Bioinformatics models greatly contribute to individualized assessments of cancer patients. However, considerable research neglected some critical technological points, including comparisons of multiple modeling algorithms, evaluating gain effects of constructed model, comprehensive bioinformatics analyses and validation of clinical cohort. These issues are worthy of emphasizing, which will better serve future cancer research.
Background: Cellular prion protein (PrPC) is a widely expressed membrane-anchored glycoprotein, which has been associated with the development and progression of several types of human malignancies, controlling cancer stem cell activity. However, the different molecular mechanisms regulated by PrPC in normal and tumor cells have not been characterized yet.
Methods: To assess the role of PrPC in patient-derived glioblastoma stem cell (GSC)-enriched cultures, we generated cell lines in which PrPC was either overexpressed or down-regulated and investigated, in 2D and 3D cultures, its role in cell proliferation, migration, and invasion. We evaluated the role of PrPC in supporting GSC stemness and the intracellular signaling involved using qRT-PCR, immunocytofluorescence, and Western blot.
Results: Stable PrPC down-regulation leads to a significant reduction of GSC proliferation, migration, and invasiveness. These effects were associated with the inhibition of the expression of stemness genes and overexpression of differentiation markers. At molecular level PrPC down-regulation caused a significant inhibition of Wnt/β-catenin pathway, through a reduced expression of Wnt and Frizzled ligand/receptor subtypes, resulting in the inhibition of β-catenin transcriptional activity, as demonstrated by the reduced expression of its target genes. The specificity of PrPC in these effects was demonstrated by rescuing the phenotype and the biological activity of PrPC down-regulated GSCs by re-expressing the protein. To get insights into the distinct mechanisms by which PrPC regulates proliferation in GSCs, but not in normal astrocytes, we analyzed structural features of PrPC in glioma stem cells and astrocytes using Western blot and immunofluorescence techniques. Using Pi-PLC, an enzyme that cleaves GPI anchors, we show that, in GSCs, PrP is retained within the plasma membrane in an immature Pro-PrP isoform whereas in astrocytes, it is expressed in its mature PrPC form, anchored on the extracellular face of the plasma membrane.
Conclusions: The persistence of Pro-PrP in GSCs is an altered cellular mechanism responsible of the aberrant, constitutive activation of Wnt/β-catenin pathway, which contributes to glioblastoma malignant features. Thus, the activity of Pro-PrP may represent a targetable vulnerability in glioblastoma cells, offering a novel approach for differentiating and eradicating glioblastoma stem cells.
Background: Incessant ovulation is the main etiologic factor of ovarian high-grade serous carcinomas (HGSC), which mostly originate from the fallopian tube epithelium (FTE). Receptor tyrosine kinase (RTK) ligands essential for follicle development and ovulation wound repair were abundant in the follicular fluid (FF) and promoted the transformation of FTE cells. This study determined whether RTK ligands are present in FF exosomes and whether epidermal growth factor receptor (EGFR) signaling is essential for oncogenic activity.
Methods: The FF of women undergoing in vitro fertilization was fractionated based on the richness of exosomes and tested for transformation toward FTE cells under different RTK inhibitors. EGFR ligands in FF exosomes were identified, and downstream signaling proteins in FTE cells were characterized.
Results: The transforming activity of FF was almost exclusively enriched in exosomes, which possess a high capacity to induce anchorage-independent growth, clonogenicity, migration, invasion, and proliferation of FTE cells. EGFR inhibition abolished most of these activities. FF and FF exosome exposure markedly increased EGFR phosphorylation and the downstream signal proteins, including AKT, MAPK, and FAK. Multiple EGF family growth factors, such as amphiregulin, epiregulin, betacellulin, and transforming growth factor-alpha, were identified in FF exosomes.
Conclusions: Our results demonstrate that FF exosomes serve as carriers of EGFR ligands as well as ligands of other RTKs that mediate the transformation of FTE cells and underscore the need to further explore the content and roles of FF exosomes in HGSC development.
Telomerase, an enzyme crucial for maintaining telomere length, plays a critical role in cellular immortality and is overexpressed in most cancers. This ubiquitous presence makes telomerase, and specifically its catalytic subunit, human telomerase reverse transcriptase (hTERT), an attractive target for cancer immunotherapy. This review explores the development and application of telomerase-based vaccines, focusing on DNA and peptide-based approaches. While DNA vaccines demonstrate promising immunogenicity, peptide vaccines, such as UV1, UCPVax, and Vx-001, have shown clinical efficacy in certain cancer types. Recent advancements in vaccine design, including multiple peptides and adjuvants, have enhanced immune responses. However, challenges remain in achieving consistent and durable anti-tumor immunity. Accordingly, we discuss the mechanisms of action, preclinical and clinical data, and the potential of these vaccines to elicit robust and durable anti-tumor immune responses. This review highlights the potential of telomerase-based vaccines as a promising strategy for cancer treatment and identifies areas for future research.
Background: Epithelial-mesenchymal transition (EMT) plays a crucial role in the migration and invasion capabilities of glioblastoma (GBM) cells. Several studies have established tubulin as a significant regulator of the EMT process. Tubulin beta 2B class IIb (TUBB2B), a critical component of microtubules, has been linked to the prognosis of various tumors. However, the specific biological function and mechanism of TUBB2B in GBM remain unclear.
Methods: In vitro experiments demonstrated that TUBB2B knockdown inhibited the migration and invasion of GBM cells, while its overexpression enhanced these capabilities. Western blot, immunofluorescence (IF) and co-immunoprecipitation (Co-IP) assays revealed that TUBB2B interacts with Vimentin. Molecular docking and residue mutation scanning indicated that TUBB2B interacts with Vimentin at the R391/K392/A393/F394 sites. In vivo experiments using nude mice confirmed that TUBB2B knockdown inhibited GBM cell invasion and migration.
Results: TUBB2B was upregulated in GBM tissue samples compared with normal tissues. The sites of TUBB2B(R391/K392/A393/F394) physically interacts with Vimentin to induce EMT, which promotes migration and invasion.
Conclusion: TUBB2B may regulate EMT and promote the migration and invasion of GBM cells through its interaction with Vimentin, highlighting TUBB2B as a potential therapeutic target for GBM.
Background: Epigenetic phytochemicals are considered as an efficacious and safe alternative to synthetic drugs in drug discovery. In this regard, combinatorial interventions enable simultaneously targeting various neoplastic pathways to eradicate multiple tumorigenic clones. Therefore, we evaluated the effects of the epigenetic-modifying compounds phenethyl isothiocyanate (PEITC) and withaferin A (WA) alone and in combination on cancer hallmarks and miRNome profiles of breast cancer (BC) cells in addition to their impact on multiple epigenetic regulatory pathways.
Methods: We performed MTT assay, flow cytometry-based cell cycle analysis, apoptosis assay, stem cell population analysis, and mammosphere assay on MCF-7 and MDA-MB-231 BC cells to evaluate the effect of combinatorial PEITC and WA treatment on cancer hallmarks. To assess the epigenetic effects of the combinatorial PEITC and WA treatment, we conducted HDAC activity assay, DNMT activity assay, western blot analysis, siRNA-mediated gene knockdown, and RT-qPCR analysis. Additionally, we explored the effect of the PEITC + WA combination on miRNome profiles in MCF-7 and MDA-MB-231 BC cells through miRNA-seq analysis and miRNA Real-Time PCR assay.
Results: Our results indicated a synergistic effect of PEITC and WA on inhibiting MCF-7 and MDA-MB-231 BC cells by triggering G2/M-phase arrest, apoptosis induction, tumor formation efficiency decrease, and stem cell population decline. Combinatorial PEITC and WA treatment significantly reduced global DNA methyltransferase (DNMT) and histone deacetylase (HDAC) activity in addition to decreasing multiple Class I HDACs and de novo DNMTs expression in MCF-7 and MDA-MB-231 cells. PEITC + WA combination targets histone acetylation and DNA methylation pathways since the expressional changes of cell cycle and apoptosis-related proteins due to PEITC + WA treatment closely mimic the alterations seen when HDAC8 and DNMT3B are silenced. Furthermore, treating these cells with PEITC and WA significantly alters the expression of several BC-associated miRNAs.
Conclusion: Overall, our investigation demonstrated that combined PEITC and WA is effective in inhibiting MCF-7 and MDA-MB-231 BC cells by impacting multiple epigenetic regulatory pathways.
Breast cancer (BC) is the leading cause of cancer-related mortality among women globally, affecting approximately one-quarter of all female cancer patients and accounting for one-sixth of cancer-related deaths in women. Despite significant advancements in diagnostic and therapeutic approaches, breast cancer treatment remains challenging due to issues such as recurrence and metastasis. Recently, a novel form of regulated cell death, termed cuproptosis, has been identified. This process disrupts mitochondrial respiration by targeting the copper-dependent cellular pathways. The role of cuproptosis has been extensively investigated in various therapeutic contexts, including chemotherapy, immunotherapy, radiotherapy, and nanotherapy, with the development of novel drugs significantly improving clinical outcomes. This article aims to further elucidate the connection between cuproptosis and breast cancer, focusing on its therapeutic targets, signaling pathways, and potential biomarkers that could enhance treatment strategies. These insights may offer new opportunities for improved patient care and outcomes in breast cancer therapy.
Background: The development of resistance to therapy is characteristic of head and neck squamous cell carcinoma (HNSCC), the 6th most common cancer, and is often attributed to cancer stem cells (CSCs). By proteomic approach, we determined that UFMylation plays an important role in HNSCC CSCs. Because of the necessity for innovative therapeutic strategies, we explore here the therapy targeting CSCs based on mithramycin and its inhibitory effect on Sp1 transcription factor, UFMylation, and CSCs survival and stemness.
Methods: HNSCC-derived cancer cell lines Detroit 562, FaDu, and Cal27, and tumor spheres are used as a model for CSCs. Proteomic analysis identified the importance of the UFMylation pathway in CSCs which we further studied by bioinformatics, western blot, immunocytochemistry, and cytotoxicity assay.
Results: Proteomic analysis and subsequent confirmation revealed UFSP2 and DDRGK1 were strongly expressed in tumor spheres. Bioinformatic analysis indicated high expression of UFM1 is linked with worse overall and disease-free survival, and it correlated with main EMT proteins (Zeb, Twist, and Fn) in HNSCC. UFM1 was also strongly expressed in tumor spheres compared to the adherent cells. Silencing of UFM1 reduced sphere number, size, and stemness. As Sp1 is the main transcription factor for the genes of the UFMylation system, we explored its inhibitor mithramycin, as a potential drug for CSCs inhibition. We proved mithramycin inhibits CSCs survival, induces apoptosis, and reduces UFMylation and stemness.
Conclusion: UFMylation is an important process in CSCs, and mithramycin, or its lesser toxic analogs, should be further explored as CSCs targeted therapy in HNSCC.
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