Cold-inducible RNA-binding protein promotes epithelial-mesenchymal transition by activating ERK and p38 pathways

Abstract Background: The interaction between LncRNA and RNA-binding protein (RBPs) plays an essential role in the regulation over the malignant progression of tumors. Previous studies on the mechanism of SNHG1, an emerging lncRNA, have primarily focused on the competing endogenous RNA (ceRNA) mechanism. Nevertheless, the underlying mechanism between SNHG1 and RBPs in tumors remains to be explored, especially in prostate cancer (PCa).Methods：SNHG1 expression profiles in PCa were determined through the analysis of TCGA data and tissue microarray at the mRNA level. Gain- and loss-of-function experiments were performed to investigate the biological role of SNHG1 in PCa initiation and progression. RNA-seq, immunoblotting, RNA pull-down and RNA immunoprecipitation analyses were utilized to clarify potential pathways with which SNHG1 might be involved. Finally, rescue experiments were carried out to further confirm this mechanism.Results: We found that SNHG1 was dominantly expressed in the nuclei of PCa cells and significantly upregulated in PCa patients. The higher expression level of SNHG1 was dramatically correlated with tumor metastasis and patient survival. Functionally, overexpression of SNHG1 in PCa cells induced epithelial–mesenchymal transition (EMT), accompanied by down-regulation of the epithelial marker, E-cadherin, and up-regulation of the mesenchymal marker, vimentin. Increased proliferation and migration, as well as accelerated xenograft tumor growth, were observed in SNHG1-overexpressing PCa cells, while opposite effects were achieved in SNHG1-silenced cells. Mechanistically, SNHG1 competitively interacted with hnRNPL to impair the translation of protein E-cadherin, thus activating the effect of SNHG1 on the EMT pathway, eventually promoting the metastasis of PCa. Conclusion: Our findings demonstrate that SNHG1 is a positive regulator of EMT activation through the SNHG1-hnRNPL-CDH1 axis. SNHG1 may serve as a novel potential therapeutic target for PCa.

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RNA-binding protein IGF2BP2 enhances circ_0000745 abundancy and promotes aggressiveness and stemness of ovarian cancer cells via the microRNA-3187-3p/ERBB4/PI3K/AKT axis

Journal of Ovarian Research ◽

10.1186/s13048-021-00917-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Shengtan Wang ◽

Zaihong Li ◽

Genhai Zhu ◽

Lan Hong ◽

Chunyan Hu ◽

...

Keyword(s):

Ovarian Cancer ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Binding Protein ◽

Rna Binding Protein ◽

Circular Rnas ◽

Ovarian Cancer Cells ◽

Loss Of Function ◽

Mesenchymal Transition ◽

Repressive Effect

Abstract Background Circular RNAs (circRNAs) are increasingly recognized as important regulators in cancer including ovarian cancer (OC). This work focuses on the effects of circ_0000745 on the OC development of and molecules involved. Methods Expression of circ_0000745 in collected OC tissues and the acquired OC cell lines was examined by RT-qPCR. The stability of circ_0000745 in cells was examined by RNase R treatment. The target transcripts interacted with circ_0000745 were predicted using bioinformatic systems. Gain- and loss-of-function studies of circ_0000745, microRNA (miR)-3187-3p and erb-b2 receptor tyrosine kinase 4 (ERBB4) were conducted to determine their functions on proliferation, migration, invasion and stem cell property of OC cells. Results Circ_0000745 and ERBB4 were abundantly expressed while miR-3187-3p was poorly expressed in OC tissues and cells. Circ_0000745 sequestered miR-3187-3p and blocked its repressive effect on ERBB4. Downregulation of circ_0000745 reduced proliferation, aggressiveness, epithelial-mesenchymal transition, and stemness of SK-OV-3 cells, but this reduction was blocked upon miR-3187-3p inhibition or ERBB4 upregulation. By contrast, artificial induction of circ_0000745 upregulation, miR-3187-3p upregulation and ERBB4 downregulation led to inverse trends in ES-2 cells. ERBB4 promoted the phosphorylation of the PI3K/AKT signaling pathway. An RNA binding protein IGF2BP2 was found to circ_0000745 bind to and promote its expression and stability. Conclusion This study demonstrated that circ_0000745 upregulated by IGF2BP2 promotes aggressiveness and stemness of OC cells through a miR-3187-3p/ERBB4/PI3K/AKT axis. Circ_0000745 may serve as a promising target for OC treatment.

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LncRNA SNHG1 and RNA binding protein hnRNPL form a complex and coregulate CDH1 to boost the growth and metastasis of prostate cancer

Cell Death and Disease ◽

10.1038/s41419-021-03413-4 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Xiao Tan ◽

Wen-bin Chen ◽

Dao-jun Lv ◽

Tao-wei Yang ◽

Kai-hui Wu ◽

...

Keyword(s):

Prostate Cancer ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Binding Protein ◽

Expression Profiles ◽

Rna Binding Protein ◽

Underlying Mechanism ◽

Loss Of Function ◽

Mesenchymal Transition ◽

E Cadherin

AbstractThe interaction between LncRNA and RNA-binding protein (RBPs) plays an essential role in the regulation over the malignant progression of tumors. Previous studies on the mechanism of SNHG1, an emerging lncRNA, have primarily focused on the competing endogenous RNA (ceRNA) mechanism. Nevertheless, the underlying mechanism between SNHG1 and RBPs in tumors remains to be explored, especially in prostate cancer (PCa). SNHG1 expression profiles in PCa were determined through the analysis of TCGA data and tissue microarray at the RNA level. Gain- and loss-of-function experiments were performed to investigate the biological role of SNHG1 in PCa initiation and progression. RNA-seq, immunoblotting, RNA pull-down and RNA immunoprecipitation analyses were utilized to clarify potential pathways with which SNHG1 might be involved. Finally, rescue experiments were carried out to further confirm this mechanism. We found that SNHG1 was dominantly expressed in the nuclei of PCa cells and significantly upregulated in PCa patients. The higher expression level of SNHG1 was dramatically correlated with tumor metastasis and patient survival. Functionally, overexpression of SNHG1 in PCa cells induced epithelial–mesenchymal transition (EMT), accompanied by down-regulation of the epithelial marker, E-cadherin, and up-regulation of the mesenchymal marker, vimentin. Increased proliferation and migration, as well as accelerated xenograft tumor growth, were observed in SNHG1-overexpressing PCa cells, while opposite effects were achieved in SNHG1-silenced cells. Mechanistically, SNHG1 competitively interacted with hnRNPL to impair the translation of protein E-cadherin, thus activating the effect of SNHG1 on the EMT pathway, eventually promoting the metastasis of PCa. Our findings demonstrate that SNHG1 is a positive regulator of EMT activation through the SNHG1-hnRNPL-CDH1 axis. SNHG1 may serve as a novel potential therapeutic target for PCa.

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An RNA-Binding Protein, Hu-antigen R, in Pancreatic Cancer Epithelial to Mesenchymal Transition, Metastasis, and Cancer Stem Cells

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-19-0822 ◽

2020 ◽

Vol 19 (11) ◽

pp. 2267-2277

Author(s):

Ruochen Dong ◽

Ping Chen ◽

Kishore Polireddy ◽

Xiaoqing Wu ◽

Tao Wang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Epithelial To Mesenchymal Transition ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Mesenchymal Transition ◽

Hu Antigen R

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CPEB3-mediated MTDH mRNA translational suppression restrains hepatocellular carcinoma progression

Cell Death and Disease ◽

10.1038/s41419-020-02984-y ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

He Zhang ◽

Chendan Zou ◽

Zini Qiu ◽

Fang E ◽

Qiang Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Binding Protein ◽

Mrna Translation ◽

Luciferase Assay ◽

Mesenchymal Transition

Abstract Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein. We had reported that CPEB3 is involved in hepatocellular carcinoma (HCC) progression. However, the underlying mechanisms of CPEB3 in HCC remain unclear. In this study, we firstly performed RNA immunoprecipitation to uncover the transcriptome-wide CPEB3-bound mRNAs (CPEB3 binder) in HCC. Bioinformatic analysis indicates that CPEB3 binders are closely related to cancer progression, especially HCC metastasis. Further studies confirmed that metadherin (MTDH) is a direct target of CPEB3. CPEB3 can suppress the translation of MTDH mRNA in vivo and in vitro. Besides, luciferase assay demonstrated that CPEB3 interacted with 3′-untranslated region of MTDH mRNA and inhibited its translation. Subsequently, CPEB3 inhibited the epithelial–mesenchymal transition and metastasis of HCC cells through post-transcriptional regulation of MTDH. In addition, cpeb3 knockout mice are more susceptible to carcinogen-induced hepatocarcinogenesis and subsequent lung metastasis. Our results also indicated that CPEB3 was a good prognosis marker, which is downregulated in HCC tissue. In conclusion, our results demonstrated that CPEB3 played an important role in HCC progression and targeting CPEB3-mediated mRNA translation might be a favorable therapeutic approach.

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Circ_0000079 Decoys the RNA-Binding Protein FXR1 to Interrupt Formation of the FXR1/PRCKI Complex and Decline Their Mediated Cell Invasion and Drug Resistance in NSCLC

Cell Transplantation ◽

10.1177/0963689720961070 ◽

2020 ◽

Vol 29 ◽

pp. 096368972096107

Author(s):

Chen Chen ◽

Min Zhang ◽

Yan Zhang

Keyword(s):

Drug Resistance ◽

Cell Invasion ◽

Rna Binding ◽

Binding Protein ◽

Glycogen Synthesis ◽

Rna Binding Protein ◽

Cell Counting ◽

Mesenchymal Transition ◽

Potential Biomarker ◽

Nsclc Patients

Nonsmall cell lung cancer (NSCLC) has gradually become one of the deadliest threats to human health and life worldwide. Although reports have shown that circular RNAs (circRNAs) are associated with progression and metastasis of NSCLC, the biological functions of circRNAs during these processes remain largely unknown. Our study showed that circ_0000079 (CiR79) levels were significantly downregulated in NSCLC patients, especially in cisplatin (DDP)-resistant NSCLC patients, and low circ_0000079 levels were significantly associated with poor overall survival of NSCLC patients. Then, results from Cell Counting Kit-8 (CCK-8) cell viability assay and transwell cell invasion assay in A549/DDP and H460/DDP cells transfected with pCDH-CiR79 expression vector showed that circ_0000079 overexpression significantly inhibited cell proliferation and invasion of these DDP-resistant NSCLC cells. The online bioinformatic program StarBase and RNA-binding protein immunoprecipitation predicted and demonstrated that circ_0000079 could bind with the Fragile X-Related 1 (FXR1) protein rather than with protein kinase C, iota (PRKCI), which was shown to form a complex with FXR1 to promote invasion and growth of NSCLC cells. Co-immunoprecipitation combined with Western blot assays indicated that FXR1 levels were remarkably decreased, but PRKCI levels remained unchanged in pCDH-ciR79 transfected NSCLC cells. Moreover, circ_0000079 negatively regulated FXR1/PRKCI-mediated phosphorylation of glycogen synthesis kinase 3β and activator protein 1, thus suppressing the protein level of the Snail gene, an important promoter gene regulating cancer cell growth and epithelial-mesenchymal transition. Furthermore, DDP resistance of A549/DDP and H460/DDP cells was inhibited by circ_0000079 overexpression but was restored by FXR1. Hence, our findings demonstrated that circ_0000079 might inhibit cell invasion and drug resistance in NSCLC by interrupting the formation of the FXR1/PRCKI complex by interacting with FXR1, and circ_0000079 could act as a potential biomarker and therapeutic target for NSCLC.

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CELF1 is an EIF4E binding protein that promotes translation of epithelial-mesenchymal transition effector mRNAs

10.1101/640300 ◽

2019 ◽

Author(s):

Arindam Chaudhury ◽

Rituraj Pal ◽

Natee Kongchan ◽

Na Zhao ◽

Yingmin Zhu ◽

...

Keyword(s):

Translation Initiation ◽

Mammalian Cells ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Binding Protein ◽

Mrna Translation ◽

Scaffolding Protein ◽

Initiation Factor ◽

Eukaryotic Initiation Factor ◽

Mesenchymal Transition

AbstractMounting evidence is revealing a granularity within gene regulation that occurs at the level of mRNA translation. Within mammalian cells, canonical cap-dependent mRNA translation is dependent upon the interaction between the m7G cap-binding protein eukaryotic initiation factor 4E (eIF4E) and the scaffolding protein eukaryotic initiation factor 4G (eIF4G), the latter of which facilitates pre-translation initiation complex assembly, mRNA circularization, and ultimately ribosomal scanning. In breast epithelial cells, we previously demonstrated that the CELF1 RNA-binding protein promotes the translation of epithelial to mesenchymal transition (EMT) effector mRNAs containing GU-rich elements (GREs) within their 3’ untranslated regions (UTRs). Here we show that within this context, CELF1 directly binds to both the eIF4E cap-binding protein and Poly(A) binding protein (PABP), promoting translation of GRE-containing mRNAs in mesenchymal cells. Disruption of this CELF1/eIF4E interaction inhibits both EMT induction and experimental metastasis. Our findings illustrate a novel way in which non-canonical mechanisms of translation initiation underlie transitional cellular states within the context of development or human disease.

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