scholarly journals RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer

Gut ◽  
2020 ◽  
pp. gutjnl-2020-320652
Author(s):  
Lei Sun ◽  
Arabella Wan ◽  
Zhuolong Zhou ◽  
Dongshi Chen ◽  
Heng Liang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Tumour Progression ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Cancer Therapeutics ◽  
Mitochondrial Metabolism ◽  
The Cancer Genome Atlas ◽  
Colorectal Tumour ◽  
Specific Subset

ObjectiveDysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood.DesignWe analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models.ResultsWe identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m6A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models.ConclusionsCollectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.

scholarly journals TIA-1 Cytotoxic Granule-Associated RNA Binding Protein Improves the Prognostic Performance of CD8 in Mismatch Repair-Proficient Colorectal Cancer

PLoS ONE ◽  
2010 ◽  
Vol 5 (12) ◽  
pp. e14282 ◽  
Author(s):  
Inti Zlobec ◽  
Eva Karamitopoulou ◽  
Luigi Terracciano ◽  
Salvatore Piscuoglio ◽  
Giandomenica Iezzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Prognostic Performance ◽  
Cytotoxic Granule

RNA-binding protein CELF1 enhances cell migration, invasion, and chemoresistance by targeting ETS2 in colorectal cancer

2020 ◽  
Vol 134 (14) ◽  
pp. 1973-1990
Author(s):  
Huaiming Wang ◽  
Rongkang Huang ◽  
Wentai Guo ◽  
Xiusen Qin ◽  
Zifeng Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Malignant Tumors ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tumor Growth Model

Abstract Colorectal cancer (CRC) is often diagnosed at later stages after it has metastasized to other organs. The development of chemoresistance also contributes to a poor prognosis. Therefore, an increased understanding of the metastatic properties of CRC and chemoresistance could improve patient survival. CUGBP elav-like family member 1 (CELF1) is an RNA-binding protein, which is overexpressed in many human malignant tumors. However, the influence of CELF1 in CRC is unclear. V-ets erythroblastosis virus E26 oncogene homologue 2 (ETS2) is an evolutionarily conserved proto-oncogene known to be overexpressed in a variety of human cancers including CRC. In thespresent tudy, we investigated the association between CELF1 and ETS2 in CRC tumorigenesis and oxaliplatin (L-OHP) resistance. We found a positive correlation between the elevated expression of CELF1 and ETS2 in human CRC tissues. Overexpression of CELF1 increased CRC cell proliferation, migration, and invasion in vitro and in a xenograft tumor growth model in vivo, and induced resistance to L-OHP. In contrast, CELF1 knockdown improved the response of CRC cells to L-OHP. Overexpression of ETS2 increased the malignant behavior of CRC cells (growth, migration, and invasion) and L-OHP resistance in vitro. Moreover, L-OHP resistance induced by CELF1 overexpression was reversed by ETS2 knockdown. The results of luciferase reporter and ribonucleoprotein immunoprecipitation assays indicated that CELF1 up-regulates ETS2 by binding to its 3′-UTR. Taken together, our findings have identified that CELF1 regulates ETS2 in a mechanism that results in CRC tumorigenesis and L-OHP resistance, and CELF1 may be a promising target for overcoming chemoresistance in CRC.

733 - The RNA Binding Protein HUR Regulates Extracellular Vesicle Secretion in Colorectal Cancer

2018 ◽  
Vol 154 (6) ◽  
pp. S-151-S-152
Author(s):  
Ranjan Preet ◽  
Wei-Ting Hung ◽  
Vikalp Vishwakarma ◽  
Lane Christenson ◽  
Dan A. Dixon
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Extracellular Vesicle ◽  
Vesicle Secretion

scholarly journals The Underlying Molecular Mechanisms and Prognostic Factors of Rna Binding Protein in Colorectal Cancer: A Study Based on Multiple Online Databases

2021 ◽  
Author(s):  
Qinglian He ◽  
Ziqi Li ◽  
Xue Lei ◽  
Qian Zou ◽  
Haibing Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Regression Analysis ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Aberrant Expression ◽  
Online Databases ◽  
Prognosis Model

Abstract Background: RNA binding protein (RBP) is an active factor involved in the occurrence and development of colorectal cancer (CRC). Therefore, the potential mechanism of RBP in CRC needs to be clarified by dry-lab analyses or wet-lab experiments.Methods: The differential RBP gene obtained from the GEPIA 2 (Gene Expression Profiling Interactive Analysis 2) were performed functional enrichment analysis. Then, the alternative splicing (AS) events related to survival were acquired by univariate regression analysis, and the correlation between RBP and AS was analyzed by R software. The online databases were conducted to analyze the mutation and methylation of RBPs in CRC. Moreover, 5 key RBP signatures were obtained through univariate and multivariate Cox regression analysis and established as RBP prognosis model. Subsequently, the above model was verified through another randomized group of TCGA CRC cohorts. Finally, multiple online databases and qRT-PCR analysis were carried to further confirm the expression of the above 5 RBP signatures in CRC.Results: Through a comprehensive bioinformatics analysis, it was revealed that RBPs had genetic and epigenetic changes in CRC. We obtained 300 differentially expressed RBPs in CRC samples. The functional analysis suggested that they mainly participated in spliceosome. Then, a regulatory network for RBP was established to participate in AS and DDX39B was detected to act as a potentially essential factor in the regulation of AS in CRC. Our analysis discovered that 11 differentially expressed RBPs with a mutation frequency higher than 5%. Furthermore, we found that 10 differentially expressed RBPs had methylation sites related to the prognosis of CRC, and a prognostic model was constructed by the 5 RBP signatures. In another randomized group of TCGA CRC cohorts, the prognostic performance of the 5 RBP signatures was verified. Conclusion: The potential mechanisms that regulate the aberrant expression of RBPs in the development of CRC was explored, a network that regulated AS was established, and the RBP-related prognosis model was constructed and verified, which could improve the individualized prognosis prediction of CRC.

Abstract A41: The RNA binding protein HuR enhances exosome secretion in colorectal cancer

2016 ◽  
Author(s):  
Ranjan Preet ◽  
Shufei Zhuang ◽  
Wei-Ting Hung ◽  
Lane K. Christenson ◽  
Dan A. Dixon
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein

scholarly journals RNA-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Meng Zhang ◽  
Senlin Zhao ◽  
Cong Tan ◽  
Yanzi Gu ◽  
Xuefeng He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Erk Signaling ◽  
Luciferase Reporter ◽  
Migration And Invasion

Abstract Background MEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), however, MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism. Methods To investigate the clinical significance of IMP3, we analyzed its expression levels in publicly available dataset and samples from Fudan University Shanghai Cancer Center. The effects of IMP3 on proliferation, migration, and invasion were determined by in vitro and in vivo experiments. To investigate the role of IMP3 in colon carcinogenesis, conditional IMP3 knockout C57BL/6 mice was generated. The IMP3/MEKK1/MEK/ERK signaling axis in CRC was screened and validated by RNA-sequencing, RNA immunoprecipitation, luciferase reporter and western blot assays. Results We find RNA binding protein IMP3 directly bind to MEKK1 mRNA 3′-UTR, which regulates its stability, promote MEKK1 expression and sequentially activates MEK1/ERK signaling. Functionally, IMP3 promote the malignant biological process of CRC cells via MEKK1/MEK1/ERK signaling pathway both in vitro and in vivo, Moreover, IMP3−/− mice show decreased the expression of MEKK1 as well as colorectal tumors compared with wild-type mice after treatment with azoxymethane/dextran sodium sulfate. Clinically, the expression of IMP3 and MEKK1 are positive correlated, and concomitant IMP3 and MEKK1 protein levels negatively correlate with metastasis in CRC patients. In addition, MEK1 inhibitor in combination with shRNA-IMP3 have a synergistic effect both in vitro and in vivo. Conclusion Our study demonstrates that IMP3 regulates MEKK1 in CRC, thus activating the MEK1/ERK signaling in the progression of colorectal cancer, Furthermore, these results provide new insights into potential applications for combining MEK1 inhibitors with other target therapy such as IMP3 in preclinical trials for CRC patients.

scholarly journals Development and Validation of a Novel Five-Gene-Based RNA Binding Protein Associated Prognostic Model for Human Colon Cancer

2020 ◽  
Author(s):  
Haoling Liu ◽  
Qingquan Bai ◽  
Zhaoyang Lu ◽  
Xuan Song ◽  
Yao Liu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Prognostic Model ◽  
Rna Binding ◽  
Malignant Tumors ◽  
Binding Protein ◽  
Characteristic Curve ◽  
Rna Binding Protein ◽  
The Cancer Genome Atlas ◽  
Human Colon Cancer ◽  
Good Ability

Abstract Background: Dysregulation of RNA binding protein (RBP) expression has been reported in various malignant tumors, and it is related to the occurrence and development of cancer. However, the role of RBPs in colon cancer remains unclear. Methods: We downloaded the RNA sequencing data of colon cancer from The Cancer Genome Atlas (TCGA) database, and determined the differently expressed RBPs between normal and cancer tissues. Then, through a series of bioinformatics analysis, we systematically studied the expression and prognostic value of these RBPs.Result: A total of 490 different expression differently expressed RBPs were identified, including 323 up-regulated and 167 down regulated RBPs. Five RBPs (PNLDC1, NSUN6, NOL3, PPARGC1A, LRRFIP2) were identified as prognosis related genes for the construction of prognostic model. Further analysis showed that the overall survival rate (OS) of patients in the high-risk subgroup was worse than that in the low-risk subgroup based on this model. The area under the characteristic curve of time-dependent receiver was 0.691 in TCGA and 0.624 in GEO, which confirmed the prognostic model to be a good one. We also established a nominal map based on the internal validation in 5 RBPs mRNAs and TCGA sequeues, showing a good ability to differentiate colon cancer.Conclusions: We screened RBPs expression differences between colon cancer and adjacent non tumor colon tissues using the TCGA database to identify potential gene biomarkers.Besides,a very effective prediction model was constructed and tested based on the differential expression of RBPs using the TCGA and Gene Expression Omnibus (GEO) database.We also Validated of the relationship between the expression of five RBPs and prognosis

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