Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer

Piqué, Laia; Paz, Alexia Martínez de; Piñeyro, David; Martínez-Cardús, Anna; Moura, Manuel Castro de; Llinàs‐Arias, Pere; Setién, Fernando; Gómez-Miragaya, Jorge; Gonzalez-Suarez, Eva; Sigurdsson, Stefan; Jonasson, Jón G.; Villanueva, Alberto; Vidal, August; Dávalos, Verónica; Esteller, Manel

doi:10.1038/s41388-019-0936-x

Cited by 54 publications

(43 citation statements)

References 24 publications

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“…Our results above indicated that CRNDE inhibited the expression of CELF2, an important tumor suppressor in several cancer types 44 – 46 . However, the implication of CELF2 in HCC has not yet been well understood to date.…”

Section: Resultssupporting

confidence: 61%

LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma

et al. 2020

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Our study aimed to investigate the expression, functional significance, and related mechanism of long noncoding RNA CRNDE (colorectal neoplasia differentially expressed) in hepatocellular carcinoma (HCC) pathogenesis. The resulted revealed that CRNDE was significantly overexpressed in HCC tissues and cell lines, and was statistically correlated with poor clinical outcome. CRNDE knockdown markedly decreased HCC cell proliferation, migration, and chemoresistance. In addition, in vivo experiments confirmed the suppressive effect of CRNDE knockdown on HCC progression. Mechanically, CRNDE directly bound to EZH2 (enhancer of zeste homolog), SUZ12 (suppressor of zeste 12), SUV39H1, and mediated their inhibition of tumor suppressor genes, including CUGBP Elav-like family member 2 (CELF2) and large tumor suppressor 2 (LATS2). CELF2 exerted tumor suppressive effect in HCC and was involved in CRNDE-mediated oncogenic effect. In addition, the oncogenic effects of CRNDE on HCC proliferation, migration and tumorigenesis, as well as its inhibition of Hippo pathway were abolished by LATS2 overexpression. Together, our work demonstrated the importance of CRNDE in HCC progression and elucidated the underlying molecular mechanisms. These findings provided new insights into HCC pathogenesis and chemoresistance mediated by CRNDE.

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Section: Resultssupporting

confidence: 61%

LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma

et al. 2020

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“…WARS may partially promote the growth of UM cells by activating the PI3K/AKT signaling pathway, thereby accelerating tumor development [44]. In addition to EDNRB and WARS, the remaining 19 genes showing evidence interacting in the progress of various types of cancer [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68], but left few traces showing the connection with UM prognosis in the previous research. https://doi.org/10.1371/journal.pone.0242263.g004…”

Section: Plos Onementioning

confidence: 99%

Identification of prognostic genes in uveal melanoma microenvironment

Luo

2020

PLoS ONE

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Background Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Many previous studies have demonstrated that the infiltrating of immune and stromal cells in the tumor microenvironment contributes significantly to prognosis. Methods Dataset TCGA-UVM, download from TCGA portal, was taken as the training cohort, and GSE22138, obtained from GEO database, was set as the validation cohort. ESTIMATE algorithm was applied to find intersection differentially expressed genes (DEGs) among tumor microenvironment. Kaplan-Meier analysis and univariate Cox regression model were performed on intersection DEGs to initial screen for potential prognostic genes. Then these genes entered into the validation cohort for validation using the same methods as that in the training cohort. Moreover, we conducted correlation analyses between the genes obtained in the validation cohort and the status of chromosome 3, chromosome 8q, and tumor metastasis to get prognosis genes. At last, the immune infiltration analysis was performed between the prognostic genes and 6 main kinds of tumor-infiltrating immune cells (TICs) for understanding the role of the genes in the tumor microenvironment. Results 959 intersection DEGs were found in the UM microenvironment. Kaplan-Meier and Cox analysis was then performed in the training and validation cohorts on these DEGs, and 52 genes were identified with potential prognostic value. After comparing the 52 genes to chromosome 3, chromosome 8q, and metastasis, we obtained 21 genes as the prognostic genes. The immune infiltration analysis showed that Neutrophil had the potential prognostic ability, and almost every prognostic gene we had identified was correlated with abundances of Neutrophil and CD8+ T Cell. Conclusions Identifying 21 prognosis genes (SERPINB9, EDNRB, RAPGEF3, HFE, RNF43, ZNF415, IL12RB2, MTUS1, NEDD9, ZNF667, AZGP1, WARS, GEM, RAB31, CALHM2, CA12, MYEOV, CELF2, SLCO5A1, ISM1, and PAPSS2) could accurately identify patients' prognosis and had close interactions with Neutrophil in the tumor environment, which may provide UM patients with personalized prognosis prediction and new treatment insights.

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“…Previous studies reported that SRSF1 is up-regulated in varies types of human tumors, including colon, thyroid, breast, kidney, small intestine and lung cancers 30 − 31 . Piqué et al 32 reported that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-linked transcriptional silencing in the breast cancer. Duan et al 32 suggested the aberrant splicing variants in renal cell cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Piqué et al 32 reported that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-linked transcriptional silencing in the breast cancer. Duan et al 32 suggested the aberrant splicing variants in renal cell cancer. AS was also found to regulate some apoptotic genes.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing events implicated in carcinogenesis and prognosis of thyroid gland cancer

Zhong

Cai³

2020

Preprint

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Background: Alternative splicing events (ASEs), a critical post-transcriptional regulatory mechanism, expands gene expression patterns, resulting in increased protein diversity and more than 95% of human genes experience AS and encode splice variants in the regular physiological processes. While the role of AS in the thyroid cancer as yet missing, therefore, it was necessary to carry out this study to provide more information about the combination of splicing and clinical parameters, as well as potential mechanism of the survival-related splicing events in thyroid cancer. Materials and methods: Here, we draw all-around AS profiles of thyroid cancer by analyzing RNA-seq data. We also constructed prognostic models via combining splicing signatures and clinicopathological parameters. Splicing network was constructed as a way to offer functional insight into the full practical knowledge of AS in the initiation and development of thyroid cancer. Results: There were 10446 genes, and 45150 AS events in 506 TC patients, which indicates that ASEs are universal in TC. Moreover, 1819 AS signatures were identified to be significantly related to OS of TC patients and among the seven types of ASES, ES was the most common, followed by AP and AT. Kaplan-Meier survival curves results suggested that seven types of ASEs were related to bad prognosis in TC patients (P<0.05). In TC, AA (AUC: 0.937), AD (AUC: 0.965), AT (AUC: 0.964), ES (AUC: 0.999), ME (AUC: 0.999), RI (AUC: 0.837) all demonstrated an AUC over 0.6, of which ES and ME best predict the incidence of TC. We found that age and risk score (All) were risk factors for TC patients. As for ASEs is regulated by SFs, we study if the TC-ASEs were regulated by various SFs and the results demonstrated that the expression of 90 SFs was related to 469 ASEs OS in the TC cohort. Conclusions: In sum, the findings in the current study may provide a basis for spliceosomes in TC, and the methods used in this study could provide novel perspectives in other fields of tumor study to help shed light on future oncology research.

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Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer

Cited by 54 publications

References 24 publications

LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma

LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma

Identification of prognostic genes in uveal melanoma microenvironment

Alternative splicing events implicated in carcinogenesis and prognosis of thyroid gland cancer

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