Cancer Genomics & Proteomics最新文献

Background/aim: Lysine lactylation (Kla) is a recently identified post-translational modification derived from lactate that regulates diverse biological processes. Although Kla has been studied in several cancers, its role in prostate cancer (PC) remains unclear. The objective of this study is to profile Kla in PC in order to explore the mechanisms involved in PC progression.

Materials and methods: We performed global Kla profiling in PC-3M prostate cancer cells using affinity enrichment with anti-Kla antibodies, followed by LC-MS/MS. Bioinformatics analyses were conducted to explore the functional roles of Kla-modified proteins.

Results: We identified 681 Kla sites across 379 proteins, with modifications predominantly located in nuclear and cytoplasmic proteins. Enrichment analysis indicated Kla involvement in mRNA splicing, chromatin organization, and glycolysis/gluconeogenesis. Several multifunctional proteins, including AHNAK and nucleolin (NCL) harbor multiple Kla sites. Motif analysis indicated conserved amino acid patterns surrounding Kla sites. Notably, PC-3M cells showed reduced expression of sirtuin (SIRT)3, SIRT5, and SIRT6, which may underlie elevated Kla levels.

Conclusion: This study presents the first comprehensive Kla landscape in PCa, suggesting its potential regulatory role in tumor progression. These findings provide a valuable resource for future studies and support Kla as a possible target for therapeutic intervention in prostate cancer.

Background/aim: Bone morphogenetic protein 1 (BMP1) plays a role in the activation of both transforming growth factor-β (TGFβ) and BMP signaling pathways. We investigated whether BMP1 is involved in G-protein coupled estrogen receptor 1 (GPER1)-regulated progression of luminal A-type breast cancer cells.

Materials and methods: Publicly available transcriptomic data from MCF7 breast cancer cells treated with the selective GPER1 agonist G1 were analyzed and the results, in particular the altered BMP1 expression, were validated by qPCR. Signs of epithelial-mesenchymal transition (EMT) were visualized by immune cytology. Invasion was quantified by modified Boyden chamber assay. Tamoxifen-resistant sublines of the MCF7 and T47D cell lines were established.

Results: Activation of GPER1 by the agonist G1 increased the expression of BMP1 in MCF7 and T47D luminal A breast cancer cells. In addition, EMT and invasion was enhanced after GPER1 activation. This effect could be prevented in part by the BMP1 inhibitor UK383367. Tamoxifen-resistant MCF7-TR and T47D-TR cells exhibited higher BMP1 expression, signs of EMT and enhanced invasiveness compared to their tamoxifen-sensitive wild type. Blocking GPER1 in MCF7-TR and T47D-TR cells using the antagonist G36 led to reduction in BMP1 expression, a slight decrease in EMT, reduced cell invasion, and increased sensitivity to tamoxifen.

Conclusion: BMP1 appears to be involved in GPER1-mediated progression of luminal A breast cancer cells. In addition, BMP1 may play a role in tamoxifen-resistance.

Background/aim: Prostate cancer is the second most common malignancy among men worldwide, with progression to castration-resistant prostate cancer (CRPC) posing significant therapeutic challenges. Enzalutamide, a second-generation androgen receptor antagonist, initially demonstrates efficacy in treating metastatic CRPC; however, resistance inevitably develops. Dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway has been implicated in therapy resistance and metastatic progression. Secretory carrier membrane protein 3 (SCAMP3) and epidermal growth factor receptor substrate 8 (EPS8) are known regulators of EGFR trafficking and signaling. This study aimed to investigate their cooperative roles in enzalutamide-resistant prostate cancer cells.

Materials and methods: LNCap prostate cancer cells and their enzalutamide-resistant derivatives (LNCap-Enz) were treated with 100 ng/ml epidermal growth factor (EGF). Protein expression and interactions were analyzed by Western blotting and co-immunoprecipitation. SCAMP3 and EPS8 were knocked down using shRNA technology, while complementary overexpression studies were conducted using pcDNA-SCAMP3 and pcDNA-EPS8 vectors. Effects on EGF receptor (EGFR) expression and downstream signaling molecules (STAT3, AKT, ERK) were evaluated in both loss-of-function and gain-of-function models.

Results: EGF stimulation enhanced the expression of EGFR, SCAMP3, and EPS8 in both LNCap and LNCap-Enz cells while promoting formation of a protein complex involving these proteins and the androgen receptor (AR-V7). Knockdown of SCAMP3 or EPS8 reduced EGFR expression and attenuated STAT3, AKT, and ERK activation. Conversely, overexpression of SCAMP3 or EPS8 increased EGFR levels and enhanced downstream signaling activation. These bidirectional effects highlight the functional interdependence between SCAMP3 and EPS8 in regulating EGFR stability and signaling.

Conclusion: SCAMP3 and EPS8 cooperatively maintain EGFR stability and signaling in prostate cancer cells, playing a critical role in enzalutamide resistance and metastatic progression. Targeting the SCAMP3-EPS8-EGFR axis offers promising therapeutic opportunities for advanced prostate cancer.

Background/aim: Hepatocellular carcinoma (HCC) is one of the leading causes of hepatic malignancy with a higher prevalence in males compared to females; however, the distinct underlying mechanisms contributing to this disparity remain poorly understood.

Materials and methods: In this study, we aimed to investigate comparative proteome profiling of a diethylnitrosamine (DEN) induced HCC model in male and female Balb/c mice. We extracted proteins from the liver tissue of DEN-treated male and female mice and their corresponding controls and subjected them to mass spectrometry and subsequent bioinformatics analyses.

Results: We identified 170 and 146 differentially expressed proteins (DEPs) in female and male mice, respectively. We identified chemical carcinogenesis, oxidative phosphorylation, actin binding and mitochondrial respiration as the shared pathways between the two groups. In addition, we identified distinct signaling pathways in DEN-treated male and female mice. Female mice showed enrichment in fatty acid biosynthesis, metabolism, degradation, and cytochrome P450 clusters. In contrast, in male mice, pathways were enriched in tryptophan metabolism, apoptotic execution phase and glutathione metabolism. Further, we identified the top ten genes ranked by highest maximal clique centrality, by protein-protein interaction analysis of differentially expressed proteins (DEPs) in both sexes. Of these hub genes, female mice showed up-regulation of previously unimplicated, NDUFA8 and ATP5H proteins which were associated with poor patient survival. On the other hand, in DEN-treated male mice up-regulation of RPS3 was associated with poor survival.

Conclusion: In conclusion, our research provides sex-specific proteomic signatures in DEN-induced HCC. The identification of proteins associated with ribosomal subunits in males, and two previously unimplicated mitochondrial complex I proteins in females as prognostic markers suggests novel therapeutic targets that may inform sex-tailored treatment strategies for HCC.

Background/aim: Pancreatic adenocarcinoma (PAAD) is one of the most lethal cancers worldwide, with more than 95% of PAAD patients not surviving beyond 5 years. Due to its rapid progression, in most cases there is no time for treatment by the time the disease is diagnosed, and metastases have developed in many organs. Therefore, there is currently a need to discover prognostic markers. Anillin actin-binding protein (ANLN) is an actin-binding protein involved in cell division. Its increased expression has been reported in many types of cancer, suggesting that it may be strongly involved in the progression of cancer malignancy, such as invasion and metastasis. The purpose of this study was to use bioinformatics to examine the possibility that ANLN may be a useful prognostic marker for PAAD.

Materials and methods: The Gene Expression Profiling Interactive Analysis (GEPIA) and the University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) bioinformatics platforms were used to analyze ANLN mRNA expression, protein revel, and survival in patients with PAAD from The Cancer Genome Atlas (TCGA) database.

Results: ANLN mRNA and protein levels were found to be significantly higher in PAAD tissues compared to normal pancreatic tissues, and this elevation correlated with poor prognosis in PAAD patients.

Conclusion: Increased expression of ANLN mRNA and protein was detected in PAAD tissues compared to normal pancreatic tissues by the GEPIA and UALCAN platforms of the TCGA database. Increased ANLN expression correlated with poor patient prognosis. These results suggest that ANLN may be a promising prognostic biomarker in PAAD.

Background/aim: Hepatocellular carcinoma (HCC) is a heterogeneous liver cancer with limited treatment options and a poor prognosis in advanced stages. To identify novel biomarkers and therapeutic targets, we investigated the role of chromosome 1 open reading frame 50 (C1orf50), a gene with a previously uncharacterized function in HCC.

Materials and methods: We performed a comprehensive transcriptome data analysis of the human hepatocellular carcinoma project from The Cancer Genome Atlas (TCGA) and subsequently validated the oncogenic roles of C1orf50 using HCC cell lines.

Results: Using transcriptomic and clinical data from TCGA, we stratified 355 primary HCC samples based on C1orf50 expression levels. Patients with high C1orf50 expression exhibited significantly shorter overall survival, suggesting its association with aggressive tumor behavior. Differential expression and enrichment analyses revealed that C1orf50-high tumors were enriched in oncogenic pathways, including epithelial-mesenchymal transition (EMT), cell cycle activation, and stemness-related properties. Transcriptional regulatory network analysis detected 456 significantly dysregulated regulons, including ZEB1/2 and E2F2, key drivers of EMT and cell cycle, in the C1orf50-high group. In addition, we observed increased YAP1/TAZ signaling, further linking C1orf50 to stemness and therapeutic resistance. Functional data from CRISPR-based dependency screening suggested that several transcription factors up-regulated in the C1orf50-high state, such as ZBTB11 and CTCE, are essential for the survival of HCC cells. These findings indicate potential therapeutic vulnerabilities and support the rationale for targeting C1orf50-associated pathways.

Conclusion: C1orf50 is a novel biomarker of poor prognosis in HCC and a key regulator of oncogenic features such as EMT, cell cycle progression, and stemness. This study highlights the therapeutic potential of targeting C1orf50-related networks in aggressive subtypes of liver cancer.

Background/aim: Prostate cancer, a leading global malignancy, exhibits variable progression influenced by angiogenesis, the formation of new blood vessels critical for tumor growth and metastasis. We investigated the impact of genetic variants of angiogenesis-related genes on the survival outcomes of patients with prostate cancer receiving androgen deprivation therapy (ADT).

Materials and methods: We conducted a genetic association study of 87 single-nucleotide polymorphisms across seven angiogenic genes in 630 patients with prostate cancer undergoing ADT. Survival analysis was used to assess progression-free survival (PFS) and overall survival (OS). Functional analyses, including gene ontology and pathway enrichment, were performed to elucidate the underlying biological mechanisms.

Results: ANGPT2 rs2959822 was significantly associated with PFS [hazard ratio (HR)=1.22, p=0.015] and OS (HR=1.22, p=0.021). The minor allele A increased the risk of disease progression and mortality. Functional analyses revealed that rs2959822 influenced ANGPT2 expression. Elevated ANGPT2 expression was correlated with higher Gleason score, advanced tumor stage, and shorter PFS. Gene set enrichment analysis linked ANGPT2 to epithelial-mesenchymal transition (EMT), demonstrating positive correlations with several key EMT genes, along with increased immune cell infiltration, indicating its multifaceted oncogenic roles.

Conclusion: ANGPT2 rs2959822 influences the survival outcomes of patients with prostate cancer undergoing ADT. In addition to angiogenesis, ANGPT2 plays a critical role in prostate cancer progression by promoting EMT and modulating the tumor immune microenvironment.

Background/aim: Verbascoside, a natural phenylethanoid glycoside, has demonstrated significant therapeutic potential in castration-resistant prostate cancer (CRPC). This study aimed to elucidate the mechanistic pathways through which verbascoside exerts its antisenescence and anti-metastatic effects, focusing on epithelial-mesenchymal transition (EMT), oxidative stress response, and mitochondrial biogenesis regulation in CRPC cells.

Materials and methods: CRPC cell models were treated under various concentrations of verbascoside. EMT markers, oxidative stress-related proteins, mitochondrial biogenesis regulators, and proinflammatory cytokines were assessed using Western blotting and ELISA. Cellular senescence and proliferation were evaluated through analysis of p38 MAPK activation and key cell cycle regulators (p16, p21, p27, and retinoblastoma protein (Rb).

Results: Verbascoside treatment inhibited EMT, reduced oxidative stress markers, and enhanced mitochondrial biogenesis, supporting cellular energy homeostasis. It also suppressed the secretion of proinflammatory cytokines, including interleukin (IL)-6, IL-8, and IL-1, associated with the senescence-associated secretory phenotype. Downstream signaling analysis revealed that verbascoside decreased p38 MAPK activation and down-regulated p16, p21, p27, and Rb, thereby attenuating prosenescence signaling and proliferation control.

Conclusion: Verbascoside attenuates CRPC progression by modulating EMT, alleviating oxidative damage, enhancing mitochondrial function, and inhibiting prosenescence signaling pathways. These findings highlight its therapeutic potential for targeting senescence-related mechanisms in aggressive prostate cancer and provide a basis for future CRPC management strategies.

Background/aim: The progression of hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC) as a result of resistance to androgen deprivation therapy (ADT) remains a major challenge in prostate cancer treatment.

Materials and methods: To explore the underlying mechanisms, we performed deep comparative proteomic profiling of HSPC and CRPC cell lines. LNCaP and C4-2 cell lines were cultured in isotopically labeled medium, combined, and digested, followed by liquid chromatography-mass spectrometry (LC-MS/MS) and bioinformatic analyses.

Results: Using SILAC-based proteomic analysis, 3,578 proteins were identified, with 2,474 quantified. In C4-2 cells, 41 proteins were significantly up-regulated, while 201 were down-regulated (fold-change >1.5 or <1.5-1, p<0.05). KEGG pathway analysis linked the increased proteins to fatty acid metabolism and biosynthesis of unsaturated fatty acids. Lipidomic analysis showed a significant rise in fatty acids like DHA, palmitic acid, stearic acid, and arachidic acid, aligning with the proteomic findings.

Conclusion: These results suggest that fatty acids play a key role in HSPC's progression to CRPC, possibly indicating that CRPC cells themselves may generate fatty acids.

Background/aim: Hepatocellular carcinoma (HCC) accounts for ~90% of primary liver cancer, which ranks as the third-leading cause of global cancer mortality. Emerging evidence establishes cancer stem cells (CSCs) as central regulators of HCC progression, metastasis, and therapeutic resistance, with stemness-related pathways like Wnt/β-catenin signaling critically maintaining CSC self-renewal. In this study, we aimed to investigate the role of Peptidyl-prolyl isomerase-like 1 (PPIL1) in HCC progression and CSC self-renewal.

Materials and methods: PPIL1 expression patterns were systematically analyzed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data and validated in primary HCC specimens via qRT-PCR and western blot. PPIL1 was knocked down in HCC cell lines using shRNAs, and cell viability, migration, and sphere formation were assessed in vitro. Xenograft mouse models were established to evaluate the effects of PPIL1 on tumor growth kinetics and liver CSC-related properties. Transcriptome analysis was performed to identify downstream targets and signaling pathways affected by PPIL1 knockdown.

Results: Our analysis revealed significantly elevated PPIL1 expression in HCC tumors and liver CSCs, with its expression level positively correlating with tumor stage and histological grade. PPIL1 knockdown effectively suppressed HCC cell proliferation, migration, and in vivo tumor growth. The essential role of PPIL1 in liver CSC maintenance was demonstrated by impaired sphere-forming capacity and diminished tumor initiation potential. Mechanistic studies identified PPIL1 as a regulator of Wnt/β-catenin signaling through transcriptional up-regulation of dishevelled associated activator of morphogenesis 2 (DAAM2).

Conclusion: Our findings suggest PPIL1 to be a crucial regulator of HCC progression and liver CSC maintenance via DAAM2-mediated Wnt/β-catenin activation. This positions PPIL1 as a promising molecular target for HCC therapy, with particular relevance for addressing CSC-driven therapeutic resistance.