Cancerous Protein Network That Inhibits the Tumor Suppressor Function of WW Domain-Containing Oxidoreductase (WWOX) by Aberrantly Expressed Molecules

Saigo, Chiemi; Kito, Yusuke; Takeuchi, Tamotsu

doi:10.3389/fonc.2018.00350

Cited by 13 publications

(19 citation statements)

References 49 publications

(71 reference statements)

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“…FRA16D, which is a focus of genomic instability and is predisposed to breakage and germline and somatic copy number variation. Thus, WWOX is a commonly deleted target in various cancers, 28,29 such as breast cancer, 30 non-small cell lung cancer, 31 bladder cancer, 32 prostate cancer. 33 In the present study, WWOX was reduced in ADC tissues.…”

Section: Discussionmentioning

confidence: 99%

<p>LncRNA HOTAIRM1 Inhibits the Proliferation and Invasion of Lung Adenocarcinoma Cells via the miR-498/WWOX Axis</p>

Chen¹,

Gao²,

Tian³

et al. 2020

CMAR

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Background: Lung adenocarcinoma (ADC) is a major form of lung cancer, which is a main cause of global cancer-related death in male and female patients. LncRNAs are implicated in tumor development. However, the functions and mechanisms of the LncRNA HOTAIRM1 in ADC are not known. Materials and Methods: Here, the downregulated HOTAIRM1 in ADC was selected by TCGA analysis. Subsequently, qRT-PCR, CCK-8, EdU, cell apoptosis, cell cycle and cell invasion assays were utilized for evaluating the roles of HOTAIRM1 in ADC. Finally, we explored the mechanism of HOTAIRM1 in ADC. Results: HOTAIRM1 expression was considerably decreased in ADC tissues. The knockdown of HOTAIRM1 promoted the cell cycle, growth, and invasion of ADC. Moreover, HOTAIRM1 competitively bound miR-498 to regulate the expression of WWOX. Conclusion: HOTAIRM1 suppressed the proliferation and invasion of ADC cells via the modulation of miR-498/WWOX axis. This finding suggested that it might be clinically valuable as a biomarker for ADC. Furthermore, the findings suggest LncRNA HOTAIRM1 as a candidate therapeutic target in ADC.

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Section: Discussionmentioning

confidence: 99%

<p>LncRNA HOTAIRM1 Inhibits the Proliferation and Invasion of Lung Adenocarcinoma Cells via the miR-498/WWOX Axis</p>

Chen¹,

Gao²,

Tian³

et al. 2020

CMAR

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“…WWOX also controls many biological functions, including bubbling cell death and genomic stability (Abu-Remaileh et al, 2015;Chen et al, 2015), suggesting that WWOX plays an important role in normal cellular/physiological homeostasis maintenance. Moreover, the first WW domain of WWOX participates in protein-protein interactions in multiple signaling pathways (Abu-Odeh et al, 2014;Liu et al, 2018;Saigo et al, 2018). Crosstalk of WWOX with many signal pathways also implies the involvement of WWOX in development and stemness maintenance (Chen et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Chou

Lai

Chang

et al. 2020

Front. Cell Dev. Biol.

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Deficiency of tumor suppressor WW domain-containing oxidoreductase (WWOX) in humans and animals leads to growth retardation and premature death during postnatal developmental stages. Skin integrity is essential for organism survival due to its protection against dehydration and hypothermia. Our previous report demonstrated that human epidermal suprabasal cells express WWOX protein, and the expression is gradually increased toward the superficial differentiated cells prior to cornification. Here, we investigated whether abnormal skin development and homeostasis occur under Wwox deficiency that may correlate with early death. We determined that keratinocyte proliferation and differentiation were decreased, while apoptosis was increased in Wwox −/− mouse epidermis and primary keratinocyte cultures and WWOX-knockdown human HaCaT cells. Without WWOX, progenitor cells in hair follicle junctional zone underwent massive proliferation in early postnatal developmental stages and the stem/progenitor cell pools were depleted at postnatal day 21. These events lead to significantly decreased epidermal thickness, dehydration state, and delayed hair development in Wwox −/− mouse skin, which is associated with downregulation of prosurvival MEK/ERK signaling in Wwox −/− keratinocytes. Moreover, Wwox depletion results in substantial downregulation of dermal collagen contents in mice. Notably, Wwox −/− mice exhibit severe loss of subcutaneous adipose tissue and significant hypothermia. Collectively, our knockout mouse model supports the validity of WWOX in assisting epidermal and adipose homeostasis, and the involvement of prosurvival ERK pathway in the homeostatic responses regulated by WWOX.

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“…The binding event contributes to the inhibition of cancer growth in vivo. Indeed, WWOX physically binds to many cellular proteins, such as p53, Hyal-2, Smad3 and 4, JNK1, Tau, Zfra, and many others [ 11 , 12 , 13 , 14 , 15 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In stark contrast, when both Zfra4-10 and WWOX7-21 peptides are introduced simultaneously to mice via tail veins, these mice have significantly reduced levels of WWOX complex formation with proteins in the aforementioned organs.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo

Wan

Wang

Chang

et al. 2020

Cancers

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Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.

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Cancerous Protein Network That Inhibits the Tumor Suppressor Function of WW Domain-Containing Oxidoreductase (WWOX) by Aberrantly Expressed Molecules

Cited by 13 publications

References 49 publications

<p>LncRNA HOTAIRM1 Inhibits the Proliferation and Invasion of Lung Adenocarcinoma Cells via the miR-498/WWOX Axis</p>

<p>LncRNA HOTAIRM1 Inhibits the Proliferation and Invasion of Lung Adenocarcinoma Cells via the miR-498/WWOX Axis</p>

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo

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