Alternative splicing within the Wnt signaling pathway: role in cancer development

Sumithra, B; Saxena, Urmila; Das, Asim Bikas

doi:10.1007/s13402-015-0266-0

Cited by 23 publications

(14 citation statements)

References 142 publications

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“…Many oncogenes and tumor suppressors are differentially spliced in cancer cells, and many of these cancer‐specific isoforms contribute to the transformed phenotype of cancer cells . An undiscovered cancer‐specific OCT4 isoform might contribute to CSC maintenance; however, further investigations of OCT4 variants at the mRNA and protein levels are needed to determine relationships between OCT4 isoforms and oncogenesis and their potential as CSC markers.…”

Section: Introductionmentioning

confidence: 99%

Conclusive Evidence for OCT4 Transcription in Human Cancer Cell Lines: Possible Role of a Small OCT4-Positive Cancer Cell Population

et al. 2018

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The role of octamer-binding transcription factor 4 (OCT4) in human cancer is still debated. Although many studies have been published on human OCT4, determining which of the findings are accurate or which are false-positives is currently challenging. We thus developed the most reliable method to date for highly specific and comprehensive detection of genuine OCT4-transcript variants without false-positive results. Our results provided clear evidence that the transcripts of OCT4A, OCT4B, OCT4B1, and other novel splicing variants are indeed present in many cancer cell lines, but are rarely detected in normal tissue-derived differentiated cells. Using the tagged genomic transgene, we then verified endogenous OCT4A translation in cancer cell subpopulations. Moreover, analysis of possible other protein isoforms by enforced expression of OCT4B variants showed that the B164 isoform, designated human OCT4C, is preferentially produced in a cap-dependent manner. We confirmed that the OCT4C isoform, similar to OCT4A, can transform non-tumorigenic fibroblasts in vitro. Finally, ablation of OCT4-positive cells using promoter-driven diphtheria toxin A in high malignant cancer cells caused a significant decrease in migration and Matrigel invasion. These findings strongly suggest a significant contribution of OCT4 to the phenotype of human cancer cells. Stem Cells 2018.

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Section: Introductionmentioning

confidence: 99%

Conclusive Evidence for OCT4 Transcription in Human Cancer Cell Lines: Possible Role of a Small OCT4-Positive Cancer Cell Population

et al. 2018

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“…Although β‐catenin has been shown to be downregulated by miR‐214 in other cancers, our data show that β‐catenin escapes downregulation by miR‐214. Alternative splicing of mRNAs in the Wnt signaling pathway and the consequent loss of regulatory binding sites on mRNA for posttranscriptional regulation have been described . Alternate splicing can also result stabilization of the target mRNA .…”

Section: Discussionmentioning

confidence: 99%

“…Alternative splicing of mRNAs in the Wnt signaling pathway and the consequent loss of regulatory binding sites on mRNA for posttranscriptional regulation have been described. 46 Alternate splicing can also result stabilization of the target mRNA. 47 For example, in prostate cancer alternate splice variant of splicing factor, hnRNPA2, binds to β-catenin mRNA thereby stabilizing the mRNA and protein which in turn increased prostate cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Role of miR‐214 in regulation of β‐catenin and the malignant phenotype of melanoma

Prabhakar

Rodríguez

Jayanthy

et al. 2019

Molecular Carcinogenesis

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Wnt/β‐catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. β‐catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/β‐catenin signaling is frequently activated in melanoma through oncogenic mutations of β‐catenin and elevated β‐catenin levels are positively correlated with melanoma aggressiveness. Molecular mechanisms that regulate β‐catenin expression in melanoma are not fully understood. MicroRNA‐214 is known to function as a tumor suppressor by targeting β‐catenin in several types of cancer cells. Here, we investigated the regulation of β‐catenin by miR‐214 and its role in melanoma. We show that β‐catenin mRNA levels are negatively correlated with miR‐214 in melanoma. However, overexpression of miR‐214 paradoxically increased β‐catenin protein levels and promoted malignant properties of melanoma cells including resistance to mitogen‐activated protein kinase inhibitors (MAPKi). RNA‐seq analysis revealed that melanoma cells predominantly express a β‐catenin mRNA isoform lacking miR‐214 target site. Using matched miRNA and mRNA‐seq and bioinformatics analysis, we identified novel miR‐214 targets, ankyrin repeat domain 6 (ANKRD6) and C‐terminal binding protein 1 (CTBP1), that are involved in negative regulation of Wnt signaling. Overexpression of miR‐214 or knockdown of the novel miR‐214 targets, ANKRD6 or CTBP1, increased melanoma cell proliferation, migration, and decreased sensitivity to MAPKi. Our data suggest that in melanoma cells β‐catenin is not regulated by miR‐214 and the functions of miR‐214 in melanoma are mediated partly by regulating proteins involved in attenuation of Wnt/β‐catenin signaling.

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“…Dysregulation of the WNT pathway is involved in several pathways (Lecarpentier et al, 2014). Aberrant WNT/beta-catenin pathway is observed in cancer development (Sumithra, Saxena, and Das, 2016). WNT extracellular ligands bind Frizzled (FZD) receptors and low density lipoprotein receptor-related protein 5 and 6 (LRP 5/6) and disheveled (DSH), which induce betacatenin accumulation and then beta-catenin nuclear translocation for binding T-cell factor/lymphoid enhancer factor (TCF/LEF).…”

Section: Canonical Wnt/beta-catenin Pathwaymentioning

confidence: 99%

Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas

Vallée¹,

Lecarpentier²,

Vallée³

2019

Current Issues in Molecular Biology

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Primary central nervous system lymphomas (PCNSLs) are angiocentric neoplasia which present dense monoclonal lymphocyte proliferation, and occur in brain parenchyma in 90% of the cases. Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL) subtype represents more than 90% of PCNSLs and is the most aggressive subtype with a cure rate of only 40%. One of the characteristics of ABC-DLBCL subtype is neuroinflammation through the activation of NF-kappaB pathway. c-Myc alterations and protein expression have been shown in aggressive DLBCL. c-Myc is considered as a key prognostic and predictive biomarker for survival in DLBCL, its expression is associated with worst survival rates. Although mRNA of c-Myc is increased by low levels gains of c-Myc, several studies have s h o w n t h a t cM y c p r o t e i n e x p r e s s i o n i s overexpressed without c-Myc abnormalities. These high levels of c-Myc protein in DLBCL without genetic abnormalities suggest that c-Myc protein expression may be also increased by other mechanisms or signaling pathways which regulate its expression. In PCNSLs, the canonical WNT/betacatenin pathway is upregulated while PPAR gamma is downregulated. The opposite interplay between WNT/beta-catenin pathway and PPAR gamma is reviewed here. Activation of WNT/beta-catenin pathway leads to the transcription of genes involved in cell proliferation, mitochondrial metabolism, protein synthesis, and tumor growth, such as c-Myc. PPAR gamma agonists induce the inhibition of several signaling pathways such as NF-kappaB, STAT, PI3K/Akt and WNT/beta-catenin pathway. Activation of PPAR gamma agonists may have a major negative key role in the regulation of PCNSLs progression.

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Alternative splicing within the Wnt signaling pathway: role in cancer development

Cited by 23 publications

References 142 publications

Conclusive Evidence for OCT4 Transcription in Human Cancer Cell Lines: Possible Role of a Small OCT4-Positive Cancer Cell Population

Conclusive Evidence for OCT4 Transcription in Human Cancer Cell Lines: Possible Role of a Small OCT4-Positive Cancer Cell Population

Role of miR‐214 in regulation of β‐catenin and the malignant phenotype of melanoma

Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas

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