scholarly journals Decreased c-Myc mRNA Stability via the MicroRNA 141-3p/AUF1 Axis Is Crucial for p63α Inhibition of Cyclin D1 Gene Transcription and Bladder Cancer Cell Tumorigenicity

2018 ◽  
Vol 38 (21) ◽  
Author(s):  
Xin Li ◽  
Zhongxian Tian ◽  
Honglei Jin ◽  
Jiheng Xu ◽  
Xiaohui Hua ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cyclin D1 ◽  
Gene Transcription ◽  
Mrna Stability ◽  
Rna Binding ◽  
D1 Protein ◽  
Protein Translation ◽  
The United States ◽  
Negative Regulator ◽  
Anchorage Independent Growth

ABSTRACTBladder cancer (BC) ranks as the sixth most common cancer in the United States and is the leading cause of death in patients with urinary malignancies. p63 is a member of the p53 family and is believed to function as a tumor suppressor in human BCs. Our most recent studies revealed a previously unknown function of the RING of XIAP in promoting microRNA 4295 (miR-4295) transcription, thereby reducing p63α protein translation and enhancing normal urothelial transformation, whereas p63α upregulates hsp70 transcription, subsequently activating the HSP70/Wasf3/Wave3/matrix metalloproteinase 9 (MMP-9) axis and promoting BC cell invasion via initiating the transcription factor E2F1. In this study, we found that p63α inhibited cyclin D1 protein expression, subsequently decreasing the ability of BC cell anchorage-independent growthin vitroand tumorigenicityin vivo. Mechanistic studies demonstrated that p63α expression is able to downregulate cyclin D1 gene transcription through attenuation of c-Myc mRNA stability. We further show that the reduction of miR-141-3p expression by p63α directly releases its inhibition of 3′ untranslated region (UTR) activity of AU-rich element RNA-binding factor 1 (AUF1) mRNA, thereby increasing AUF1 protein translation and further resulting in degradation of c-Myc mRNA, which, in turn, reduces cyclin D1 gene transcription and BC cell anchorage-independent growth. Collectively, our results demonstrate that p63α is a negative regulator of BC cell tumorigenic growth, a distinctly different function than its promotion of BC invasion, thus providing further new insight into the “two faces” of p63α in regulation of BC cell tumorigenic growth and progression/invasion.

scholarly journals Upregulation of RBM24 Exacerbates Bladder Cancer Progression by Formatting Runx1t1/TCF4/miR-625-5p Feedback Loop

2020 ◽  
Author(s):  
Yue-Wei Yin ◽  
Kai-Long Liu ◽  
Bao-Sai Lu ◽  
Wei Li ◽  
Ya-Lin Niu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Mrna Stability ◽  
Feedback Loop ◽  
Rna Binding ◽  
Luciferase Assay ◽  
Proximity Ligation Assay ◽  
Binding Motif ◽  
Mrna Levels

Abstract Background: RNA-binding motif protein 24 (RBM24) acts as a multifunctional determinant of cell fate, proliferation, apoptosis, and differentiation during development through regulation of pre-mRNA splicing and mRNA stability. It is also implicated in carcinogenesis, but the functions of RBM24 in bladder cancer (BC) remains unclear.Methods: Cell viability was examined by colony forming and MTT assays. Real-time quantitative PCR (RT-qPCR) and western blot analysis were used to detect the protein and mRNA levels. Co-immunoprecipitation (CoIP) and proximity ligation assay (PLA) were used to determine the protein-protein interaction. Chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and oligo pull-down assays were used to verify DNA/RNA–protein interactions. Luciferase assay analysis was used to detect effects on transcription factor activity.Results: In the present study, we revealed that RBM24 was upregulated in BC tissues. Importantly, we found that higher level of RBM24 was correlated with poor prognosis in BC patients. Overexpression of RBM24 promoted while depletion of RBM24 inhibited BC cell proliferation in vivo and in vitro. Mechanically, RBM24 positively regulated Runx1t1 expression in BC cells by binding to and enhancing Runx1t1 mRNA stability. Runx1t1 in turn promoted RBM24 expression by interacting with TCF4. Furthermore, Runx1t1 in turn promoted RBM24 expression by interacting with the transcription factor TCF4 and depressing transcription of miR-625-5p, which directly targets and normally suppresses RBM24 expression. RBM24-regulated BC cells proliferation was moderated via the Runx1t1/TCF4/miR-625-5p feedback loop.Conclusions: In summary, these results indicate that a RBM24/Runx1t1/TCF4/miR-625-5p positive feedback loop plays a key role in BC oncogenesis. Disruption of this pathway may be a potential therapeutic strategy for BC treatment.

scholarly journals Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100)

Oncotarget ◽  
2016 ◽  
Vol 7 (23) ◽  
pp. 34112-34130 ◽  
Author(s):  
Jiawei Xu ◽  
Yulei Wang ◽  
Xiaohui Hua ◽  
Jiheng Xu ◽  
Zhongxian Tian ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
D1 Protein ◽  
Protein Translation ◽  
Suppressive Effect ◽  
Cyclin D1 Protein ◽  
Tumor Suppressive Effect

scholarly journals Interaction of BIR2/3 of XIAP with E2F1/Sp1 Activates MMP2 and Bladder Cancer Invasion by Inhibiting Src Translation

2018 ◽  
Author(s):  
Jiheng Xu ◽  
Honglei Jin ◽  
Jingxia Li ◽  
Junlan Zhu ◽  
Xiaohui Hua ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Ectopic Expression ◽  
Direct Interaction ◽  
Protein Translation ◽  
Negative Regulator ◽  
Human Bladder ◽  
Design Synthesis ◽  
Cell Behaviors ◽  
Apoptosis Protein ◽  
Insight Into

AbstractAlthough X-linked inhibitor of apoptosis protein (XIAP) is associated with cancer cell behaviors, the structure-based function of XIAP in promotion human bladder cancer (BC) invasion is barely explored. Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and invasion in XIAP-deleted BC cells, while Src was further defined as a XIAP downstream negative regulator for MMP2 activation and BC invasion. The inhibition of Src expression by BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation resulting from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, consequently leading to fully activation of E2F1/Sp1. Our findings provide a novel insight into understanding of specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

scholarly journals XIAP Interaction with E2F1 and Sp1 via its BIR2 and BIR3 domains specific activated MMP2 to promote bladder cancer invasion

Oncogenesis ◽  
2019 ◽  
Vol 8 (12) ◽  
Author(s):  
Jiheng Xu ◽  
Xiaohui Hua ◽  
Rui Yang ◽  
Honglei Jin ◽  
Jingxia Li ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Invasion ◽  
Feedback Loop ◽  
Ectopic Expression ◽  
Direct Interaction ◽  
Protein Translation ◽  
Negative Regulator ◽  
Cancer Cell Invasion ◽  
Design Synthesis ◽  
First Time

AbstractXIAP has generally been thought to function in bladder cancer. However, the potential function of structure-based function of XIAP in human BC invasion has not been well explored before. We show here that ectopic expression of the BIR domains of XIAP specifically resulted in MMP2 activation and cell invasion in XIAP-deleted BC cells, while Src was further defined as an XIAP downstream negative regulator for MMP2 activation and BC cell invasion. The inhibition of Src expression by the BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation; which was resulted from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, respectively. The interaction of BIR2/BIR3 with E2F1/Sp1 unexpectedly occurred, which could be blocked by serum-induced XIAP translocation. Taken together, our studies, for the first time revealed that: (1) BIR2 and BIR3 domains of XIAP play their role in cancer cell invasion without affecting cell migration by specific activation of MMP2 in human BC cells; (2) by BIR2 interacting with E2F1 and BIR3 interacting with Sp1, XIAP initiates E2F1/Sp1 positive feedback loop-dependent transcription of miR-203, which in turn inhibits Src protein translation, further leading to MMP2-cleaved activation; (3) XIAP interaction with E2F1 and Sp1 is observed in the nucleus. Our findings provide novel insights into understanding the specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

scholarly journals Identification of Peptidyl-Prolyl Cis-Trans Isomerase-Like 4 as a Disease Causing Gene in Intracranial Aneurysms and its Role in Vertebrate CNS Specific Angiogenesis

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Tanyeri Barak ◽  
Adife Gulhan Ercan Sencicek ◽  
Danielle F Miyagishima ◽  
Octavian Henegariu ◽  
Ketu Mishra Gorur ◽  
...  
Keyword(s):  
Mrna Stability ◽  
Rna Binding ◽  
The United States ◽  
Rna Modification ◽  
Control Group ◽  
Fisher Exact Test ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Exact Test

Abstract INTRODUCTION Intracranial aneurysm (IA) is a significant health burden affecting nearly 6 million people in the United States with an estimated prevalence of 3.2% worldwide. Using whole exome sequencing (WES) of 728 European IA cases, we identified damaging mutations in and RNA binding protein peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4) in both familial and sporadic IA cases. METHODS We performed WES in 728 European IA cases followed by a mutational burden analysis between IA cases and a European (Finnish + Non-Finnish) control group of 1443 unaffected individuals, and European subjects (non-Finnish + Finnish) in the ExAC and gnomAD databases. Fisher exact test was used to determine the significance of the enrichment of rare (ExAC MAF <0.0001) and deleterious variants consisting of loss of function and deleterious missense mutations (MetSVM-D). Mutant ppil4 lines were generated using Crispr-CAS9 in zebrafish and X.tropicalis. RNA-seq and Slam-Seq were performed to identify transcriptome-wide changes in RNA half-life mediated by PPIL4. RESULTS Burden analysis revealed a significant enrichment of rare and deleterious PPIL4 variants in European IA cases when compared to 1443 controls (OR = INF., Fisher P = 3.17 × 10–4), ExAC (OR = 12.26, Fisher P = 5 × 10–4) or gnomAD (OR = 13.14, Fisher P = 3.4 × 10–4). PPIL4 mutants both in zebrafish and X.tropicalis models displayed cerebral hemorrhage and cerebrovascular simplification. Slam-seq analysis revealed that PPIL4 promotes mRNA stability of the genes implicated in VEGF signaling (FDR = 3.75E-07) and Focal adhesion pathways (FDR = 2.04E-06). CONCLUSION In this study, we identified PPIL4 as a candidate gene in IA pathogenesis and demonstrated morphological and hemodynamic impairment in vivo upon abrogating PPIL4 in 2 vertebrate models. Furthermore, we demonstrated that PPIL4 plays a major role in CNS angiogenesis and IA pathogenesis through promoting mRNA stability of key angiogenesis related genes, emphasizing the role of post-transcriptional RNA modification in cerebrovascular development and pathologies.

scholarly journals RBM24 exacerbates bladder cancer progression by forming a Runx1t1/TCF4/miR-625-5p feedback loop

2021 ◽  
Author(s):  
Yue-Wei Yin ◽  
Kai-Long Liu ◽  
Bao-Sai Lu ◽  
Wei Li ◽  
Ya-Lin Niu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bladder Cancer ◽  
Cell Fate ◽  
Cancer Progression ◽  
Mrna Stability ◽  
Feedback Loop ◽  
Rna Binding ◽  
Binding Motif

AbstractRNA–binding motif protein 24 (RBM24) acts as a multifunctional determinant of cell fate, proliferation, apoptosis, and differentiation during development by regulating premRNA splicing and mRNA stability. It is also implicated in carcinogenesis, but the functions of RBM24 in bladder cancer (BC) remain unclear. In the present study, we revealed that RBM24 was upregulated in BC tissues. Importantly, we found that a higher level of RBM24 was correlated with poor prognosis in BC patients. Overexpression of RBM24 promoted BC cell proliferation, while depletion of RBM24 inhibited BC cell proliferation in vivo and in vitro. Mechanistically, RBM24 positively regulated Runx1t1 expression in BC cells by binding to and enhancing Runx1t1 mRNA stability. Furthermore, Runx1t1 in turn promoted RBM24 expression by interacting with the transcription factor TCF4 and suppressing the transcription of miR-625-5p, which directly targets RBM24 and suppresses RBM24 expression. RBM24-regulated BC cell proliferation was moderated via the Runx1t1/TCF4/miR-625-5p feedback loop. These results indicate that the RBM24/Runx1t1/TCF4/miR-625-5p positive feedback loop participates in BC progression. Disruption of this pathway may be a potential therapeutic strategy for BC treatment.

scholarly journals MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Fengxia Chen ◽  
Qingqing Wang ◽  
Xiaoyan Yu ◽  
Ningning Yang ◽  
Yuan Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Alternative Splicing ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Negative Regulator ◽  
Breast Epithelial Cell

AbstractTriple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15–20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.

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