scholarly journals RBM45 Promoted HCC Growth and Metastasis by Stabilizing BCL2 and Twist1 mRNA

2021 ◽  
Author(s):  
Lili Han ◽  
Lin Wang ◽  
Fei Wu
Keyword(s):  
Rna Binding ◽  
Binding Motif ◽  
Potential Therapeutic Target ◽  
Transcriptional Regulatory ◽  
Rna Immunoprecipitation ◽  
Post Transcriptional Regulation ◽  
Rip Assay

Abstract The post-transcriptional of mRNA expression involved in the hepatocellular carcinoma (HCC) pathogenesis and progression need to be further explored. RBPs, the main undertaker of post-transcriptional regulatory process, has been shown to impact HCC carcinogenesis and progression. However, the role of RBP, RNA-binding motif 45 (RBM45) in hepatocarcinogenesis and its interaction with its potential target mRNA remains entirely unknown. The expression of RBM45 was significantly increased in HCC and was associated with poor clinicopathological features and clinical outcome of HCC patients. RBM45 promoted HCC cells growth, invasion, migration and EMT in vitro and in vivo. Mechanistically, RNA immunoprecipitation sequencing (RIP-seq) approach was utilized to screen the important differentially expressed RBM45 genes in HCC. Furthermore, RIP assay, pull-down assay and mRNA decay assay were carried out to uncover the effect of RBM45 on its downstream genes. And the results revealed that RBM45 mediated the stabilization of BCL2 and Twist1 mRNA via respectively binding to their 3`UTR. Further assay results suggested RBM45 promoted HCC growth and metastasis upon BCL2 and Twist1. In short, we unveiled a novel role of RBM45 in promoting hepatocarcinogenesis via the post-transcriptional regulation of BCL2 and Twist1 expression. The results proposes that RBM45 may serve as a potential therapeutic target for HCC.

scholarly journals Prognostic value and oncogenic effect of increased RBM8A expression in colon adenocarcinoma

2021 ◽  
Author(s):  
Zhongpeng Xie ◽  
Yu Wu ◽  
Yahui Huang ◽  
Yuxiang Cai ◽  
Yanyan Wang ◽  
...  
Keyword(s):  
Rna Binding ◽  
Colon Adenocarcinoma ◽  
Clinicopathological Characteristics ◽  
Survival Prediction ◽  
Binding Motif ◽  
Depth Of Invasion ◽  
Protein Levels

RNA Binding Motif Protein 8A (RBM8A) is a component of the spliceosome, which couples pre- and post-mRNA splicing events. Dysregulated expression of RBM8A has been recently discovered in hepatocellular carcinoma and gastric cancer. This study aimed to investigate the expression pattern of RBM8A protein in colon adenocarcinoma and to explore its correlation with patients’ clinicopathological characteristics as well as clinical outcomes. Accordingly, we initially found that RBM8A was significantly higher in colon adenocarcinoma tissues compared to adjacent tissues on both mRNA and protein levels. Meanwhile, RBM8A protein was positively correlated with tumor size, depth of invasion, and lymph node metastasis. Furthermore, patients with increased RBM8A expression or positive lymph nodes exhibited a poorer overall survival. Consistently, immunoblotting data showed that RBM8A was higher in SW480 and SW620 colon adenocarcinoma cell lines compared to nontumorous cells. Finally, in vitro and in vivo assays elucidated the role of RBM8A on promoting colon cancer growth by using knockdown strategy. Taken together, our study demonstrated that RBM8A may act as a proto-oncogene, which could be a promising biomarker and therapeutic target in the survival prediction and treatment of colon adenocarcinoma.

scholarly journals LncRNA SNHG11 Promotes Temozolomide Resistance in Glioblastoma via Promoting MGMT Expression

2021 ◽  
Author(s):  
Tao Ji ◽  
Xiao Lyu ◽  
Yongping You
Keyword(s):  
Rna Binding ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Promoter Regions ◽  
Mgmt Expression ◽  
Potential Biomarker ◽  
Rip Assay

Abstract Background Acquired TMZ resistance is considered as the main reason for the poor prognosis of glioblastoma (GBM) patients. However, underlying mechanism remains unknown. Long noncoding RNAs (lncRNAs) have emerged as important regulators in multiple biological processes. Methods SNHG11 expression in cells and GBM tissues was measured using qRT-PCR. In vitro studies, including CCK-8, colony formation assay, flow cytometry and western blot, were employed to measure the role of SNHG11. Interaction between miR-7-5p, SNHG11, and IRS2 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. CHIP assays were used to measure the role of SNHG11/miR-7-5p/IRS2 axis on modulating the H3K9 acetylation of MGMT. Results SNHG11 overexpression in GBM tissues contributes to TMZ resistance. In vitro and in vivo studies confirmed that SNHG11 promoted TMZ resistance in GBM cells. In addition, SNHG11 conferred TMZ resistance through increasing MGMT expression. Furthermore, SNHG11 could function as ceRNA by sponging miR-7-5p, which led to increased IRS2 expression. SNHG11/miR-7-5p/IRS2 axis increased MGMT expression by promoting the acetylation of H3K9 in MGMT promoter regions. Conclusion Taken together, our results revealed that targeting SNHG11 is a potential therapy to overcome TMZ resistance. And SNHG11 in GBM tissues is a potential biomarker for predicting response to TMZ.

scholarly journals Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zizhen Si ◽  
Lei Yu ◽  
Haoyu Jing ◽  
Lun Wu ◽  
Xidi Wang
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Cancer Proliferation ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

scholarly journals Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jun-Xian Du ◽  
Yi-Hong Luo ◽  
Si-Jia Zhang ◽  
Biao Wang ◽  
Cong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
High Risk Group ◽  
Clinical Samples ◽  
Binding Motif ◽  
Ki 67 ◽  
Tissue Samples

Abstract Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

scholarly journals YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Lan Jin ◽  
Yunhe Chen ◽  
Dan Cheng ◽  
Zhikai He ◽  
Xinyi Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Transcriptional Coactivator ◽  
Inhibitory Protein ◽  
Potential Therapeutic Target ◽  
Related Cell ◽  
Autophagy Inhibition

AbstractColorectal cancer (CRC) is one of the most aggressive and lethal cancers. The role of autophagy in the pathobiology of CRC is intricate, with opposing functions manifested in different cellular contexts. The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor-suppressor pathway, functions as an oncoprotein in a variety of cancers. In this study, we found that YAP could negatively regulate autophagy in CRC cells, and consequently, promote tumor progression of CRC in vitro and in vivo. Mechanistically, YAP interacts with TEAD forming a complex to upregulate the transcription of the apoptosis-inhibitory protein Bcl-2, which may subsequently facilitate cell survival by suppressing autophagy-related cell death; silencing Bcl-2 expression could alleviate YAP-induced autophagy inhibition without affecting YAP expression. Collectively, our data provide evidence for YAP/Bcl-2 as a potential therapeutic target for drug exploration against CRC.

scholarly journals RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing

Oncogene ◽  
2021 ◽  
Author(s):  
Qiuxia Yan ◽  
Peng Zeng ◽  
Xiuqin Zhou ◽  
Xiaoying Zhao ◽  
Runqiang Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Aerobic Glycolysis ◽  
Histological Grade ◽  
Migration And Invasion ◽  
Binding Motif ◽  
Hnrnp A1

AbstractThe prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.

scholarly journals Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 587 ◽  
Author(s):  
Matilda Munksgaard Thorén ◽  
Katarzyna Chmielarska Masoumi ◽  
Cecilia Krona ◽  
Xiaoli Huang ◽  
Soumi Kundu ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Target ◽  
Functional Role ◽  
Treatment Strategies ◽  
Antibody Drug Conjugate ◽  
Potential Therapeutic Target ◽  
Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

scholarly journals Therapeutic modulation of RNA-binding protein Rbm38 facilitates re-endothelialization after arterial injury

2019 ◽  
Vol 115 (12) ◽  
pp. 1804-1810 ◽  
Author(s):  
Kristina Sonnenschein ◽  
Jan Fiedler ◽  
Angelika Pfanne ◽  
Annette Just ◽  
Saskia Mitzka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Balloon Angioplasty ◽  
Carotid Arteries ◽  
Rna Binding ◽  
Luciferase Reporter ◽  
Binding Motif ◽  
Cell Functions ◽  
Endothelial Regeneration

Abstract Aims Delayed re-endothelialization after balloon angioplasty in patients with coronary or peripheral artery disease impairs vascular healing and leads to neointimal proliferation. In the present study, we examined the effect of RNA-binding motif protein 38 (Rbm38) during re-endothelialization in a murine model of experimental vascular injury. Methods and results Left common carotid arteries of C57BL/6 mice were electrically denudated and endothelial regeneration was evaluated. Profiling of RNA-binding proteins revealed dysregulated expression of Rbm38 in the denudated and regenerated areas. We next tested the importance of Rbm38 in human umbilical vein endothelial cells (HUVECS) and analysed its effects on cellular proliferation, migration and apoptosis. Rbm38 silencing in vitro demonstrated important beneficial functional effects on migratory capacity and proliferation of endothelial cells. In vivo, local silencing of Rbm38 also improved re-endothelialization of denuded carotid arteries. Luciferase reporter assay identified miR-98 and let-7f to regulate Rbm38 and the positive proliferative properties of Rbm38 silencing in vitro and in vivo were mimicked by therapeutic overexpression of these miRNAs. Conclusion The present data identified Rbm38 as an important factor of the regulation of various endothelial cell functions. Local inhibition of Rbm38 as well as overexpression of the upstream regulators miR-98 and let-7f improved endothelial regeneration in vivo and thus may be a novel therapeutic entry point to avoid endothelial damage after balloon angioplasty.

scholarly journals In Vivo Effect of Mutations at the PRPP Binding Site of the Bacillus subtilis Purine Repressor

2003 ◽  
Vol 185 (22) ◽  
pp. 6728-6731 ◽  
Author(s):  
Pekka Rappu ◽  
Terhi Pullinen ◽  
Pekka Mäntsälä
Keyword(s):  
Bacillus Subtilis ◽  
Binding Site ◽  
Binding Motif

ABSTRACT The Bacillus subtilis PurR mediates adenine repression and guanosine induction of purA. PRPP inhibits binding of PurR to DNA in vitro. Mutations in the PRPP binding motif of PurR caused strong repression regardless of purine exclusions or additions, establishing the role of PRPP as regulator of PurR.

scholarly journals Mutations in the Gal83 Glycogen-Binding Domain Activate the Snf1/Gal83 Kinase Pathway by a Glycogen-Independent Mechanism

2004 ◽  
Vol 24 (1) ◽  
pp. 352-361 ◽  
Author(s):  
Heather A. Wiatrowski ◽  
Bryce J. W. van Denderen ◽  
Cristin D. Berkey ◽  
Bruce E. Kemp ◽  
David Stapleton ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Metabolic Stress ◽  
Binding Domain ◽  
Glycogen Accumulation ◽  
Snf1 Kinase ◽  
Transcriptional Regulatory ◽  
Amp Activated Protein Kinase

ABSTRACT The yeast Snf1 kinase and its mammalian ortholog, AMP-activated protein kinase (AMPK), regulate responses to metabolic stress. Previous studies identified a glycogen-binding domain in the AMPK β1 subunit, and the sequence is conserved in the Snf1 kinase β subunits Gal83 and Sip2. Here we use genetic analysis to assess the role of this domain in vivo. Alteration of Gal83 at residues that are important for glycogen binding of AMPK β1 abolished glycogen binding in vitro and caused diverse phenotypes in vivo. Various Snf1/Gal83-dependent processes were upregulated, including glycogen accumulation, expression of RNAs encoding glycogen synthase, haploid invasive growth, the transcriptional activator function of Sip4, and activation of the carbon source-responsive promoter element. Moreover, the glycogen-binding domain mutations conferred transcriptional regulatory phenotypes even in the absence of glycogen, as determined by analysis of a mutant strain lacking glycogen synthase. Thus, mutation of the glycogen-binding domain of Gal83 positively affects Snf1/Gal83 kinase function by a mechanism that is independent of glycogen binding.

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