The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B

Guo, Qinhao; Wu, Yong; Guo, Xueqi; Cao, Le; Xu, Fei; Zhao, Hong; Zhu, Jun; Wen, Hao; Ju, Xingzhu; Wu, Xiaohua

doi:10.1016/j.omtn.2020.10.011

Cited by 44 publications

(47 citation statements)

References 48 publications

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“…Multiple studies have confirmed that CELF2 exerts tumour suppressive effects in most tumours, which is significantly increased in developing thymocytes and activated T cells, but its comprehensive understanding within the TME remains unknown 16–26 . Therefore, it is necessary to investigate the relationships between CELF2 expression and TIIC infiltration in the TME.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have demonstrated that CELF2 could regulate multiple steps of RNA processing, such as pre‐mRNA splicing, RNA editing, polyadenylation, mRNA stability and translation 14,15 . Over the past decade, substantial studies have confirmed that CELF2 played a tumour suppressor role in breast cancer, lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, glioma and acute myeloid leukaemia, suggesting that it can be used as a candidate biomarker to predict cancer prognosis 16–23 . Additionally, CELF2 expression was significantly elevated in developing thymocytes and activated T cells and promoted T‐cell receptor expression and signalling through alternative splicing 24–26 .…”

Section: Introductionmentioning

confidence: 99%

“…14,15 Over the past decade, substantial studies have confirmed that CELF2 played a tumour suppressor role in breast cancer, lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, glioma and acute myeloid leukaemia, suggesting that it can be used as a candidate biomarker to predict cancer prognosis. [16][17][18][19][20][21][22][23] Additionally, CELF2 expression was significantly elevated in developing thymocytes and activated T cells and promoted T-cell receptor expression and signalling through alternative splicing. [24][25][26] However, the comprehensive understanding of the impacts of CELF2 on the tumour immune microenvironment remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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CELF2 is a candidate prognostic and immunotherapy biomarker in triple‐negative breast cancer and lung squamous cell carcinoma: A pan‐cancer analysis

Wang

Лонг

Guo

et al. 2021

J Cellular Molecular Medi

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CUGBP Elav‐like family member 2(CELF2) plays crucial roles in the development and activation of T cell. However, the impacts of CELF2 on tumour‐infiltrating immune cells (TIICs) and clinical outcomes of tumours remain unclear. In this study, we found that elevated CELF2 expression was markedly correlated with prolonged survival in multiple tumours, particularly in breast and lung cancers. Notably, CELF2 only impacted the prognosis of triple‐negative breast cancer (TNBC) with lymph node metastasis. Further investigation showed CELF2 expression was positively correlated with the infiltration abundance of dendritic cells (DCs), CD8+ T cells and neutrophils in breast invasive carcinoma (BRCA) and DCs in lung squamous cell carcinoma (LUSC). CELF2 also had strong correlations with markers of diverse TIICs such as T cells, tumour‐associated macrophages and DCs in BRCA and LUSC. Importantly, CELF2 was significantly associated with plenty of immune checkpoint molecules (ICMs) and outperformed five prevalent biomarkers including PD‐1, PD‐L1, CTLA‐4, CD8 and tumour mutation burden in predicting immunotherapeutic responses. Immunohistochemistry also revealed lower protein levels of CELF2 in TNBC and LUSC compared to normal tissues, and patients with high expression showed significantly prolonged prognosis. In conclusion, we demonstrated that increased CELF2 expression was closely related to better prognosis and superior TIIC infiltration and ICM expression, particularly in BRCA and LUSC. CELF2 also performed well in evaluating the immunotherapeutic efficacy, suggesting CELF2 might be a promising biomarker.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CELF2 is a candidate prognostic and immunotherapy biomarker in triple‐negative breast cancer and lung squamous cell carcinoma: A pan‐cancer analysis

Wang

Лонг

Guo

et al. 2021

J Cellular Molecular Medi

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“…In addition, RPS3 stabilized SIRT1 mRNA by binding to AUUUA motifs on the 3’UTR of SIRT1 mRNA. In ovarian cancer, CELF2 could stabilize FAM198B mRNA by binding to AU/U-rich elements (AREs) in the 3’UTR ( 25 ). Moreover, ZFP36L1 bound to the HIF1A 3’UTR and mediated HIF1A mRNA degradation in bladder and breast cells ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

The RNA-Binding Protein NELFE Promotes Gastric Cancer Growth and Metastasis Through E2F2

et al. 2021

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Worldwide, the incidence rate of gastric cancer ranks fifth, and the mortality rate of gastric cancer ranks third among all malignant tumors. However, the pathogenesis of gastric cancer remains poorly understood. In this study, we demonstrated that the expression level of NELFE is higher in human gastric cancer tissues than in adjacent nontumor tissues. A high level of NELFE is associated with worse postoperative overall survival (OS) and relapse-free survival (RFS) rates in patients with gastric cancer. Moreover, the expression of NELFE is correlated with high tumor grade and lymph node metastasis in gastric cancer patients. Knockdown of NELFE dramatically inhibits the cell proliferation and metastasis of gastric cancer xenografts in vivo. Furthermore, we found that NELFE binding to the 3’UTR of E2F2 affects the mRNA stability of E2F2 to regulate the expression level of E2F2. In gastric cancer, E2F2 also acts as an oncogene to inhibit the proliferation and migration of gastric cancer cells by knocking down the expression level of E2F2. However, overexpressing E2F2 in cells with NELFE knockdown significantly reverses the inhibition of cell proliferation and migration induced by NELFE knockdown. Therefore, NELFE at least partially functions as an oncogene through E2F2. Moreover, CIBERSORTx analysis of the proportion of tumor-infiltrating immune cells (TICs) revealed that immune cells are correlated with NELFE and E2F2 expression, suggesting that NELFE and E2F2 might be responsible for the preservation of the immunodominant status for gastric cancer. In conclusion, NELFE acts as an oncogene in gastric cancer and can be used as a potential therapeutic target.

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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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The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B

Cited by 44 publications

References 48 publications

CELF2 is a candidate prognostic and immunotherapy biomarker in triple‐negative breast cancer and lung squamous cell carcinoma: A pan‐cancer analysis

CELF2 is a candidate prognostic and immunotherapy biomarker in triple‐negative breast cancer and lung squamous cell carcinoma: A pan‐cancer analysis

The RNA-Binding Protein NELFE Promotes Gastric Cancer Growth and Metastasis Through E2F2

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

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