melanoma.

Conclusion: This study is the first to identify C1orf50 as a prognostic biomarker in melanoma. The clinical relevance of our results sheds light on the importance of further investigation into the biological mechanisms underpinning C1orf50's impact on melanoma progression and patient prognosis.

Background/aim: The relationship between protein kinase C zeta (PKCζ) expression and medical treatment resistance in breast cancer subtypes is unclear. Therefore, the present study aimed to analyze this relationship using disease-specific survival.

Materials and methods: Open-source datasets with clinical and gene expression information (METABRIC, n=2509; and TCGA Pan-Cancer Atlas, n=1084) were downloaded and Kaplan-Meier survival and Cox proportional hazard analyses were performed.

Results: High expression of PKCζ indicated a poor prognosis in patients with luminal B type treated with endocrine therapy and aromatase inhibitor as endocrine therapy. Furthermore, catenin beta interacting protein 1 (CTNNBIP1) was identified as a differentially expressed gene between the PKCζ ^high and PKCζ ^low luminal B breast cancer cohorts treated with endocrine therapy and aromatase inhibitors. PKCζ ^high CTNNBIP1 ^high luminal B breast cancer treated with endocrine therapy and aromatase inhibitor indicated a poor prognosis. These results suggest that PKCζ and CTNNBIP1 are involved in breast cancer progression and contribute to reduced susceptibility to endocrine therapy in the luminal B breast cancer subtype.

Conclusion: PKCζ and CTNNBIP1 may serve as a prognostic biomarker for predicting the efficacy of endocrine therapy in the luminal B breast cancer.

Background/aim: Cluster of differentiation 84 (CD84), a member of the signalling lymphocytic activating molecule (SLAM) family, has emerged as a potential prognostic biomarker and therapeutic target in breast cancer. This study explored CD84 expression and its correlation with clinicopathological features in a well-characterised cohort.

Materials and methods: Using quantitative real-time PCR, mRNA expression levels of CD84 and related molecules, including PDL1, CD74, and other immune tolerance markers, were analysed.

Results: The findings reveal that elevated CD84 expression predicts poor overall survival, independent of conventional prognostic factors such as the Nottingham Prognostic Index (NPI). Notably, a combined signature of CD84, CD48, VAV1, and CTNNB1 demonstrated stronger prognostic power than individual markers. CD84 exhibited significant correlations with immunosuppressive molecules, including PDL1 and CD74, underscoring its role in fostering immune tolerance within the tumour microenvironment.

Conclusion: CD84 may mediate an immunosuppressive phenotype, facilitating immune evasion in breast cancer. This highlights its potential as a therapeutic target, particularly in triple-negative breast cancer, to overcome immune resistance and enhance treatment efficacy.