Regulation of cell signaling and apoptosis by tumor suppressor WWOX

Lo, J.; Chou, Ying Tsen; Lai, Feng‐Jie; Hsu, Li Jin

doi:10.1177/1535370214566747

Cited by 23 publications

(21 citation statements)

References 60 publications

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“…3 It was indicated that the restoration of WWOX could promote cell apoptosis and autophagy against the tumor growth. [19][20][21] Based on bioinformatics analysis and previously reported studies in other types of cancers, miR-214 could regulate the expression levels of both PTEN and WWOX. 15,22 However, the crosstalk between miR-214 and PTEN or WWOX in NPC still remains unclear, and is thus worthy of further investigation.…”

Section: Introductionmentioning

confidence: 99%

MiR-214 Mediates Cell Proliferation and Apoptosis of Nasopharyngeal Carcinoma Through Targeting Both WWOX and PTEN

Han

Huang

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Background: Nasopharyngeal carcinoma (NPC) was highly prevalent with poor prognosis among the patients. MiR-214 reported as an important NPC biomarker was associated with regulation of biological functions. This study aimed to investigate interactions between miR-214, PTEN, and WWOX and their effect on AKT signaling during the NPC progression. Methods: The 5-8F and 6-10B NPC cells were transfected with miR-214 inhibitor. MTT and colony formation assays were performed to assess cell proliferation. PI staining assay was performed to determine distribution of cell cycle. Annexin-V/PI staining assay was used to evaluate cell apoptosis in NPC. The effects of miR-214 inhibitor on the expression levels of PTEN, WWOX, AKT signaling pathway, cell-cycle-, and apoptosisassociated proteins were assessed by western blotting or qRT-PCR assay. PTEN and WWOX were knocked down using the corresponding shRNA to investigate their effects on miR-214 inhibitor involved in proapoptosis and antiproliferation mechanisms in NPC. Results: Inhibition of miR-214 suppressed cell growth and induced apoptosis of 5-8F and 6-10B cells. MiR-214 regulated the expression of both PTEN and WWOX through targeting the 3¢-UTR. Inhibition of miR-214 promoted WWOX and PTEN expression, inactivated AKT signaling pathway, and regulated cell-cycle-and apoptosis-associated proteins. Knockdown of PTEN or WWOX reversed effects of miR-214 inhibitor on AKT signaling, cell proliferation, and apoptosis. Conclusion: MiR-214 was suggested to induce cell proliferation and inhibit cell apoptosis of NPC through directly targeting both PTEN and WWOX, which provided a novel therapeutic target for clinical treatment of NPC.

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Section: Introductionmentioning

confidence: 99%

MiR-214 Mediates Cell Proliferation and Apoptosis of Nasopharyngeal Carcinoma Through Targeting Both WWOX and PTEN

Han

Huang

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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“…Human WWOX gene is mapped to a common fragile site FRA16D on chromosome 16q23.3-24.1, and encodes a tumor suppressor WW domain-containing oxidoreductase, WWOX [11,17,56]. Deletions, loss of heterozygosity and translocations of WWOX gene have been frequently observed in various human malignancies, such as breast, prostate, ovarian, esophageal, lung, stomach, and pancreatic cancers [16,44]. Downregulation of proapoptotic WWOX expression is associated with cancer progression [7,37].…”

Section: Introductionmentioning

confidence: 99%

Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

Cheng

Chou

Lai

et al. 2020

acta neuropathol commun

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Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including microcephaly, cerebellar ataxia with epilepsy, mental retardation, retinal degeneration, developmental delay and early death. Here, we report that targeted disruption of Wwox gene in mice causes neurodevelopmental disorders, encompassing abnormal neuronal differentiation and migration in the brain. Cerebral malformations, such as microcephaly and incomplete separation of the hemispheres by a partial interhemispheric fissure, neuronal disorganization and heterotopia, and defective cerebellar midline fusion are observed in Wwox −/− mice. Degenerative alterations including severe hypomyelination in the central nervous system, optic nerve atrophy, Purkinje cell loss and granular cell apoptosis in the cerebellum, and peripheral nerve demyelination due to Schwann cell apoptosis correspond to reduced amplitudes and a latency prolongation of transcranial motor evoked potentials, motor deficits and gait ataxia in Wwox −/− mice. Wwox gene ablation leads to the occurrence of spontaneous epilepsy and increased susceptibility to pilocarpine-and pentylenetetrazol (PTZ)-induced seizures in preweaning mice. We determined that a significantly increased activation of glycogen synthase kinase 3β (GSK3β) occurs in Wwox −/− mouse cerebral cortex, hippocampus and cerebellum. Inhibition of GSK3β by lithium ion significantly abolishes the onset of PTZinduced seizure in Wwox −/− mice. Together, our findings reveal that the neurodevelopmental and neurodegenerative deficits in Wwox knockout mice strikingly recapitulate the key features of human neuropathies, and that targeting GSK3β with lithium ion ameliorates epilepsy.

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“…The protein encoded by WWOX has been found not only to contribute to cellular metabolism but also is, in turn, regulated by the relative level of glycolysis versus oxidative phosphorylation [ 31 ]. WWOX has also been widely reported to play a role in apoptotic pathways, principally through interactions with the tumor suppressor p53 (reviewed in [ 24 – 32 ]). A pro-apoptotic role for WWOX in vitro has previously been reported for many different cancer cell types; multiple myeloma [ 33 ], colon [ 34 ], gall bladder [ 35 ], cervical [ 36 ], leukaemic [ 37 ], glioblastoma [ 38 – 39 ], hepatoma [ 40 ], lung [ 17 ], pancreatic [ 18 ] and squamous epithelia [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor Suppressor WWOX Contributes to the Elimination of Tumorigenic Cells in Drosophila melanogaster

et al. 2015

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WWOX is a >1Mb gene spanning FRA16D Common Chromosomal Fragile Site, a region of DNA instability in cancer. Consequently, altered WWOX levels have been observed in a wide variety of cancers. In vitro studies have identified a large number and variety of potential roles for WWOX. Although its normal role in vivo and functional contribution to cancer have not been fully defined, WWOX does have an integral role in metabolism and can suppress tumor growth. Using Drosophila melanogaster as an in vivo model system, we find that WWOX is a modulator of TNFα/Egr-mediated cell death. We found that altered levels of WWOX can modify phenotypes generated by low level ectopic expression of TNFα/Egr and this corresponds to altered levels of Caspase 3 activity. These results demonstrate an in vivo role for WWOX in promoting cell death. This form of cell death is accompanied by an increase in levels of reactive oxygen species, the regulation of which we have previously shown can also be modified by altered WWOX activity. We now hypothesise that, through regulation of reactive oxygen species, WWOX constitutes a link between alterations in cellular metabolism observed in cancer cells and their ability to evade normal cell death pathways. We have further shown that WWOX activity is required for the efficient removal of tumorigenic cells from a developing epithelial tissue. Together these results provide a molecular basis for the tumor suppressor functions of WWOX and the better prognosis observed in cancer patients with higher levels of WWOX activity. Understanding the conserved cellular pathways to which WWOX contributes provides novel possibilities for the development of therapeutic approaches to restore WWOX function in cancer.

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Regulation of cell signaling and apoptosis by tumor suppressor WWOX

Cited by 23 publications

References 60 publications

MiR-214 Mediates Cell Proliferation and Apoptosis of Nasopharyngeal Carcinoma Through Targeting Both WWOX and PTEN

MiR-214 Mediates Cell Proliferation and Apoptosis of Nasopharyngeal Carcinoma Through Targeting Both WWOX and PTEN

Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

Tumor Suppressor WWOX Contributes to the Elimination of Tumorigenic Cells in Drosophila melanogaster

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