WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma

Zimmerli, Dario; Cecconi, Virginia; Valenta, Tomáš; Hausmann, George; Cantù, Claudio; Restivo, Gaetana; Hafner, Jürg; Basler, Konrad; Broek, Maries van den

doi:10.1038/s41388-018-0244-x

Cited by 26 publications

(25 citation statements)

References 41 publications

(63 reference statements)

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“…Recently, it has been found that LGK974, which is an inhibitor of the enzymatic activity of Porcupine, significantly reduced β-catenindependent Axin2 expression in approximately one third of 96 head and neck cancer cell lines analyzed [24]. Moreover, this compound was found to reduce Wnt/β-catenin pathway activation in papillomavirus-driven cutaneous squamous cell carcinomas [35]. IWP-2, another Porcupine inhibitor which has a chemical structure different from LGK974, was tested in our study.…”

Section: Discussionmentioning

confidence: 88%

Inhibition of CBP/β-catenin and porcupine attenuates Wnt signaling and induces apoptosis in head and neck carcinoma cells

et al. 2019

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Section: Discussionmentioning

confidence: 88%

Inhibition of CBP/β-catenin and porcupine attenuates Wnt signaling and induces apoptosis in head and neck carcinoma cells

et al. 2019

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“…This study speci ed that miR-214 could negatively target VEGFA and Bcl-2 and the subsequent activation of the Wnt/βcatenin pathway in CSCC cells. The signi cance of the Wnt/β-catenin signaling in CSCC initiation and progression has been underscored [24], and knockdown of β-catenin led to a marked decline in the colony-forming activity of SCC12 cells [25]. circ_CHFR knockdown was observed to impede the β-catenin expression via promoting miR-214-3p [26].…”

Section: Discussionmentioning

confidence: 99%

microRNA-214 prevents traits of cutaneous squamous cell carcinoma via VEGFA and Bcl-2

Zhang

et al. 2020

Preprint

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Background Dysregulation of microRNA-214 (miR-214) has been indicated in different tumors. The function of miR-214 in cutaneous squamous cell carcinoma (CSCC) is yet to be deciphered. The current study aimed to investigate the specific mechanism underpinning CSCC development with the involvement of miR-214 and its putative targets. Methods Microarray analysis of CSCC and adjacent tissues was carried out to filter the most significant downregulated miRNA. Survival analysis of patients was subsequently implemented, followed by miRNA expression determination in CSCC cells. Gain-of-function assays were performed to evaluate its function on cellular level. The targets of the determined miRNA were predicted and their expression in CSCC and adjacent tissues was evaluated. The targeting relationship was analyzed by dual-luciferase assays. Finally, rescue experiments were conducted. Results miR-214 was reduced in CSCC tissues and cells, and the survival of patients harboring overexpression of miR-214 was higher. miR-214 restoration increased CSCC cell apoptosis, while decreased proliferative, invasive and migratory activities. miR-214 interacted with vascular endothelial growth factor A (VEGFA) and B-cell CLL/lymphoma 2 (Bcl-2). VEGFA and Bcl-2, overexpressed in CSCC tissues and cells, were negatively correlated with miR-214. Moreover, VEGFA and Bcl-2 overexpression reversed the anti-tumor phenotype of miR-214 on CSCC cells. miR-214 disrupted the Wnt/β-catenin pathway through VEGFA and Bcl-2 in the CSCC cells. Conclusion Our data demonstrates that miR-214 exerts a suppressing role in CSCC. The discovery of novel targets such as miR-214 and VEGFA/Bcl-2 may facilitate the development of therapeutic options.

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“…The inhibition of Porcupine by C59 blocked the secretion of WNT-3A by dysplastic oral keratinocytes and reduced nuclear β-catenin level, leading to the inhibition of target gene (CCND1, BIRC5) expression [35]. Moreover, Porcupine inhibitors (LGK974 and C59) impaired the initiation and growth of HPV-driven cutaneous SCC and reduced the expression of CSC markers [126].…”

Section: Functional Significance Of Wnt/β-catenin Pathway Dysregulationmentioning

confidence: 99%

“…reduced stemness [102] decreased cell invasion [106] cell cycle arrest, reduced cell migration, induction of apoptosis [51,107] decreased cisplatin resistance [102] increased radiosensitivity [135] Porcupine IWP-2 inhibitor inhibition of UCA1dependent Wnt activation reduced cell proliferation and migration [84] LGK974 inhibitor reduced Wnt target gene expression reduced tumor growth [125] C59 inhibitor reduced secretion of WNT-3A, reduced CCND1 and BIRC5 expression impaired HPV-driven transformation [126] CBP ICG-001 inhibitor altered gene expression cell cycle arrest, induction of apoptosis, reduced stemness, tumor growth and metastasis [130,131] PI3K pathway emodin inhibition of PI3K/Akt/ β-catenin pathway reduced cell invasiveness [111] pyrithione zinc reduced expression of CCND1 and c-MYC reduced cell proliferation and invasion, apoptosis [119] CUL4B knockdown reduced expression of CCND1, c-MYC, MMP-7 reduced cell growth, migration and invasion [113] Funding: This work was funded by the Polish National Science Centre, grant number 2014/13/D/NZ7/00300.…”

Section: Lef1mentioning

confidence: 99%

The Significance of the Dysregulation of Canonical Wnt Signaling in Head and Neck Squamous Cell Carcinomas

Paluszczak

2020

Cells

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The knowledge about the molecular alterations which are found in head and neck squamous cell carcinomas (HNSCC) has much increased in recent years. However, we are still awaiting the translation of this knowledge to new diagnostic and therapeutic options. Among the many molecular changes that are detected in head and neck cancer, the abnormalities in several signaling pathways, which regulate cell proliferation, cell death and stemness, seem to be especially promising with regard to the development of targeted therapies. Canonical Wnt signaling is a pathway engaged in the formation of head and neck tissues, however it is not active in adult somatic mucosal cells. The aim of this review paper is to bring together significant data related to the current knowledge on the mechanisms and functional significance of the dysregulation of the Wnt/β-catenin pathway in head and neck tumors. Research evidence related to the role of Wnt signaling activation in the stimulation of cell proliferation, migration and inhibition of apoptosis in HNSCC is presented. Moreover, its role in promoting stemness traits in head and neck cancer stem-like cells is described. Evidence corroborating the hypothesis that the Wnt signaling pathway is a very promising target of novel therapeutic interventions in HNSCC is also discussed.Cells 2020, 9, 723 2 of 20 blocking the interaction between PD-1 receptor and PD-L1, may be beneficial in patients with advanced, metastatic or recurrent HNSCC [7]. However, other therapeutic options are also necessary for the better clinical management of HNSCC patients. To that end, molecular alterations observed in HNSCC need to be studied in detail, in order to point to promising drug targets. Mechanisms of Wnt/β-Catenin Pathway Activation in HNSCCRecent genomic analyses have shown the prevalence of genetic driver alterations in HNSCC, which most frequently affect genes associated with receptor tyrosine kinase (e.g., EGFR, MET, KIT), PI3K, p53, Notch or Hippo signaling pathways. On the other hand, genetic alterations in genes related to canonical Wnt signaling were rarely detected in HNSCC [8,9]. In contrast to colorectal cancers, which show molecular alterations driving Wnt signaling activation in around 90% of cases [9], HNSCC were shown to lack CTNNB1 mutations and APC mutations were present infrequently [10][11][12][13][14][15][16]. The mutations of FAT1 tumor suppressor, which encodes a protocadherin protein that binds and inactivates β-catenin, were detected in some cases of HNSCC [17]. However, the activation of the Wnt/β-catenin pathway in HNSCC seems to be more prevalent than it is suggested by genetic findings, due to cross-talk with other molecular alterations, which can lead to pathway cross-activation. Indeed, it has been shown that β-catenin can be activated via enhanced EGFR or PI3K signaling, which belong to the most frequently dysregulated signaling pathways in HNSCC. In this regard, elevated EGFR expression was associated with delocalized β-catenin expression [13]. In another study, the nuclear ...

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WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma

Cited by 26 publications

References 41 publications

Inhibition of CBP/β-catenin and porcupine attenuates Wnt signaling and induces apoptosis in head and neck carcinoma cells

Inhibition of CBP/β-catenin and porcupine attenuates Wnt signaling and induces apoptosis in head and neck carcinoma cells

microRNA-214 prevents traits of cutaneous squamous cell carcinoma via VEGFA and Bcl-2

The Significance of the Dysregulation of Canonical Wnt Signaling in Head and Neck Squamous Cell Carcinomas

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