Prognostic significance of survival-associated alternative splicing events in gastric cancer

Zhang, Shichao; Hu, Ziyi; Lan, Yingwu; Long, Ju; Wang, Yun; Chen, Xiaowen; Xu, Xiaofeng; Zeng, Zhu; Ouyang, Yu

doi:10.18632/aging.104013

Cited by 10 publications

(10 citation statements)

References 37 publications

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“…Ultimately, seven risk prediction models strati ed by AS types as well as one non-strati ed prediction model were constructed, respectively. Although prognostic AS signatures of GC had been produced in Zhen Zong et als and ZhangSetals reports 22,23 , our screening strategy seems more reasonable. We rst identi ed OS related AS events through Univariate Cox and lasso regression methods, followed by Multivariate Cox regression analysis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Prognostic Alternative Splicing Signature in Gastric Cancer

Wang¹,

Wu²,

Liu³

et al. 2021

Preprint

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Aberrant alternative splicing (AS) events serve as prognostic indicators in a large number of malignancies, whereas comprehensive analysis of prognostic AS in gastric cancer (GC) has not yet been understood. To identify prognostic AS events and clarify the function of the splicing variants in GC. RNA-Seq data, clinical information and percent spliced in (PSI) values were available in the cancer genome atlas (TCGA) and TCGA SpliceSeq data portal. A three-step regression method was conducted to screen prognostic AS events and construct multi-AS-based signatures. The associations between prognostic AS events and splicing factors were also investigated. We identified a total of 1318 survival related AS events in GC, Parent genes of which were implicated in numerous oncogenic pathways. The final prognostic signatures stratified by seven types of AS events or not stratified performed well in risk prediction for GC patients. Moreover, five signatures base on AA, AD, AT, ES and RI events function as independent prognostic indicators after multivariate adjustment of clinicalpathological variables. Splicing network also showed marked correlation between the expression of splicing factors and PSI value of AS events in GC patients. The AS derived signatures allow to predict GC prognosis and might serve as potential therapeutic target for GC.

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Section: Discussionmentioning

confidence: 99%

Identification of Prognostic Alternative Splicing Signature in Gastric Cancer

Wang¹,

Wu²,

Liu³

et al. 2021

Preprint

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“…The above studies have fully con rmed that CELF2 may be a key gene regulating the occurrence and development of PC. Previous studies have demonstrated that CELF2 could play an important role in many kinds of tumors, including liver cancer [16], ovarian cancer [17], breast cancer [18], and gastric cancer [19]. Jakstaite et al found that overexpression of CELF2 can enhance the chemosensitivity of PC cells [20].…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine-mediated CELF2 Regulates CD44 Alternative Splicing Affecting Tumorigenesis via ERAD Pathway in Pancreatic Cancer

Lai

Wang

et al. 2021

Preprint

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Background: Alternative splicing (AS) of genes has been found to affect gene stability, and its abnormal regulation can lead to tumorigenesis. CELF2 is a vital splicing factor to participate in mRNA alternative splicing. Its downregulation has been confirmed to promote the occurrence and development of pancreatic cancer (PC). However, the regulatory role and mechanisms in PC has not been elucidated.Methods: 80 patients diagnosed with PC were included in this study. The relationhip between CELF2 expression and clinicopathological characteristics was analyed. RNA immunoprecipitation qRT-PCR and RNA pull-down experiments were performed to confirm the potential mechanisms of CELF2 abnormal expression in PC. AS model of PC was established by TCGA database. Functional experiments in vitro and in vivo were conduced to reveal the effects of CELF2 or CD44 on PC cells proliferation, migration and invasion. Transcriptomic analysis was conducted to reveal the mechanism of CELF2-mediated CD44 AS in PC. Results: CELF2 was downregulated in PC tissues, which affected tumor TNM stage and tumor size, and low expression of CELF2 indicated a poor prognosis of PC. In vivo and in vitro experiments showed that abnormal expression of CELF2 affected the stemness, apoptosis, and proliferation of PC cells. Furthmore, we also found that CELF2 was targeted by ALKBH5 for m6A modification, leading to CELF2 degradation by YTHDF2. Bioinformatic analysis of AS model based on the TCGA database indicated that CELF2 could target CD44 to form different spliceosomes, thereby affecting the biological behavior of PC cells. The conversion of CD44s to CD44V is the key to tumorigenesis. Transcriptomic analysis was conducted to reveal the mechanism of CELF2-mediated CD44 AS in PC. We found that CELF2-mediated splicing of CD44 led to changes in the level of endoplasmic reticulum stress, further regulating the endoplasmic reticulum-associated degradation (ERAD) signaling pathway, thereby affecting apoptosis and cell stemness. In addition, ERAD signaling pathway inhibitor, EerI, could effectively reverse the effect of CD44 on tumors. Conclusions: This study indicates that CELF2 promotes AS of CD44, affecting the ERAD pathway and enhence the biological behavior of PC cells. CELF2 is expected to be a new target for targeted-drug development

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“…Conversely, in gastric cancer, the expression of CELF2, along with BAG2 (BAG Cochaperone 2), RBFOX2 (RNA Binding Fox-1 Homolog 20), and PTBP2 (Polypyrimidine Tract Binding Protein 2) splicing factors are associated with poor prognosis and alternative splicing events [86].…”

Section: Celf2mentioning

confidence: 99%

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

Aghdam

Jave‐Suárez

2021

IJMS

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Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology.

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Prognostic significance of survival-associated alternative splicing events in gastric cancer

Cited by 10 publications

References 37 publications

Identification of Prognostic Alternative Splicing Signature in Gastric Cancer

Identification of Prognostic Alternative Splicing Signature in Gastric Cancer

N6-methyladenosine-mediated CELF2 Regulates CD44 Alternative Splicing Affecting Tumorigenesis via ERAD Pathway in Pancreatic Cancer

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

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