The retinoblastoma tumor suppressor modulates DNA repair and radio responsiveness
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58711 | GEO | 2014/12/03
SECONDARY ACCESSION(S): PRJNA253295
REPOSITORIES: GEO
Similar Datasets
Project description:PurposePerturbations in the retinoblastoma pathway are over-represented in advanced prostate cancer; retinoblastoma loss promotes bypass of first-line hormone therapy. Conversely, preliminary studies suggested that retinoblastoma-deficient tumors may become sensitized to a subset of DNA-damaging agents. Here, the molecular and in vivo consequence of retinoblastoma status was analyzed in models of clinical relevance.Experimental designExperimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of retinoblastoma using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts.ResultsLoss of retinoblastoma enhanced the radioresponsiveness of both hormone-sensitive and castrate-resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. Retinoblastoma loss led to alteration in DNA damage repair and activation of the NF-κB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of retinoblastoma-deficient tumors exhibited diminished tumor mass, lower PSA kinetics, and decreased tumor growth after treatment with ionizing radiation (P < 0.05).ConclusionsLoss of retinoblastoma confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of retinoblastoma loss, but also credential retinoblastoma status as a putative biomarker for predicting response to radiotherapy.
| S-EPMC4216759 | biostudies-literature
Project description:Chemotherapy of retinoblastoma (RB), a malignant ocular childhood disease, is often limited by the development of resistances against commonly used drugs. We identified inositol polyphosphate 4-phosphatase type II (INPP4B) as a differentially regulated gene in etoposide resistant RB cell lines, potentially involved in the development of RB resistances. INPP4B is controversially discussed as a tumor suppressor and an oncogenic driver in various cancers, but its role in retinoblastoma in general and chemoresistant RB in particular is yet unknown. In the study presented, we investigated the expression of INPP4B in RB cell lines and patients and analyzed the effect of INPP4B overexpression on etoposide resistant RB cell growth in vitro and in vivo. INPP4B mRNA levels were significantly downregulated in RB cells lines compared to the healthy human retina, with even lower expression levels in etoposide resistant compared to the sensitive cell lines. Besides, a significant increase in INPP4B expression was observed in chemotherapy treated RB tumor patient samples compared to untreated tumors. INPP4B overexpression in etoposide resistant RB cells resulted in a significant reduction in cell viability with reduced growth, proliferation, anchorage-independent growth, and in ovo tumor formation. Caspase-3/7 mediated apoptosis was concomitantly increased, suggesting a tumor suppressive role of INPP4B in chemoresistant RB cells. No changes in AKT signalling were discernible, but p-SGK3 levels increased following INPP4B overexpression, indicating a potential regulation of SGK3 signalling in etoposide-resistant RB cells. RNAseq analysis of INPP4B overexpressing, etoposide resistant RB cell lines revealed differentially regulated genes involved in cancer progression, mirroring observed in vitro and in vivo effects of INPP4B overexpression and strengthening INPP4B`s importance for cell growth control and tumorigenicity.
2023-03-15 | GSE226408 | GEO
Project description:Primary outcome(s): 68Ga-DOTA-GCC-RB PET/CT imaging
(Assessment of 68Ga-DOTA-GCC-RB PET/CT imaging to detect lesions in patients with colorectal carcinoma)Timepoint: 45 minutes to 1 hour from time of injection
| 29930 | ecrin-mdr-crc
Project description:The processes that control the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain poorly understood. Epidermal growth factor receptor 2 (ErbB2) overexpression is common in DCIS, as is disruption of the retinoblastoma tumor suppressor (RB) pathway. Here, we examined the cooperative impact of ErbB2 and RB deregulation on facets of disease progression. Our studies demonstrate that RB deficiency altered the expression of key molecules needed for proper cellular organization and epithelial cell-cell adhesion as part of a program related to the epithelial-to-mesenchymal transition (EMT). An increase in the invasive potential of ErbB2-overexpressing cells was observed upon RB depletion. Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells. Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner. Finally, in a cohort of DCIS cases, we show that, although elevated levels of ErbB2 are associated with increased risk of a subsequent DCIS recurrence, it is not associated with progression to invasive disease. In contrast, RB loss in ErbB2-positive DCIS cases was associated with increased risk for invasive breast cancer. Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.
| S-EPMC4150690 | biostudies-literature
Project description:Background: Recent therapeutic advances have greatly improved the eye preservation rate in patients affected by retinoblastoma (RB), however local tumor control remains more difficult in the presence of resistant and/or relapsing retinal or vitreous disease. Thus, the identification of new biomarkers is crucial to design more effective treatment approaches. Recently, technological advances have allowed to safely recover aqueous humor (AH) from patients affected by RB undergoing local treatment. Methods: in order to identify specific proteins associated to active vitreous seeding, we have performed proteomic analysis of AH samples derived from patients affected by RB in different disease stages. Fifty-five AH samples were firstly included in this study. A new widened cohort was then used to validate the proteins identified in the previous discovery set. Results: a total of 808 and 630 proteins were identified in the two analysis, respectively. Five proteins resulted more expressed in the active vitreous seeding group: C19orf57, Girdin, SRFBP, GULP-1 and DCD. These proteins are involved in cytoskeleton regulation, tumor proliferation and growth, invasion and migration of cancer cells. Conclusion: reliable prognostic biomarkers are needed to guide RB management. Proteomic analysis of AH provide a unique opportunity to identify tumor associated biomarkers in patients with RB.
2023-03-10 | PXD022218 | Pride
Project description:Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 16 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify novel Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death which is exacerbated in hypoxia. These findings reveal a novel dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.
2022-08-24 | GSE196420 | GEO
Project description:During radiotherapy most cancer cells are removed, but some cells are not. These remained cancer cells become resistant to radiotherapy and lead to cancer recurrence. Radioresistnat cancer cells show different gene expression profile than radiosensitive tumor cells. Among the genes distinctly up or down-changed in expression level, some are associated with development of radioresistance. We used microarrays to select multiple genes showing distinct change in expression level for seeking genes that contribute to the develpoment of radioresistance in breast cancer cells during radiotherapy.
2021-09-18 | GSE158132 | GEO
Project description:Background: Recent therapeutic advances have greatly improved the eye preservation rate in patients affected by retinoblastoma (RB), however local tumor control remains more difficult in the presence of resistant and/or relapsing retinal or vitreous disease. Thus, the identification of new biomarkers is crucial to design more effective treatment approaches. Recently, technological advances have allowed to safely recover aqueous humor (AH) from patients affected by RB undergoing local treatment. Methods: in order to identify specific proteins associated to active vitreous seeding, we have performed proteomic analysis of AH samples derived from patients affected by RB in different disease stages. Fifty-five AH samples were firstly included in this study. A new widened cohort was then used to validate the proteins identified in the previous discovery set. Results: a total of 808 and 630 proteins were identified in the two analysis, respectively. Five proteins resulted more expressed in the active vitreous seeding group: C19orf57, Girdin, SRFBP, GULP-1 and DCD. These proteins are involved in cytoskeleton regulation, tumor proliferation and growth, invasion and migration of cancer cells. Conclusion: reliable prognostic biomarkers are needed to guide RB management. Proteomic analysis of AH provide a unique opportunity to identify tumor associated biomarkers in patients with RB.
2023-03-10 | PXD022256 | Pride
Project description:Retinoblastoma (RB) is the most prevalent ocular tumor of childhood whose extraocular invasion largely increase metastasis risk. Nevertheless, a single-cell characterization of RB local extension has been lacking. Here, we perform single-cell RNA sequencing (scRNA-seq) 4 RB samples (2 from intraocular and 2 from extraocular RB patients), and integrate public scRNA-seq datasets to characterize the local extension of RB at single-cell level.
2023-12-19 | GSE249995 | GEO
Project description:Epigenetic dysregulation is one of the molecular mechanisms contributing to retinoblastoma (RB) development. Consistent with this notion, human RB tumors show an aberrant expression of many chromatin regulators whereas normal retina or nontumoral retinal tissues do not have any detectable expression of such proteins. Among the chromatin regulators found to be misregulated in RB, this study focuses on a histone methyltransferase DOT1L to assess the therapeutic potential of its targeting for RB treatment. We found that pharmacological inhibition of DOT1L has growth-inhibitory effects on RB cells by itself and also can sensitize RB cells to standard chemotherapeutic drugs by inducing more robust apoptotic cell death when cells are subjected to combination treatments. To understand the molecular mechanisms underlying the growth inhibition and chemosensitization of RB cells upon DOT1L inhibition, we performed the gene expression profiling in Y79 cells treated with a DOT1L inhibitor EPZ5676 in comparison with a vehicle control by RNA-sequencing to identify differentially expressed genes. Our RNA-seq results revealed that DOT1L inhibition downregulates several genes which are known to be misregulated in cancers, including HMGA2.
2021-12-13 | GSE174167 | GEO