RNA binding protein RBMS3 is a common effector of EMT program that promotes Triple-Negative Breast Cancer Progression by Regulation of PRRX1 mRNA Stability
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ABSTRACT:
PROVIDER: PRJNA751095 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15309002.fastq.gz | Fastqsanger.gz | |||
| SRR15309004.fastq.gz | Fastqsanger.gz | |||
| SRR15309006.fastq.gz | Fastqsanger.gz | |||
| SRR15309008.fastq.gz | Fastqsanger.gz | |||
| SRR15309010.fastq.gz | Fastqsanger.gz |
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Project description:The epithelial-to-mesenchymal transition (EMT) has been recognized as a driving force for tumor progression in breast cancer. Recently, our group identified the RNA Binding Motif Single Stranded Interacting Protein 3 (RBMS3) to be significantly associated with an EMT transcriptional program in breast cancer. Additional expression profiling demonstrated that RBMS3 was consistently upregulated by multiple EMT transcription factors and correlated with mesenchymal gene expression in breast cancer cell lines. Functionally, RBMS3 was sufficient to induce EMT in two immortalized mammary epithelial cell line. In triple-negative breast cancer (TNBC) models, RBMS3 was necessary for maintaining the mesenchymal phenotype and invasion and migration in vitro. Loss of RBMS3 significantly impaired both tumor progression and spontaneous metastasis in vivo. Using a genome-wide approach to interrogate mRNA stability, we found that ectopic expression of RBMS3 upregulates many genes that are resistant to degradation following transcriptional blockade by actinomycin D. Specifically, RBMS3 was shown to interact with the mRNA of EMT transcription factor PRRX1 and promote PRRX1 mRNA stability. PRRX1 is required for RBMS3-mediated EMT and is partially sufficient to rescue the effect of RBMS3 knockdown in TNBC cell lines. Together, this study identifies RBMS3 as a novel and common effector of EMT, which could be a promising therapeutic target for triple-negative breast cancer treatment.
2022-07-25 | GSE181237 | GEO
Project description:The epithelial-to-mesenchymal transition (EMT) has been recognized as a driving force for tumor progression in breast cancer. Recently, our group identified the RNA Binding Motif Single Stranded Interacting Protein 3 (RBMS3) to be significantly associated with an EMT transcriptional program in breast cancer. Additional expression profiling demonstrated that RBMS3 was consistently upregulated by multiple EMT transcription factors and correlated with mesenchymal gene expression in breast cancer cell lines. Functionally, RBMS3 was sufficient to induce EMT in two immortalized mammary epithelial cell lines. In triple-negative breast cancer (TNBC) models, RBMS3 was necessary for maintaining the mesenchymal phenotype and invasion and migration in vitro. Loss of RBMS3 significantly impaired both tumor progression and spontaneous metastasis in vivo. Using a genome-wide approach to interrogate mRNA stability, we found that ectopic expression of RBMS3 upregulates many genes that are resistant to degradation following transcriptional blockade by actinomycin D (ACTD). Specifically, RBMS3 was shown to interact with the mRNA of EMT transcription factor PRRX1 and promote PRRX1 mRNA stability. PRRX1 is required for RBMS3-mediated EMT and is partially sufficient to rescue the effect of RBMS3 knockdown in TNBC cell lines. Together, this study identifies RBMS3 as a novel and common effector of EMT, which could be a promising therapeutic target for TNBC treatment.
| S-EPMC9421946 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity and treatment response, we combined functional and molecular profiling with computational analysis tools. Using these approaches, we defined transcriptional, epigenetic, and metabolic subtypes, and identified subtype-driving super-enhancers. Single cell RNA sequencing analyses revealed relative homogeneity of the three major transcriptional subtypes (luminal, basal and mesenchymal) within tumors. We found that mesenchymal TNBCs are more similar to mesenchymal neuroblastoma and rhabdoid tumors than to other TNBC subtypes, and the PRRX1 transcription factor serves as a key driver of these tumors. By directly regulating the transcription of mesenchymal genes, PRRX1 is sufficient for inducing the mesenchymal subtype but is not required for its maintenance.
2023-11-09 | GSE202767 | GEO
Project description:Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity and treatment response, we combined functional and molecular profiling with computational analysis tools. Using these approaches, we defined transcriptional, epigenetic, and metabolic subtypes, and identified subtype-driving super-enhancers. Single cell RNA sequencing analyses revealed relative homogeneity of the three major transcriptional subtypes (luminal, basal and mesenchymal) within tumors. We found that mesenchymal TNBCs are more similar to mesenchymal neuroblastoma and rhabdoid tumors than to other TNBC subtypes, and the PRRX1 transcription factor serves as a key driver of these tumors. By directly regulating the transcription of mesenchymal genes, PRRX1 is sufficient for inducing the mesenchymal subtype but is not required for its maintenance.
2023-11-09 | GSE202769 | GEO
Project description:Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity and treatment response, we combined functional and molecular profiling with computational analysis tools. Using these approaches, we defined transcriptional, epigenetic, and metabolic subtypes, and identified subtype-driving super-enhancers. Single cell RNA sequencing analyses revealed relative homogeneity of the three major transcriptional subtypes (luminal, basal and mesenchymal) within tumors. We found that mesenchymal TNBCs are more similar to mesenchymal neuroblastoma and rhabdoid tumors than to other TNBC subtypes, and the PRRX1 transcription factor serves as a key driver of these tumors. By directly regulating the transcription of mesenchymal genes, PRRX1 is sufficient for inducing the mesenchymal subtype but is not required for its maintenance.
2023-11-09 | GSE202768 | GEO
Project description:Primary human adipose stromal cells (hASCs) from rs4684847 CC risk allele carriers were cultured and induced to differentiate into adipocytes, and simultaneously transfected for 72h with non-targeting siRNA or siRNA targeting PRRX1 (n=10) or both PRRX1 and PPARG (subset of the subjects, n=4).
2013-12-01 | E-MTAB-1906 | biostudies-arrayexpress
Project description:Malignant nerve sheath tumors (MPNST) are rare types of malignant soft tissue sarcomas and characterized by high resistance for current chemotherapeutic strategies, including topoisomerase 2a (TOP2A) inhibitor, etoposide. Although the poor therapeutic or severe side effects of etoposide in MPNST patients are demonstrated, novel molecular targets that promote tumor malignancy have not been identified. Previously, we reported that paired related-homeobox 1 (PRRX1) serves as a malignant factor in human osteosarcoma. Here, we found that expression level of PRRX1 in tumor tissues, especially sarcomas, are higher than in normal tissues using database analysis. PRRX1 was expressed in various human sarcoma tissues, and its level increased during malignant progression from schwannoma or neurofibroma to MPNST. High expression of PRRX1 was also associated with poor prognosis of human MPNST patients, and PRRX1 knockdown suppressed proliferation, invasion and tumorigenic potential of human MPNST cell line, HS-PSS. Immunoprecipitation and mass spectrometry analysis revealed that PRRX1 interacts with TOP2A, and human MPNST patients with high expression of TOP2A showed poor prognosis. Interestingly, database analysis revealed that expression level of TOP2A in tumor tissues were positively correlated with PRRX1. TOP2A knockdown in HS-PSS suppressed proliferation, and inhibited the migration induced by PRRX1A overexpression. Overexpression of PRRX1 and TOP2A cooperatively increased migration and expression of tumor-malignancy associated gene sets, including EMT, mTORC1, KRAS and SRC signaling pathways. Inhibition of PRRX1-TOP2A interaction would be a novel tumor-selective therapeutic strategy that has less severe side effects than current chemotherapies.
2023-05-31 | GSE214899 | GEO
Project description:Epigenetic heterogeneity and transcriptional drivers of triple-negative breast cancer (PRRX1 ChIP-Seq)
| PRJNA837231 | ENA
Project description:Metastasis is a major obstacle to better prognosis in patients with hepatocellular carcinoma (HCC). Mesenchymal-epithelial transition (MET) is the driving force for metastatic colonization in which E-cadherin reexpression is a critical procedure. It has been reported that the loss of paired-related homeobox transcription factor 1 (PRRX1) is required for cancer cell metastasis in vivo. However, the role of PRRX1 in MET and how its downregulation triggers E-cadherin reexpression are unknown. In this study, we performed a systematic, mechanistic study regarding the role of PRRX1 in MET of HCC. We observed PRRX1 downregulation in HCC tissues which correlated with early metastasis and short overall survival time. Overexpression of PRRX1 induced EMT, but did not promote metastasis formation, while knockdown of PRRX1 promoted metastasis and colonization of circulating HCC cells as shown in in situ liver tumor model and colonization model. PRRX1 protein levels reversely correlated with E-cadherin levels in HCC cell lines. PRRX1 knockdown promoted E-cadherin reexpression and cell proliferation, inhibited cell invasion and migration. The microarray results showed that PRRX1 deficiency regulated extracellular matrix (ECM) interaction, focal adhesion, TGF-β signaling and cancer pathways. PRRX1 knockdown upregulated PITX2 (paired like homeodomain 2) and inhibited CTNNB1 (catenin beta 1) and SLUG. Silencing of PITX2 reversed CTNNB1 and SLUG inhibition and E-cadherin reexpression. PITX2 upregulation increased miR-200a and miR-200b/429, which further inhibited the transcription of CTNNB1 and SLUG, respectively, thus abrogating the inhibitory effect on E-cadherin. In conclusion, our data showed that the downregulation of PRRX1 induced E-cadherin reexpression through PITX2/miR-200a/CTNNB1 and PITX2/miR-200b/429/SLUG pathway, making PRRX1 a novel prognostic factor for HCC.
2020-04-18 | GSE148851 | GEO
Project description:To investigate downstream targets of PRRX1, we used MDA-MB-231 (MDA231) breast cancer cells which express low level of PRRX1 to generate a stable cell line where human PRRX1 was ectopically overexpressed (MDA231-PRRX1), and performed comparative microarray analyses. Interestingly, we found many miRNAs that were upregulated in MDA231-PRRX1 cells.
2019-10-18 | GSE138078 | GEO