• Journal of dental hygiene science
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• v.16 no.6
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• pp.401-408
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• 2016

Periodontal disease is one of the major dental diseases. Currently, various methods are used for healing and successful regeneration of periodontal tissue damaged by periodontal disease. The periodontal ligament and alveolar bone have received considerable interest for use in periodontal tissue regeneration and induction. However, as the functions of the factors required for tooth attachment and key regulatory factors for periodontal tissue regeneration in the cementum have recently been identified, interest in cementum formation and regeneration has increased. Dental cementum forms in the late phase of tooth development because of the reciprocal regulatory interaction between cervical loop epithelial cells and surrounding mesenchymal cells, which is regulated by various gene signaling networks. Many attempts have been made to understand the regulatory factors and cellular and molecular mechanisms associated with new cementum formation. In this paper, we reviewed the study outcomes to date on the regulatory factors that induce cementum formation and regeneration, focusing on understanding the roles and functions of Wnt signaling in the regulation of cementum formation. In addition, we aimed to obtain information on the useful reciprocal regulatory factors that mediate cementum formation and regeneration through a series of molecular mechanisms.

• BMB Reports
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• v.50 no.1
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• pp.1-2
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• 2017

Acquiring a selective growth advantage by breaking the proliferation barrier established by gatekeeper genes is a centrally important event in tumor formation. Removal of the mammalian Hippo kinase Mst1 and Mst2 in hepatocytes leads to rapid hepatocellular carcinoma (HCC) formation, indicating that the Hippo signaling pathway is a critical gatekeeper that restrains abnormal growth in hepatocytes. By rigorous genetic approaches, we identified an interacting network of the Hippo, Wnt/${\beta}$-catenin and Notch signaling pathways that control organ size and HCC development. We found that in hepatocytes, the loss of Mst1/2 leads to the activation of Notch signaling, which forms a positive feedback loop with Yap/Taz (transcription factors controlled by Mst1/2). This positive feedback loop results in severe liver enlargement and rapid HCC formation. Blocking the Yap/Taz-Notch positive feedback loop by Notch inhibition in vivo significantly reduced the Yap/Taz activities, hepatocyte proliferation and tumor formation. Furthermore, we uncovered a surprising inhibitory role of Wnt/${\beta}$-catenin signaling to Yap/Taz activities, which are important in tumor initiation. Genetic removal of ${\beta}$-catenin in the liver of the Mst1/2 mutants significantly accelerates tumoriogenesis. Therefore, Wnt/${\beta}$-catenin signaling, known for its oncogenic property, exerts an unexpected function in restricting Yap/Taz and Notch activities in HCC initiation. The molecular interplay between the three signaling pathways identified in our study provides new insights in developing novel therapeutic strategies to treat liver tumors.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.1
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• pp.21-30
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• 2024

The challenging clinical outcomes associated with advanced cervical cancer underscore the need for a novel therapeutic approach. Monensin, a polyether antibiotic, has recently emerged as a promising candidate with anti-cancer properties. In line with these ongoing efforts, our study presents compelling evidence of monensin's potent efficacy in cervical cancer. Monensin exerts a pronounced inhibitory impact on proliferation and anchorage-independent growth. Additionally, monensin significantly inhibited cervical cancer growth in vivo without causing any discernible toxicity in mice. Mechanism studies show that monensin's anti-cervical cancer activity can be attributed to its capacity to inhibit the Wnt/β-catenin pathway, rather than inducing oxidative stress. Monensin effectively reduces both the levels and activity of β-catenin, and we identify Akt, rather than CK1, as the key player involved in monensin-mediated Wnt/β-catenin inhibition. Rescue studies using Wnt activator and β-catenin-overexpressing cells confirmed that β-catenin inhibition is the mechanism of monensin's action. As expected, cervical cancer cells exhibiting heightened Wnt/β-catenin activity display increased sensitivity to monensin treatment. In conclusion, our findings provide pre-clinical evidence that supports further exploration of monensin's potential for repurposing in cervical cancer therapy, particularly for patients exhibiting aberrant Wnt/β-catenin activation.

• Genomics & Informatics
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• v.19 no.1
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• pp.5.1-5.11
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• 2021

Head and neck squamous cell carcinoma (HNSCC) is the most frequent type of head and neck cancer that usually arises from the mucosal surfaces of several organs including nasal cavity, paranasal sinuses, oral cavity, tongue, pharynx, and larynx. The Wnt signaling pathway is a crucial mechanism for cellular maintenance and development. It regulates cell cycle progression, apoptosis, proliferation, migration, and differentiation. Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers. The present study aims to assess the gene alterations in the Wnt family of genes so as to derive an association with HNSCC. Computational approaches have been utilized for the identification of gene alterations in the Wnt family of genes. Several databases such as cBioportal, STRING, and UALCAN were used for the purpose. The frequency of alteration was high in case of Wnt family member 11 (5%). Gene amplification, deep deletions, missense and truncating mutations were observed in HNSCC patients. There was a marked difference in the gene expression profile of WNT11 between grades as well as normal samples. The survival probability measured using the Kaplan-Meier curve also presented with a significant difference among male and female subjects experiencing a low/medium level expression. The female patients showed less survival probability when compared to the male subjects. This provides the prognostic significance of the WNT11 gene in HNSCC. Taken together, the present study provides clues on the possible association of WNT11 gene alterations with HNSCC, which has to be further validated using experimental approaches.

• International Journal of Oral Biology
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• v.46 no.2
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• pp.67-73
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• 2021

This study summarizes the recent cutting-edge approaches for dentin regeneration that still do not offer adequate solutions. Tertiary dentin is formed when odontoblasts are directly affected by various stimuli. Recent preclinical studies have reported that stimulation of the Wnt/β-catenin signaling pathway could facilitate the formation of reparative dentin and thereby aid in the structural and functional development of the tertiary dentin. A range of signaling pathways, including the Wnt/β-catenin pathway, is activated when dental tissues are damaged and the pulp is exposed. The application of small molecules for dentin regeneration has been suggested as a drug repositioning approach. This study reviews the role of Wnt signaling in tooth formation, particularly dentin formation and dentin regeneration. In addition, the application of the drug repositioning strategy to facilitate the development of new drugs for dentin regeneration has been discussed in this study.

• Animal Bioscience
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• v.34 no.6
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• pp.957-966
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• 2021

Objective: Ovarian follicular development, which dependent on the proliferation and differentiation of granulosa cells (GCs), is a complex biological process in which miRNA plays an important role. Our previous study showed that miR-458b-5p is associated with ovarian follicular development in chicken. The detailed function and molecular mechanism of miR-458b-5p in GCs is unclear. Methods: The luciferase reporter assay was used to verify the targeting relationship between miR-458b-5p and catenin beta-1 (CTNNB1), which is an important transcriptional regulatory factor of the Wnt/β-catenin pathway. The cell counting kit-8 (CCK-8) assay, flow cytometry with propidium iodide (PI) and annexin V-fluorescein isothiocyanate (FITC) labeling were applied to explore the effect of miR-458b-5p on proliferation, cell cycle and apoptosis of chicken GCs. Quantitative real-time polymerase chain reaction and Western blot were used to detect the mRNA and protein expression levels. Results: We demonstrated that the expression of miR-458b-5p and CTNNB1 showed the opposite relationship in GCs and theca cells of hierarchical follicles. The luciferase reporter assay confirmed that CTNNB1 is the direct target of miR-458b-5p. Using CCK-8 assay and flow cytometry with PI and Annexin V-FITC labeling, we observed that transfection with the miR-458b-5p mimics significantly reduced proliferation and has no effects on apoptosis of chicken GCs. In addition, miR-458b-5p decreased the mRNA and protein expression of CD44 molecule and matrix metallopeptidase 7, which are the downstream effectors of CTNNB1 in Wnt/β-Catenin pathway and play functional roles in cell proliferation. Conclusion: Taken together, the data indicate that miR-458b-5p regulates ovarian GCs proliferation through Wnt/β-catenin signaling pathway by targeting CTNNB1, suggesting that miR-458b-5p and its target gene CTNNB1 may potentially play a role in chicken ovarian follicular development.

• Proceedings of the Korean Society of Life Science Conference
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• 2007.10a
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• pp.72.2-72.2
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• 2007

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• Reproductive and Developmental Biology
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• v.30 no.2
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• pp.143-156
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• 2006

Major characteristics of embryonic stem cells (ESCs) are sustaining of sternness and pluripotency by self-renewal. In this report, transcriptional profiles of the molecules in the developmentally important signaling pathways including Wnt, BMP4, $TGF-\beta$, RTK, Hh, Notch, and JAK/STAT signaling pathways were investigated to understand the self-renewal of mouse ESCs (mESCs), J1 line, and compared with the NIH3T3 cell line and mouse embryonic fibroblast (MEF) cells as controls. In the Wnt signaling pathway, the expression of Wnt3 was seen widely in mESCs, suggesting that the ligand may be an important regulator for self-renewal in mESCs. In the Hh signaling pathway, the expression of Gli and N-myc were observed extensively in mESCs, whereas the expression levels of in a Shh was low, suggesting that intracellular molecules may be essential for the self-renewal of mESCs. IGF-I, IGF-II, IGF-IR and IGF-IIR of RTK signaling showed a lower expression in mESCs, these molecules related to embryo development may be restrained in mESCs. The expression levels of the Delta and HESS in Notch signaling were enriched in mESCs. The expression of the molecules related to BMP and JAK-STAT signaling pathways were similar or at a slightly lower level in mESCs compared to those in MEF and NIH3T3 cells. It is suggested that the observed differences in gene expression profiles among the signaling pathways may contribute to the self-renewal and differentiation of mESCs in a signaling-specific manner.

• Molecules and Cells
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• v.24 no.2
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• pp.177-184
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• 2007

Approximately 200 individual skeletal elements, which differ in shape and size, are the building blocks of the vertebrate skeleton. Various features of the individual skeletal elements, such as their location, shape, growth and differentiation rate, are being determined during embryonic development. A few skeletal elements, such as the lateral halves of the clavicle and parts of the skull are formed by a process called intramembranous ossification, whereby mesenchymal cells differentiate directly into osteoblasts, while the majority of skeletal elements are formed via endochondral ossification. The latter process starts with the formation of a cartilaginous template, which eventually is being replaced by bone. This requires co-regulation of differentiation of the cell-types specific for cartilage and bone, chondrocytes and osteoblasts, respectively. In recent years it has been demonstrated that Wnt family members and their respective intracellular pathways, such as non-canonical and the canonical $Wnt/{\beta}$-catenin pathway, play important and diverse roles during different steps of vertebrate skeletal development. Based on the recent discoveries modulation of the canonical Wnt-signaling pathway could be an interesting approach to direct stem cells into certain skeletal lineages.

• Natural Product Sciences
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• v.29 no.1
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• pp.31-37
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• 2023

In this study, we investigated the efficacy of Celtis choseniana Nakai (C. choseniana) as complementary herbal medicine to ameliorate androgenic alopecia (AGA). The effects of C. choseniana on AGA were evaluated using testosterone propionate-induced AGA mouse model and dihydrotestosterone-treated human hair follicle dermal papilla cells. In vivo, C. choseniana treatment deactivated androgen signaling by reducing the concentration of serum dihydrotestosterone level and expressions of 5α-reductase 2 and androgen receptor. Next, C. choseniana treatment increased the hair regrowth rate. Histological studies demonstrated that C. choseniana induced the anagen phase in testosterone propionate-induced AGA mouse model. Cellular proliferation was promoted by C. choseniana treatment via increasing the expression of proliferation factors, such as proliferating cell nuclear antigen and cyclin D1. Furthermore, C. choseniana treatment increased the expression of proteins related to the Wnt/β-catenin signaling pathway. In addition, dickkopf-1, a Wnt inhibitor, was downregulated with C. choseniana treatment. Likewise, C. choseniana treatment promoted cellular proliferation in vitro. This study demonstrated the inhibitory effect of C. choseniana on androgen-induced AGA. Moreover, C. choseniana induced activation of Wnt/β-catenin signaling, resulting in prolonged anagen and cellular proliferation. Therefore, we suggest that C. choseniana can be used as a therapeutic agent to alleviate AGA.