CRISPR-mediated modeling and functional validation of candidate tumor suppressor genes in small cell lung cancer
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PROVIDER: PRJNA579893 | ENA |
REPOSITORIES: ENA
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Project description:Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we adapt the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, p107 loss results in fewer but larger tumors, as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis, as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130. Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will greatly facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.
2019-12-19 | GSE139444 | GEO
Project description:Recent cancer genome sequencing studies have identified numerous novel candidate driver genes. In vivo functional investigation of oncogenes using somatic gene transfer has been successfully exploited as a versatile means to validate their pathogenic relevance. In contrast, such functional analyses have been hampered for candidate tumor suppressor genes, e.g. by insufficient knockdown using RNAi-mediated approaches. In order to provide a flexible method for investigating loss-of-function mutations and their potential role in tumorigenesis, we have established CRISPR/Cas9-mediated somatic gene disruption, allowing for in vivo deletion of candidate tumor suppressor genes. We demonstrate the utility of this approach by somatic disruption of the Ptch1 gene in the mouse cerebellum, leading to the formation of medulloblastoma faithfully resembling the SHH-driven subgroup of the disease. This in vivo method for validation of candidate tumor suppressor genes provides a fast and convenient system for the generation of faithful animal models of human cancer.
2014-12-31 | GSE58629 | GEO
Project description:Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we have adapted the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, loss of p107 results in fewer but larger tumors as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130 Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.
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Project description:MicroRNAs (miRs) are small non-coding RNAs that can function as tumor suppressor genes. We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent dataset and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the candidate tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer cells. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair, and actin dynamics. This observation was further corroborated with protein expression analysis and 3’-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters gH2A.X marker expression and affects the cellular organization of F-actin and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility. In this study we monitored global miRNA expression changes in prostate cancer LNCaP cells treated with the epigenetic compounds 5-Azacytidine (5-AzaC) and/or trichostatin A (TSA). Cells were treated with epigenetic drugs for 36 hours and total RNA was isolated for hybridization to miRNA microarrays. 5 independent experiments were performed (n=4 for combined treatment). The candidate prostate tumor suppressor miRNAs, miR-1, miR-206, and miR-27 were up-regulated in LNCaP cells for Affymetrix microarray analysis. LNCaP cells were transfected with pre-miR oligos and 24 hr post-transfection total RNA was collected for microarray analysis; total of three independent experiments.
2011-12-01 | E-GEOD-31620 | biostudies-arrayexpress
Project description:MicroRNAs (miRs) are small non-coding RNAs that can function as tumor suppressor genes. We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent dataset and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the candidate tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer cells. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair, and actin dynamics. This observation was further corroborated with protein expression analysis and 3’-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters gH2A.X marker expression and affects the cellular organization of F-actin and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.
2011-12-01 | GSE31620 | GEO
Project description:p38α MAP kinase plays an important tumor suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumor suppressor mechanisms coordinated by p38α have been reported to occur at the post- translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analyzed whole genome expression profiles of Ras-transformed wild- type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumors, and functional validation has identified several of them as likely mediators of the tumor suppressor effect of p38α on Ras-induced transformation. Interestingly, about 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumor suppression. We have investigated how transcriptional regulation contributes to the tumor suppressor effect of p38α, by comparing whole-genome expression profiles of wild-type (WT) and p38α- deficient (p38α-/-) mouse embryo fibroblasts (MEFs) expressing oncogenic H-RasG12V
2011-11-23 | E-GEOD-26762 | biostudies-arrayexpress
Project description:FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome
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