Epithelial Splicing Regulatory Protein 1 Inhibits the Invasion and Metastasis of Lung Adenocarcinoma

Li, Lingmei; Qi, Lisha; Qu, Tongyuan; Liu, Changxu; Cao, Lu; Huang, Qun; Song, Wangzhao; Yang, Lingyi; Qi, Hui; Wang, Yalei; Gao, Bin; Guo, Yuhong; Sun, Baocun; Meng, Bin; Zhang, Bin; Cao, Weijun

doi:10.1016/j.ajpath.2018.04.012

Cited by 20 publications

(20 citation statements)

References 32 publications

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“…ESRP-1 expression decreases during the EMT as cells transition from an epithelial state to a mesenchymal state, suggesting that patient iNCCs had remained in a more epithelial state than both mother and unrelated control iNCCs by 120h differentiation [76,77]. The significantly higher ESRP-1 expression in patient iNCCs was in agreement with the findings that patient iNCC cells had not differentiated to the same extent as the mother and unrelated control iNCC cells by 120h.…”

Section: Mis-splicing In Bmks Patient Inccssupporting

confidence: 82%

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

Wood

Rowlands

Thomas

et al. 2020

Preprint

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The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother-and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, splice site strengths and sequence motifs, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced KaryotypingKaryotyping of pluripotent iPSCs was conducted by the North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine. Apoptosis assaysCell apoptosis was assessed by annexin-V staining. For assessment of iPSCs, iPSC colonies were grown to approximately 60% confluency on VTN-treated 6-well tissue culture plates. For iNCCs, 120h differentiated iNCCs cultured on VTN-treated 6-well tissue culture plates were used. Cells were disrupted using trypsin-EDTA (Sigma) treatment and cells pelleted by centrifugation. Cells were washed once in PBS and then washed once in 1X Annexin-V Binding Buffer (ABB) (Invitrogen). The cells were resuspended at a density of 1 x 10 6 cells/ml in 1X ABB, and 7.5l APC-conjugated Annexin-V (Invitrogen) added to 100l cell suspension. The cells were incubated for 20min at room temperature in the dark, washed in 1X ABB and resuspended in 200l 1X ABB. 0.25g/ml DAPI (Invitrogen) was added and the resulting samples immediately analysed by flow cytometry. Subpopulations were ascertained in a BD LSRFortessa flow cytometer (gated using an unstained control) as f...

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Section: Mis-splicing In Bmks Patient Inccssupporting

confidence: 82%

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

Wood

Rowlands

Thomas

et al. 2020

Preprint

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“…In colon as well as head and neck squamous cell carcinoma, the downregulation of ESRPs is associated with EMT, but there are also reports that show a correlation between ESRP expression and poor survival of patients especially with breast cancer (Shapiro et al, 2011;Yae et al, 2012;Ishii et al, 2014). Recently, Li et al demonstrated an impaired expression of ESRP1 in lung adenocarcinoma and correlated this with alternatively spliced CD44 forms and enhanced EMT (Li et al, 2018).…”

Section: Introductionmentioning

confidence: 95%

Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

Seiz

Klinke

Scharlibbe

et al. 2019

Biological Chemistry

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Rac1 is a ubiquitously expressed Rho GTPase and an important regulator of the actin cytoskeleton. Its splice variant Rac1b exhibits a 19-amino acid (aa) in-frame insertion and is predominantly active. Both proteins were described in tumorigenesis or metastasis. We investigated the contribution of Rac1 and Rac1b to tumor progression of human non-small-cell lung adenocarcinoma (NSCLA). Rac1 protein was present in 8/8 NSCLA cell lines analyzed, whereas Rac1b was expressed in only 6/8. In wound-healing assays, enhanced green fluorescence protein (EGFP)-Rac1 slightly decreased cell migration, whereas proliferation was increased in both, Rac1- and Rac1b-expressing cells. In the in vivo chorioallantoic invasion model, EGFP-Rac1-expressing cells formed more invasive tumors compared to EGFP-Rac1b. This increased invasiveness correlated with enhanced phosphorylation of p38α, AKT and glycogen synthase kinase 3β (GSK3β), and activation of serum response- and Smad-dependent gene promoters by Rac1. In contrast, Rac1b solely activated the mitogen-activated protein kinase (MAPK) JNK2, together with TCF/LEF1- and nuclear factor kappa B (NFκB)-responsive gene reporters. Rac1b, as Rac1, phosphorylated p38α, AKT and GSK3β. Knockdown of the splicing factor epithelial splicing regulatory protein 1 (ESRP1), which mediates out-splicing of exon 3b from Rac1 pre-messenger RNA, resulted in increased Rac1b messenger RNA (mRNA) and suppression of the epithelial-mesenchymal transition (EMT)-associated transcription factor ZEB1. Our data demonstrate different signaling and functional activities of Rac1 and Rac1b and an important role for Rac1 in lung cancer metastasis.

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“…E-cadherin, and N-cadherin and vimentin are representative markers in epithelial cell and mesenchymal cell, respectively. They have positive correlation among expression of ESRP1, E-cadherin, and N-cadherin ( Supplementary Figure 8) (16). In conclusion, ESRP1 is an important factor that directly affects genes that regulate the epithelial-mesenchymal transition (EMT) and promote prostate cancer invasion and metastasis ( Supplementary Figure 9).…”

Section: A B Cmentioning

confidence: 85%

Epithelial Splicing Regulatory Protein (ESPR1) Expression in an Unfavorable Prognostic Factor in Prostate Cancer Patients

Lee

Park

et al. 2020

Front. Oncol.

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Background: To evaluate the role of epithelial splicing regulatory protein 1 (ESRP1) expression in survival prognoses and disease progression for prostate cancer (PC) using The Cancer Genome Atlas (TCGA) dataset and to validate it using patients' prostatectomy specimens. Methods: A preliminary investigation into the clinical significance of ESRP1 in PC was conducted using TCGA PC PRAD dataset and then using immunohistochemistry in 514 PC patients' tissue microarrays of radical prostatectomy specimens. The interpretation of immunohistochemistry was done using its intensity (high vs. low) or the semi-quantitative expression value (H-score, 0-300). The prognostic significance of ESRP1 expression was analyzed for biochemical recurrence (BCR), recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) using the Cox proportional-hazards model (p < 0.05). Results: In the publicly available prostate adenocarcinoma dataset, ESRP1 expression was significantly higher in the tumor samples compared to the normal samples (p < 0.001). Survival analysis showed that the tumor samples in the ESRP1-high group had significantly worse BCR-free survival and RFS compared to the ESRP1-low group (p < 0.05), whereas OS was not (p=0.08). These results were largely consistent with the 514 patients' clinical data during a median 91.2 months of follow-up. After adjusting for significant prognostic clinicopathological factors, the multivariable models showed that the ESRP1 was a significantly risk factor for CSS (Hazard ratio 3.37, p = 0.034) and for BCR (HR 1.34, p=0.049) without any significance for OS (p=0.464). Conclusions: The higher ESRP1 expression appeared increased risk of disease progression and cancer-specific death in PC.

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Epithelial Splicing Regulatory Protein 1 Inhibits the Invasion and Metastasis of Lung Adenocarcinoma

Cited by 20 publications

References 32 publications

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

Epithelial Splicing Regulatory Protein (ESPR1) Expression in an Unfavorable Prognostic Factor in Prostate Cancer Patients

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