Deregulation of secreted frizzled-related proteins is associated with aberrant &amp;beta;-catenin activation in the carcinogenesis of oral submucous fibrosis

Zhou, Shanghui; Chen, Ling; Mashrah, Mubarak Ahmed; Zhu, Yun; Liu, Jiannan; Yang, Xi; He, Zhijing; Wang, Lizhen; Xiang, Tingxiu; Yao, Zhigang; Guo, Feng; Yang, Wenjun; Zhang, Chenping

doi:10.2147/ott.s91460

Cited by 23 publications

(19 citation statements)

References 33 publications

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“…Additionally, SFRP2 was found methylated in the majority of OSCC samples, in contrast to corresponding normal mucosa, and its overexpression reduced tumor growth in vivo [72]. It was shown that the reduction in SFRP1 and SFRP5 expression, which was induced by gene promoter methylation, was associated with cytoplasmic/nuclear delocalization of β-catenin in oral lesions [73]. Apart from SFRP1 and SFRP2, also WIF1, DKK1 and PPP2R2B were methylated in LSCC cell lines and primary tumors [74].…”

Section: The Role Of Epigenetic Mechanisms In Wnt/β-catenin Pathway Amentioning

confidence: 99%

“…The expression of Wnt ligand antagonist WIF1 is observed in normal oral epithelium, suggesting that WIF1 plays a role in the inhibition of canonical Wnt signaling in healthy mucosa. However, the expression of WIF1 was much lower in OSCC samples [59], and this was related to the methylation of WIF1 promoter [73]. The methylation of WIF1 in OSCC was found to be cancer-specific when compared to normal mucosa [73,75].…”

Section: The Role Of Epigenetic Mechanisms In Wnt/β-catenin Pathway Amentioning

confidence: 99%

“…However, the expression of WIF1 was much lower in OSCC samples [59], and this was related to the methylation of WIF1 promoter [73]. The methylation of WIF1 in OSCC was found to be cancer-specific when compared to normal mucosa [73,75]. The aberrant methylation of SFRP2 and WIF1 was shown to be already present in dysplastic lesions and the rate of methylation increased with progression to OSCC [76].…”

Section: The Role Of Epigenetic Mechanisms In Wnt/β-catenin Pathway Amentioning

confidence: 99%

“…WNT ligands overexpression translocation of β-catenin lymph node invasion [61][62][63][64] APC mutational loss stabilization of β-catenin enhanced cell growth [10][11][12][13][14][15][16] FAT1 mutational loss reduced sequestration of β-catenin enhanced cell growth, loss of cell adhesion [60] CDH1 (epi)mutational loss release of β-catenin from cell-cell junctions enhanced cell growth, loss of cell adhesion [51,55,57,58] EGFR overexpression stabilization and nuclear translocation of β-catenin enhanced cell proliferation [13,18] c-MET overexpression Wnt activation via FZD8 increased stemness [99] SFRP1-5 epigenetic silencing reduced Wnt ligand sequestration worse prognosis [73] invasiveness, lymph node metastasis, recurrence, dedifferentiation [26,28,38,42,[44][45][46][47][48]…”

Section: Drivers Of Wnt Activationmentioning

confidence: 99%

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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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Section: The Role Of Epigenetic Mechanisms In Wnt/β-catenin Pathway Amentioning

confidence: 99%

Section: The Role Of Epigenetic Mechanisms In Wnt/β-catenin Pathway Amentioning

confidence: 99%

Section: The Role Of Epigenetic Mechanisms In Wnt/β-catenin Pathway Amentioning

confidence: 99%

Section: Drivers Of Wnt Activationmentioning

confidence: 99%

See 2 more Smart Citations

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

Paluszczak

2020

Cells

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“…WIF1 promoter methylation may account for the β-catenin activation characteristic of OSF carcinogenesis [85]. In contrast, promoter methylation suppresses the secretion of the frizzled-related proteins 1 (SFRP1) and SFRP5 and are coupled with cytoplasmic/nuclear β-catenin accumulation in OSF carcinogenesis [86]. β-catenin expression levels in the normal, hyperplastic, dysplastic, and OSCC stages of OSF merit further investigation.…”

Section: Coding Gene and Protein Biomarkers In Osf Tissuesmentioning

confidence: 99%

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy

Shih

Wang

Shieh

et al. 2019

IJMS

176

111

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Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5–15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF.

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MiR‐125b regulates SFRP5 expression to promote growth and activation of cardiac fibroblasts

Bie

Sun

Geng

et al. 2016

Cell Biology International

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Myocardial fibrosis (MF), which typically occurs after a myocardial infarction (MI), is a major factor involved in the process of ventricular remodeling and subsequent progression to heart failure. Current studies have found that various microRNAs (miRNAs), such as miR-125b, play an important role in this process. However, few studies have investigated the specific mechanism of miR-125b. Transfection of miR-125b mimics into cardiac fibroblasts (CFs) resulted in significantly increased expression of the myofibroblast marker alpha-smooth muscle actin (α-SMA) and vinculin by Western blot analysis, while transfection of miR-125b inhibitors resulted in the opposite effect. Analysis of putative CF target genes for miR-125b revealed that miR-125b specifically inhibits expression of secreted frizzled-related protein 5 (SFRP5). SFRP5 inhibited expression of α-SMA and collagen I and III in CFs, while miR-125b promoted the expression of these proteins. Cotransfection of the SFRP5 overexpression vector and miR-125b mimics did not result in significant upregulation of SFRP5 expression or downregulation of α-SMA and collagen I and III. Further analysis revealed that miR-125b promotes the proliferation and migration of CFs and inhibits their apoptosis, while SFRP5 exhibits the opposite effects. These results indicate that miR-125b can regulate SFRP5 expression and thus influence the growth and activation of CFs. Hence, this study provides important insight into possible approaches for the prevention and treatment of MF after an MI.

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Deregulation of secreted frizzled-related proteins is associated with aberrant β-catenin activation in the carcinogenesis of oral submucous fibrosis

Cited by 23 publications

References 33 publications

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

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

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy

MiR‐125b regulates SFRP5 expression to promote growth and activation of cardiac fibroblasts

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