Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions

Chanoumidou, Konstantina; Hadjimichael, Christiana; Athanasouli, Paraskevi; Ahlenius, Henrik; Klonizakis, Antonios; Nikolaou, Christoforos; Δράκος, Ηλίας; Kostouros, Antonis; Stratidaki, Irene; Grigoriou, Maria; Kretsovali, Androniki

doi:10.1038/s41598-018-31696-9

Cited by 10 publications

(10 citation statements)

References 73 publications

(68 reference statements)

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“…5K; Fisher's exact test P value = 7.3e-08; log-rank test P value = 0.031). Notably, given that AES suppresses WNT signaling 70,71 , our analysis in this part strengthened the link of WNT signaling to the stratification and clinical outcome of MMASs. Finally, upon further examination, we noticed that some MMAS-1 patient samples exhibit upregulated CMS1 signature pathways (inflammatory response and interferon response) and CMS4 signature pathways (angiogenesis, EMT, extracellular matrix mCRC, and TGF-β up) 36 .…”

Section: Characterization Of Nmf-assigned Subtypes Shows Differentialsupporting

confidence: 55%

Comprehensive transcriptome profiling of Taiwanese colorectal cancer implicates an ethnic basis for pathogenesis

Tsai

Chiang

et al. 2020

Sci Rep

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While both genetic and environmental factors have been linked to the incidence and mortality associated with CRC, an ethnic aspect of its etiology has also emerged. Since previous large-scale cancer genomics studies are mostly based on samples of European ancestry, the patterns of clinical events and associated mechanisms in other minority ethnic patients suffering from CRC are largely unexplored. We collected 104 paired and adjacent normal tissue and CRC tumor samples from Taiwanese patients and employed an integrated approach-paired expression profiles of mRNAs and microRNAs (miRNAs) combined with transcriptome-wide network analyses-to catalog the molecular signatures of this regional cohort. On the basis of this dataset, which is the largest ever reported for this type of systems analysis, we made the following key discoveries: (1) In comparison to the The Cancer Genome Atlas (TCGA) data, the Taiwanese CRC tumors show similar perturbations in expressed genes but a distinct enrichment in metastasis-associated pathways. (2) Recurrent as well as novel CRC-associated gene fusions were identified based on the sequencing data. (3) Cancer subtype classification using existing tools reveals a comparable distribution of tumor subtypes between Taiwanese cohort and TCGA datasets; however, this similarity in molecular attributes did not translate into the predicted subtype-related clinical outcomes (i.e., death event). (4) To further elucidate the molecular basis of CRC prognosis, we developed a new stratification strategy based on miRNA-mRNA-associated subtyping (MMAS) and consequently showed that repressed WNT signaling activity is associated with poor prognosis in Taiwanese CRC. In summary, our findings of distinct, hitherto unreported biosignatures underscore the heterogeneity of CRC tumorigenesis, support our hypothesis of an ethnic basis of disease, and provide prospects for translational medicine. Colorectal cancer (CRC) is one of the most prevalent types of malignancies worldwide 1. Despite surgical resection and advances in radiotherapy and chemotherapy, it remains the third leading cause of cancer mortality globally 2. The progression of CRC follows the adenoma-carcinoma sequence, developing from normal mucosa into adenoma and eventually into malignant adenocarcinoma 3. The etiology of this malignancy can be classified

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Section: Characterization Of Nmf-assigned Subtypes Shows Differentialsupporting

confidence: 55%

Comprehensive transcriptome profiling of Taiwanese colorectal cancer implicates an ethnic basis for pathogenesis

Tsai

Chiang

et al. 2020

Sci Rep

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“…AES could inhibit the Notch pathway through blocking the Notch signaling transcription complex composed of the NOTCH intracellular domain (NICD), the transcription factor RBPJ, and the cofactor MAML 11 . AES also inhibited HIF1α-mediated transcription as well as AR and BMP signaling 13 , 14 , 48 . Furthermore, AES has been shown to inhibit the Wnt/β-catenin signaling cascade through interacting with TCF4 and disrupting β-catenin and TCF4 binding 12 .…”

Section: Discussionmentioning

confidence: 92%

“…Amino-terminal enhancer of split (AES), a member of the Groucho/transducin-like enhancer of split/Grorelated gene (Gro/TLE/Grg) family of transcriptional co-repressors, has been identified as a metastasis suppressor for CRC 11 . Previous studies showed that AES could inhibit several signaling pathways, including the Notch pathway, the Wnt/β-catenin pathway, the Androgen Receptor (AR) and Bone Morphogenetic Protein (BMP) signaling pathways 11 - 14 . These studies indicate that AES may exert its suppressive effect on CRC metastasis through mediating the multiple pathways.…”

Section: Introductionmentioning

confidence: 99%

The CK1δ/ε-AES axis regulates tumorigenesis and metastasis in colorectal cancer

et al. 2021

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Background: Amino-terminal enhancer of split (AES) has been identified as a tumor and metastasis suppressor in some cancers including colorectal cancer (CRC), but very little is known about the regulation of AES expression. Methods: Bioinformatics analysis was used to investigate the expression patterns of AES, CK1δ and CK1ε. The co-immunoprecipitation, GST pull-down, Western Blot, real-time PCR and immunohistochemistry were performed to study the mechanism underlying the regulation of AES expression by CK1δ/ε. The biological function was assessed by in vitro colony formation, transwell, sphere formation, tumor organoids, in vivo tumor metastasis model and patient-derived colorectal tumor xenografts (PDTX) model. Results: A strong inverse relationship was observed between the expression of AES and the expression of CK1δ/ε. Mechanically, AES could interact with CK1δ/ε and SKP2 using its Q domain. SKP2 mediated the ubiquitination and degradation of AES in a CK1δ/ε-dependent manner. CK1δ/ε phosphorylated AES at Ser121 and accelerated the SKP2-mediated ubiquitination and degradation of AES. In colon cancer cells, CK1δ/ε antagonized the effect of wild-type AES but not that of its mutant (S121A) on Wnt and Notch signaling, leading to an increase in the expression of Wnt target genes and Notch target genes. By downregulating the expression of AES, CK1δ/ε enhanced anchorage-independent growth, migration, invasion and sphere formation in colon cancer cells. CK1δ/ε also promoted the growth of APC min/+ colorectal tumor organoids and liver metastasis in colon cancer mouse models through the regulation of AES degradation. Furthermore, CK1 inhibitor SR3029 treatment suppressed tumor growth via stabilizing AES in APC min/+ colorectal tumor organoids and patient-derived colorectal tumor xenografts (PDTX). Conclusions: Our results revealed that the CK1δ/ε-AES axis is important for CRC tumorigenesis and metastasis, and targeted inhibition of this axis may be a potential therapeutic strategy for CRC.

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“…Additional references: (Bain et al., 1995; Chanoumidou et al., 2018; Eiraku & Sasai, 2011; Forouzanfar et al., 2015; Rao et al., 2020). …”

Section: Neural Induction From Mammalian Es Cellsmentioning

confidence: 99%

Neural induction: Historical views and application to pluripotent stem cells

2021

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Embryonic stem (ES) cells are a useful experimental material to recapitulate the differentiation steps of early embryos, which are usually invisible and inaccessible from outside of the body, especially in mammals. ES cells have greatly facilitated the analyses of gene expression profiles and cell characteristics. In addition, understanding the mechanisms during neural differentiation is important for clinical purposes, such as developing new therapeutic methods or regenerative medicine. As neurons have very limited regenerative ability, neurodegenerative diseases are usually intractable, and patients suffer from the disease throughout their lifetimes. The functional cells generated from ES cells in vitro could replace degenerative areas by transplantation. In this review, we will first demonstrate the historical views and widely accepted concepts regarding the molecular mechanisms of neural induction and positional information to produce the specific types of neurons in model animals. Next, we will describe how these concepts have recently been applied to the research in the establishment of the methodology of neural differentiation from mammalian ES cells. Finally, we will focus on examples of the applications of differentiation systems to clinical purposes. Overall, the discussion will focus on how historical developmental studies are applied to state‐of‐the‐art stem cell research.

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Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions

Cited by 10 publications

References 73 publications

Comprehensive transcriptome profiling of Taiwanese colorectal cancer implicates an ethnic basis for pathogenesis

Comprehensive transcriptome profiling of Taiwanese colorectal cancer implicates an ethnic basis for pathogenesis

The CK1δ/ε-AES axis regulates tumorigenesis and metastasis in colorectal cancer

Neural induction: Historical views and application to pluripotent stem cells

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