Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma
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PROVIDER: PRJNA940148 | ENA |
REPOSITORIES: ENA
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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:The chemotherapy of retinoblastoma (RB), a malignant ocular childhood disease, is often limited by the development of resistance 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 signaling were discernible, but p-SGK3 levels increased following INPP4B overexpression, indicating a potential regulation of SGK3 signaling 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.
| S-EPMC10042642 | biostudies-literature
Project description:Genomic losses on chromosome 16q are among the most frequent alterations found in retinoblastoma. In this study, Affymetrix GeneChip analyses along with LOH analysis of microsatellie markers was used to identify candidate tumor suppressor loci in a set of retinoblastoma. We used microarrays to identify genes differentially expressed in retinoblastoma with LOH on 16q (M19484, M22590, M22641, M22860) compared to retinoblastoma without alterations in this region (M20517, M22067, M22233, M23209, M23449, M23818, M23896, M23978) Keywords: Disease progression
2007-01-29 | GSE5222 | GEO
Project description:Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in patient prognosis. One of these groups, the basal-like carcinomas, are poorly differentiated, highly metastatic, and genomically unstable. These tumors also contain specific genetic alterations with one example being frequent p53 mutations. The loss of the tumor suppressor gene encoded by the retinoblastoma (RB1) locus is a well-characterized occurrence in many tumor types, however, its role in breast cancer is less clear with many reports demonstrating a Loss of Heterozygosity (LOH) that does not correlate with loss of RB1 protein expression. Here we report that LOH of the RB1 locus was observed at a high frequency in basal-like and luminal B tumors. These tumors also concurrently have low expression of RB1 mRNA as assessed by DNA microarray. As in previous reports, we also did not see a significant correlation between RB1 LOH and protein expression as measured by immunohistochemistry (IHC). p16INK4a, however, was highly expressed both by microarray and IHC, in basal-like tumors only presumably due to a previously reported feedback loop caused by RB1 loss. These results suggest that the functional loss of RB1 is a common event in the progression of basal-like and luminal B breast tumors, which may play a key role in dictating therapeutic responses Keywords: reference x sample Comparison of reference samples against treatment
2010-06-25 | E-GEOD-10884 | biostudies-arrayexpress
Project description:Genomic losses on chromosome 16q are among the most frequent alterations found in retinoblastoma. In this study, Affymetrix GeneChip analyses along with LOH analysis of microsatellie markers was used to identify candidate tumor suppressor loci in a set of retinoblastoma. We used microarrays to identify genes differentially expressed in retinoblastoma with LOH on 16q (M19484, M22590, M22641, M22860) compared to retinoblastoma without alterations in this region (M20517, M22067, M22233, M23209, M23449, M23818, M23896, M23978) Experiment Overall Design: To compare the transcriptosomes of retinoblastoma with and without LOH on 16q, total RNA was isolated from a 30 mg block of each tumor and subjected to Affymetrix microarray analysis on HG-U133A arrays.
2009-04-24 | E-GEOD-5222 | biostudies-arrayexpress
Project description:Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell-fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 in retinal development and retinoblastoma by using molecular and cellular approaches. Brg1 regulated retinal size by controlling cell cycle length, cell cycle exit, and cell survival during development. Brg1 was not required for cell-fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death, and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, thereby making them more susceptible to retinoblastoma. ChIP-seq analysis provided insight into the underlying molecular mechanisms of these complex Brg1-regulated cellular processes during retinal development.
2015-12-02 | GSE74181 | GEO
Project description:Here we report the characterization of a novel role for the retinoblastoma protein (pRb) as a regulator of osteoblast adhesion. Abrogation of pRb in osteoblasts resulted in aberrant cadherin expression and loss of adherens junctions. This produced defects suggestive of a transformed phenotype such as impaired cell-to-cell adhesion, loss of contact-dependent growth arrest, and the capacity to evade anoikis. This also resulted in profound abnormalities in bone structure. Consistent with this, microarray analyses showed that pRb regulates a wide repertoire of osteoblast cell adhesion genes. In addition, pRb loss also resulted in altered expression and function of several known regulators of cellular adhesion and adherens junction assembly, such as the Rho GTPase Rac1 and the merlin tumor suppressor. Taken together, our results show that pRb controls cell adhesion by regulating the expression and adherens junction components and by regulating the function of molecules involved in adherens junction assembly and stability. Microarray results helped us to portrait the overall influence on cell adhesion via both individual genes and pathway analysis. Experiment Overall Design: MC3T3 cells were obtained from immortalizing primary cultured mouse osteoblast cells by using 3T3 protocol. There are 3 biological replicates for each group, 6 samples in total were analyzed.
2009-12-14 | E-GEOD-19299 | biostudies-arrayexpress
Project description:Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell-fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 in retinal development and retinoblastoma by using molecular and cellular approaches. Brg1 regulated retinal size by controlling cell cycle length, cell cycle exit, and cell survival during development. Brg1 was not required for cell-fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death, and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, thereby making them more susceptible to retinoblastoma. ChIP-seq analysis provided insight into the underlying molecular mechanisms of these complex Brg1-regulated cellular processes during retinal development.
2015-12-02 | GSE74268 | GEO
Project description:Here we report the characterization of a novel role for the retinoblastoma protein (pRb) as a regulator of osteoblast adhesion. Abrogation of pRb in osteoblasts resulted in aberrant cadherin expression and loss of adherens junctions. This produced defects suggestive of a transformed phenotype such as impaired cell-to-cell adhesion, loss of contact-dependent growth arrest, and the capacity to evade anoikis. This also resulted in profound abnormalities in bone structure. Consistent with this, microarray analyses showed that pRb regulates a wide repertoire of osteoblast cell adhesion genes. In addition, pRb loss also resulted in altered expression and function of several known regulators of cellular adhesion and adherens junction assembly, such as the Rho GTPase Rac1 and the merlin tumor suppressor. Taken together, our results show that pRb controls cell adhesion by regulating the expression and adherens junction components and by regulating the function of molecules involved in adherens junction assembly and stability. Microarray results helped us to portrait the overall influence on cell adhesion via both individual genes and pathway analysis.
2009-12-04 | GSE19299 | GEO
Project description:Mutations in genes encoding the various subunits of the SWI/SNF chromatin remodeling complex are frequently observed in different human cancers. In diffuse large B-cell lymphoma (DLBCL), genetic changes in BCL7A, a subunit of the SWI/SNF complex, have been recently reported but the functional role of such genetic changes remains unknown. BCL7A mutations concentrate at the first exon and the most frequently mutated hotspot is the splice donor site of the first intron. By using in vitro and in vivo analyses, we show that restoration of BCL7A drives a tumor suppressor-like phenotype. Further, we found that splice site mutations block the tumor suppressor phenotype and prevent BCL7A from binding to the SWI/SNF complex. Finally, we identified that the SWI/SNF complex accumulates mutations in a third of DLBCL tumors, especially in the GCB subtype. These discoveries highlight the tumor suppressor role of BCL7A mutations in DLBCL, and suggest that the SWI/SNF complex is involved in DLBCL pathogenesis.
2020-10-21 | PXD014795 | Pride