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Translational Cancer Research Apr 2024Among human papillomavirus (HPV) type, HPV16 displays the strongest carcinogenic capacity for cervical cancer, but the mechanism underlying this phenomenon remains...
BACKGROUND
Among human papillomavirus (HPV) type, HPV16 displays the strongest carcinogenic capacity for cervical cancer, but the mechanism underlying this phenomenon remains unclear. We investigated the effect and the underlying mechanism of HPV16 on higher carcinogenic capacity than HPV58.
METHODS
We collected 4,030 cervical exfoliated cell samples for genotyping HPV using HybriBio's proprietary flow-through hybridization technique, liquid-based cytology (LBC), colposcopy, and biopsies if indicated. Four plasmids containing E6 and E7 of HPV16 and 58 were constructed and transfected into 293T and U2OS cells. We detected the cell phenotype using Cell Counting Kit 8 (CCK8) assay, Transwell assay, flow cytometry, and apoptosis assay; the expression of retinoblastoma protein (Rb) and phosphorylated Rb (pRb) was determined via Western blot; and the cell activity was determined via a zebrafish model treated with or without roscovitine.
RESULTS
The positive rates of HPV16 and 58 were, respectively, 18.9% and 19.7% in the ≤ low-grade squamous intraepithelial lesion (LSIL) group, 49.5% and 19.6% (P<0.001) in the high-grade squamous intraepithelial lesion (HSIL) group, 65.3% and 9.0% (P<0.001) in the cancer group. , both 293T and U2OS cells with overexpressed HPV16 E6 and E7 displayed significantly higher cell proliferation, faster cell invasion, decreased cell apoptosis, and accelerated cell cycle from G1 phase to S phase compared to those with overexpressed HPV58 E6 and E7 (all P values <0.05). Rb loss of function was observed in cells with HPV16 E7 overexpression, while a greater level of phosphorylated Rb was observed in cells with HPV58 E7 overexpression. Roscovitine restored Rb expression and decreased the cell activity in zebrafish.
CONCLUSIONS
HPV16 possesses a stronger carcinogenic ability than does HPV 58, and the mechanism underlying this effect may be the impairment of the E7-Rb pathway.
PubMed: 38737678
DOI: 10.21037/tcr-23-1211 -
Clinical and Translational Medicine May 2024
Topics: Humans; ErbB Receptors; Lung Neoplasms; Retinoblastoma Binding Proteins; Small Cell Lung Carcinoma; Genotype; Mutation; Ubiquitin-Protein Ligases; Male; Female; Middle Aged
PubMed: 38736106
DOI: 10.1002/ctm2.1683 -
Journal of Clinical Medicine Apr 2024Intraocular surgeries are conventionally contraindicated for patients with active retinoblastoma (Rb) due to the potential risk of tumor dissemination. However, surgery...
Intraocular surgeries are conventionally contraindicated for patients with active retinoblastoma (Rb) due to the potential risk of tumor dissemination. However, surgery is occasionally necessary to preserve vision in patients with a single eye when the eye is complicated by rhegmatogenous retinal detachment (RRD). This study aims to evaluate the outcomes of surgical repair for RRD in pediatric patients with active Rb utilizing a non-drainage scleral buckling approach. This cohort included six eyes from six patients who harbored active Rb and presented with RRD; one had a concurrent tractional component. All eyes (100%) had active intraocular Rb and were undergoing active therapy (systemic chemotherapy, cryotherapy, and thermal laser therapy) when RRD developed. RRD consistently manifested at the site of recent cryotherapy in all cases. RRD repair in the affected eyes was performed by scleral buckling without subretinal fluid drainage. Five of the six eyes (83%) achieved complete retinal reattachment. One eye (17%) with a tractional component exhibited partial reattachment and was eventually enucleated due to persistent active disease. At a median follow-up of 15 months (range 12-180 months) after scleral buckling, all five eyes had persistent retinal attachment, and no case developed orbital or distant metastasis. Our study demonstrates that nondrainage scleral buckling is an effective and safe method for the surgical repair of RRD in eyes harboring active Rb, as most cases achieved persistent complete retinal reattachment without the risk of tumor spread.
PubMed: 38731040
DOI: 10.3390/jcm13092511 -
Cancers Apr 2024Retinoblastoma (RB) is the most common malignant intraocular tumor in early childhood. Gene expression profiling revealed that the gastric inhibitory polypeptide...
Retinoblastoma (RB) is the most common malignant intraocular tumor in early childhood. Gene expression profiling revealed that the gastric inhibitory polypeptide receptor (GIPR) is upregulated following trefoil factor family peptide 1 (TFF1) overexpression in RB cells. In the study presented, we found this G protein-coupled transmembrane receptor to be co-expressed with TFF1, a new diagnostic and prognostic RB biomarker for advanced subtype 2 RBs. Functional analyses in two RB cell lines revealed a significant reduction in cell viability and growth and a concomitant increase in apoptosis following stable, lentiviral GIPR overexpression, matching the effects seen after TFF1 overexpression. In chicken chorioallantoic membrane (CAM) assays, GIPR-overexpressing RB cells developed significantly smaller CAM tumors. The effect of GIPR overexpression in RB cells was reversed by the GIPR inhibitor MK0893. The administration of recombinant TFF1 did not augment GIPR overexpression effects, suggesting that GIPR does not serve as a TFF1 receptor. Investigations of potential GIPR up- and downstream mediators suggest the involvement of miR-542-5p and p53 in GIPR signaling. Our results indicate a tumor suppressor role of GIPR in RB, suggesting its pathway as a new potential target for future retinoblastoma therapy.
PubMed: 38730608
DOI: 10.3390/cancers16091656 -
Biomarker Research May 2024Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular...
BACKGROUND
Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited.
METHODS
The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion.
RESULTS
Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications.
CONCLUSIONS
This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.
PubMed: 38730450
DOI: 10.1186/s40364-024-00596-8 -
WMJ : Official Publication of the State... May 2024
Topics: Humans; Wisconsin; Retinoblastoma; Incidence; Retinal Neoplasms; Infant; Public Health; Female; Child, Preschool; Male
PubMed: 38718232
DOI: No ID Found -
Revista Da Associacao Medica Brasileira... 2024This prospective study aimed to provide a comprehensive analysis of the methylation status of two pivotal genes, CDKN2A/p16INK4A (cyclin-dependent kinase inhibitor 2A)...
OBJECTIVE
This prospective study aimed to provide a comprehensive analysis of the methylation status of two pivotal genes, CDKN2A/p16INK4A (cyclin-dependent kinase inhibitor 2A) and RB1 (retinoblastoma transcriptional corepressor 1), in breast cancer patients.
METHODS
Samples were obtained from 15 women diagnosed with breast cancer and who underwent a total mastectomy. DNA was extracted from the tumor, non-tumor tissue, and peripheral blood (circulating cell-free DNA). The methylation pattern of cell-free DNA extracted from blood collected on the day of mastectomy was compared with the methylation pattern of cell-free DNA from blood collected 1 year post-surgery. The methylation analysis was carried out by sodium bisulfite conversion and polymerase chain reaction, followed by electrophoresis.
RESULTS
Methylation of CDKN2A/p16INK4A was identified in 13 tumor samples and 12 non-tumor tissue samples. Two patients exhibited CDKN2A/p16INK4A methylation in the cell-free DNA of the first blood collection, while another showed methylation only in the cell-free DNA of the subsequent blood collection. Regarding RB1, 11 tumors and 8 non-tumor tissue samples presented methylation of the gene.
CONCLUSION
This study presents a novel approach for monitoring breast cancer patients through the analysis of cell-free DNA methylation. This analysis can detect changes in methylation patterns before any visible sign of cancer appears in breast tissue and could help predict the recurrence of malignant breast tumors.
Topics: Adult; Aged; Female; Humans; Middle Aged; Biomarkers, Tumor; Breast Neoplasms; Cell-Free Nucleic Acids; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; Mastectomy; Polymerase Chain Reaction; Prospective Studies; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 38716944
DOI: 10.1590/1806-9282.20231358 -
BMJ Open Apr 2024Retinoblastoma (Rb) is a rare childhood eye cancer, with 45% of individuals impacted by heritable disease and the remainder impacted non-heritably. The condition can...
OBJECTIVE AND DESIGN
Retinoblastoma (Rb) is a rare childhood eye cancer, with 45% of individuals impacted by heritable disease and the remainder impacted non-heritably. The condition can leave survivors with life-long psychological and social challenges. This qualitative study examined the psychosocial needs of teenagers and young adults living beyond Rb.
SETTING
A qualitative, exploratory study was conducted using focus groups with teenagers and interviews with young adults. Participants were recruited via the Childhood Eye Cancer Trust and the two national Rb treatment centres in the UK. Reflexive thematic analysis was used to analyse data using exploratory and inductive methods.
PARTICIPANTS
32 young survivors of Rb (10 heritable, 21 non-heritable, 1 unknown; 23 unilateral, 9 bilateral) aged between 13 and 29 years (12 male, 20 female).
RESULTS
Data were rich and spanned the life course: three key themes were generated, containing eight subthemes. Theme 1 describes participants' experiences of childhood and trauma, including survivor guilt, memories from treatment and impact on personality. Theme 2 focuses on the challenges of adolescence, including the psychological impact of Rb, the impact on identity, and the sense of normality and adaptation to late effects. The third theme considered adulthood and the development of acceptance, a state of being widely considered unachievable during childhood, as well as the 'work' needed to feel supported, including seeking out information, peer support and therapeutic strategies.
CONCLUSIONS
This study provides in-depth insight into the experiences of life beyond Rb. Findings highlight the need for specific psychosocial interventions informed by codesign.
Topics: Humans; Retinoblastoma; Female; Male; Adolescent; Qualitative Research; Young Adult; Adult; Cancer Survivors; Focus Groups; Adaptation, Psychological; Retinal Neoplasms; United Kingdom
PubMed: 38688668
DOI: 10.1136/bmjopen-2023-082779 -
Journal of Cancer Research and... Apr 2024This study aimed to investigate BVD-523 (ulixertinib), an adenosine triphosphate (ATP)-dependent extracellular signal-regulated kinases 1/2 inhibitor, for its antitumor...
OBJECTIVE
This study aimed to investigate BVD-523 (ulixertinib), an adenosine triphosphate (ATP)-dependent extracellular signal-regulated kinases 1/2 inhibitor, for its antitumor potential in thyroid cancer.
MATERIALS AND METHODS
Ten thyroid cancer cell lines known to carry mitogen-activated protein kinase (MAPK)-activated mutations, including v-Raf murine sarcoma viral oncogene homolog B (BRAF) and rat sarcoma virus (RAS) mutations, were examined. Cells were exposed to a 10-fold concentration gradient ranging from 0 to 3000 nM for 5 days. The half-inhibitory concentration was determined using the Cell Counting Kit-8 assay. Following BVD-523 treatment, cell cycle analysis was conducted using flow cytometry. In addition, the impact of BVD-523 on extracellular signal-regulated kinase (ERK)- dependent ribosomal S6 kinase (RSK) activation and the expression of cell cycle markers were assessed through western blot analysis.
RESULTS
BVD-523 significantly inhibited thyroid cancer cell proliferation and induced G1/S cell cycle arrest dose-dependently. Notably, cell lines carrying MAPK mutations, especially those with the BRAF V600E mutation, exhibited heightened sensitivity to BVD-523's antitumor effects. Furthermore, BVD-523 suppressed cyclin D1 and phosphorylated retinoblastoma protein expression, and it robustly increased p27 levels in an RSK-independent manner.
CONCLUSION
This study reveals the potent antitumor activity of BVD-523 against thyroid cancer cells bearing MAPK-activating mutations, offering promise for treating aggressive forms of thyroid cancer.
Topics: Humans; Thyroid Neoplasms; Cell Proliferation; Cell Line, Tumor; Protein Kinase Inhibitors; Pteridines; Proto-Oncogene Proteins B-raf; Mitogen-Activated Protein Kinase 3; Antineoplastic Agents; Mitogen-Activated Protein Kinase 1; Mutation; MAP Kinase Signaling System; Aminopyridines; Pyrroles
PubMed: 38687926
DOI: 10.4103/jcrt.jcrt_1504_23 -
Nature Communications Apr 2024The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous...
The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous signalling pathways and cell-autonomous transcriptional machinery orchestrate the stem cell-like characteristics of CSCs is still poorly understood. Here we use a quantitative proteomic approach for identifying secreted proteins of CSCs in pancreatic cancer. We uncover that the cell-autonomous E2F1/4-pRb/RBL2 axis balances non-cell-autonomous signalling in healthy ductal cells but becomes deregulated upon KRAS mutation. E2F1 and E2F4 induce whereas pRb/RBL2 reduce WNT ligand expression (e.g. WNT7A, WNT7B, WNT10A, WNT4) thereby regulating self-renewal, chemoresistance and invasiveness of CSCs in both PDAC and breast cancer, and fibroblast proliferation. Screening for epigenetic enzymes identifies GCN5 as a regulator of CSCs that deposits H3K9ac onto WNT promoters and enhancers. Collectively, paracrine signalling pathways are controlled by the E2F-GCN5-RB axis in diverse cancers and this could be a therapeutic target for eliminating CSCs.
Topics: Humans; Neoplastic Stem Cells; Paracrine Communication; E2F1 Transcription Factor; Cell Line, Tumor; Pancreatic Neoplasms; E2F4 Transcription Factor; Animals; Carcinoma, Pancreatic Ductal; Wnt Proteins; Retinoblastoma Protein; Breast Neoplasms; p300-CBP Transcription Factors; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins p21(ras); Female; Cell Proliferation; Mice; Signal Transduction; Drug Resistance, Neoplasm
PubMed: 38678032
DOI: 10.1038/s41467-024-47680-z