• Journal of Life Science
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• v.21 no.9
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• pp.1301-1309
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• 2011

The major function of adipocytes is to store fat in the form of triglycerides. One of the signaling pathways known to affect adipogenesis, i.e. fat formation, is the WNT/${\beta}$-catenin pathway which inhibits the expression and activity of key regulators of adipogenesis. The purpose of this research is to find genes among the WNT/${\beta}$-catenin pathway which regulate adipogenesis by using small interfering (si) RNA and to find the association of single nucleotide polymorphisms (SNPs) of the gene with serum triglyceride levels in the human population. To elucidate the effects of ${\beta}$-catenin siRNA on adipogenesis key factors, PPAR${\gamma}$ and C/EBP${\alpha}$, we performed real-time PCR and western blotting experiments for the analyses of mRNA and protein levels. It was found that the siRNA-mediated knockdown of ${\beta}$-catenin upregulates adipogenesis key factors. However, upstream regulators of the WNT/${\beta}$-catenin pathway, such as DVL2 and LRP6, had no significant effects compared to ${\beta}$-catenin. These results indicate that ${\beta}$-catenin is a candidate gene for human fat accumulation. In general, serum triglyceride level is a good indicator of fat accumulation in humans. According to statistical analyses of the association between serum triglyceride level and SNPs of ${\beta}$-catenin, -10,288 C>T SNP (rs7630377) in the promoter region was significantly associated with serum triglyceride levels (p<0.05) in 290 Korean subjects. On the other hand, serum cholesterol levels were not significantly associated with SNPs of the ${\beta}$-catenin gene. The results of this study showed that ${\beta}$-catenin is associated with fat accumulation both in vitro and in the human population.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.13
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• pp.5187-5190
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• 2015

This study aimed to investigate the correlation between ${\beta}$-catenin immunoexpression and histopathological grades of lower lip squamous cell carcinoma (LSCC). $\beta$-Catenin abnormal expression was found in 29% of the squamous cells of well differentiated LSCC, 63% of moderately differentiated and 86% of poorly differentiated, and therefor was significantly associated with histological grade (p=0.000). Nuclear $\beta$-catenin expression appeared in 5% of the cells and was also correlated with the histological grades (p=0.000). In 14.7% of the cells it was localized in the cytoplasm, again correlating with histology (p=0.002). According to this study the expression of $\beta$-catenin is an independent prognostic factor for histological grade and to the tumor differentiation. This appears to reflect a structural association and the role of $\beta$-catenin in tumor progression.

• The Journal of Korean Medicine
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• v.32 no.3
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• pp.35-43
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• 2011

Objectives: This study was performed to screen target-specific inhibitors of ${\beta}$-catenin/TCF signaling whose functional activation plays an important role in early events in carcinogenesis. Methods: To investigate the activation or suppression of ${\beta}$-catenin/TCF transcription, we established a transiently transfected cell line with a constitutively active ${\beta}$-catenin mutant gene whose product is not degraded. This cell line was also co-transfected with luciferase reporter gene constructs containing either an optimized (TOPflash) or mutant (FOPflash) TCF-binding element. We investigated cytotoxic effects using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay. To find effective inhibitors of ${\beta}$-catenin/TCF signaling from medicinal herbs, the crude extracts of 99 types of medicinal herbs were screened using a luciferase assay system in HEK-293 and SH-SY5y cells. Results: At a concentration of $50{\mu}g$/ml, extracts of Angelica koreanae radix, Cannabis sativa semen, Ephedrae intermedia Schrenk radix, and Vitis rotundifolia fruit showed the following inhibitory effects on ${\beta}$-catenin/TCF signaling: $40{\pm}5.6%$, $23{\pm}6.1%$, $8{\pm}5.1%$, and $22{\pm}9.8%$ in ${\beta}$-catenin-activated HEK-293 cells and $9{\pm}4.7%$, $39{\pm}8.1%$, $39{\pm}6.4%$, and $42{\pm}10.1%$ in ${\beta}$-catenin-activated SH-SY5y cells, respectively. Crude extracts of E. radix were isolated by silica gel column chromatography, and two non-polar fractions of these extracts showed inhibitory effects on ${\beta}$-catenin/TCF signaling. Conclusions: In this study, we established a transiently transfected cell line as a screening system and found that various medicinal herb extracts had inhibitory effects on ${\beta}$signaling.

• Toxicological Research
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• v.33 no.3
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• pp.211-218
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• 2017

Cytochrome P450 1B1 (CYP1B1) acts as a hydroxylase for estrogen and activates potential carcinogens. Moreover, its expression in tumor tissues is much higher than that in normal tissues. Despite this association between CYP1B1 and cancer, the detailed molecular mechanism of CYP1B1 on cancer progression in HeLa cells remains unknown. Previous reports indicated that the mRNA expression level of Herc5, an E3 ligase for ISGylation, is promoted by CYP1B1 suppression using specific small interfering RNA, and that ISGylation may be involved in ubiquitination related to ${\beta}-catenin$ degradation. With this background, we investigated the relationships among CYP1B1, Herc5, and ${\beta}-catenin$. RT-PCR and western blot analyses showed that CYP1B1 overexpression induced and CYP1B1 inhibition reduced, respectively, the expression of $Wnt/{\beta}-catenin$ signaling target genes including ${\beta}-catenin$ and cyclin D1. Moreover, HeLa cells were treated with the CYP1B1 inducer $7,12-dimethylbenz[{\alpha}]anthracene$ (DMBA) or the CYP1B1 specific inhibitor, tetramethoxystilbene (TMS) and consequently DMBA increased and TMS decreased ${\beta}-catenin$ and cyclin D1 expression, respectively. To determine the correlation between CYP1B1 expression and ISGylation, the expression of ISG15, a ubiquitin-like protein, was detected following CYP1B1 regulation, which revealed that CYP1B1 may inhibit ISGylation through suppression of ISG15 expression. In addition, the mRNA and protein expression levels of Herc5 were strongly suppressed by CYP1B1. Finally, an immunoprecipitation assay revealed a direct physical interaction between Herc5 and ${\beta}-catenin$ in HeLa cells. In conclusion, these data suggest that CYP1B1 may activate $Wnt/{\beta}-catenin$ signaling through stabilization of ${\beta}-catenin$ protein from Herc5-mediated ISGylation for proteosomal degradation.

• Korean Journal of Plant Resources
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• v.32 no.2
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• pp.109-115
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• 2019

In this study, we evaluated the anti-cancer activity and potential molecular mechanism of 70% ethanol extracts of branches from Taxillus yadoriki parasitic to Neolitsea sericea (TN-NS-B) against human lung cancer cells, A549. TY-NS-B dose-dependently suppressed the growth of A549 cells. TY-NS-B decreased ${\beta}$-catenin protein level, but not mRNA level in A549 cells. The downregulation of ${\beta}$-catenin protein level by TY-NS-B was attenuated in the presence of MG132. Although TY-NS-B phosphorylated ${\beta}$-catenin protein, the inhibition of $GSK3{\beta}$ by LiCl did not blocked the reduction of ${\beta}$-catenin by TY-NS-B. In addition, TY-NS-B decreased ${\beta}$-catenin protein in A549 cells transfected with Flag-tagged wild type ${\beta}$-catenin or Flag-tagged S33/S37/T41 mutant ${\beta}$-catenin construct. Our results suggested that TN-NS-B may downregulate ${\beta}$-catenin protein level independent on $GSK3{\beta}$-induced ${\beta}$-catenin phosphorylation. Based on these findings, TY-NS-B may be a potential candidate for the development of chemopreventive or therapeutic agents for human lung cancer.

• Journal of Life Science
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• v.10 no.1
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• pp.57-63
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• 2000

${\beta}$-catenin, which plays a critical role in both the cytoskeleton and in transcriptional regulation in variousadherent cell types, undergoes degradation during adherent cell apoptosis. Although ${\beta}$-catenin has been reported to be present in Jurkat T-acute lymphoblastic leukemia cells, the regulation of ${\beta}$-catenin in hematologic malignancies have not been examined. The data presented here demonstrate that treatment of the T cell leukemia Jurkat iwht the apoptosis inducer anti-Fas induced proteolytic cleavage of ${\beta}$-catenin. ${\beta}$-catenin was cleaved at both the N- and C-terminus after anti-Fas treatment. Cleavage of intact ${\beta}$-catenin was completely inhibited by caspase selective protease inhibitors. These data demonstrate that ${\beta}$ -catenin proteolysis is triggered by the cross-linking of the Fas receptor on Jurkat cells and subsequent activation of caspase protease. There was a clear accumulatio of the large proteolytic fragment in Jurkat cells treated with lactacystin of ALLM. These are potent inhibitors of proteasome and calpain. these results suggest that both the proteasome and clapain may recognize the large ${\beta}$-catenin fragment as a substrate fot further degradation and that these pathewasy may act downstream of scapase in response to Fas receptor activation. Therefore, we suggest that ${\beta}$-catenin may play a role in promoting Jurkat survival.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.7277-7284
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• 2015

Background: The Wnt/${\beta}$-catenin signaling pathway is an important regulator of cellular functions such as proliferation, survival and cell adhesion. Wnt/${\beta}$-catenin signaling is associated with tumor initiation and progression; ${\beta}$-catenin mutations explain only 30% of aberrant signaling found in breast cancer, indicating that other components and/or regulation of the Wnt/${\beta}$-catenin pathway may be involved. Objective: We evaluated AXIN2 rs2240308 and rs151279728 polymorphisms, and expression profiles of ${\beta}$-catenin destruction complex genes in breast cancer patients. Materials and Methods: We collected peripheral blood samples from 102 breast cancer and 102 healthy subjects. The identification of the genetic variation was performed using PCR-RFLPs and DNA sequencing. RT-qPCR was used to determine expression profiles. Results: We found significant association of AXIN2 rs151279728 and rs2240308 polymorphisms with breast cancer risk. Significant increase was observed in AXIN2 level expression in breast cancer patients. Further analyses showed APC, ${\beta}$-catenin, CK1${\alpha}$, GSK3${\beta}$ and PP2A gene expression to be associated to clinic-pathological characteristics. Conclusions: The present study demonstrated, for the first time, that AXIN2 genetic defects and disturbance of ${\beta}$-catenin destruction complex expression may be found in breast cancer patients, providing additional support for roles of Wnt/${\beta}$-catenin pathway dysfunction in breast cancer tumorigenesis. However, the functional consequences of the genetic alterations remain to be determined.

• Biomolecules & Therapeutics
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• v.23 no.1
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• pp.26-30
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• 2015

Wnt/${\beta}$-catenin signaling pathway was mutated in about 90% of the sporadic and hereditary colorectal cancers. The abnormally activated ${\beta}$-catenin increases the cancer cell proliferation, differentiation and metastasis through increasing the expression of its oncogenic target genes. In this study, we identified an inhibitor of ${\beta}$-catenin dependent Wnt pathway from rhizomes of Atractylodes macrocephala Koidzumi (Compositae). The active compound was purified by activity-guided purification and the structure was identified as 2,8-dimethyl-6-hydroxy-2-(4-methyl-3-pentenyl)-2H-chromene (atractylochromene, AC). AC suppressed b-catenin/Tcell factor transcriptional activity of HEK-293 reporter cells when they were stimulated by Wnt3a or inhibitor of glycogen synthase kinase-$3{\beta}$. AC down-regulated the nuclear level of ${\beta}$-catenin through the suppression of galectin-3 mediated nuclear translocation of ${\beta}$-catenin in SW-480 colon cancer cells. Furthermore, AC inhibits proliferation of colon cancer cell. Taken together, AC from A. macrocephala might be a potential chemotherapeutic agent for the prevention and treatment of human colon cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.4089-4093
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• 2016

Purpose: This study aimed to explore the association of ${\beta}-catenin$ expression pattern with pathological response after neoadjuvant chemotherapy in breast cancer (BC) patients. Materials and Methods: In this retrospective exploratory study, data for 50 BC patients who received neoadjuvant chemotherapy were recorded. ${\beta}-catenin$ expression in tumours was assessed using immunohistochemistry and classified as either membranous or cytoplasmic according to the pattern of staining. Distributions of different clinico-pathological parameters according to ${\beta}-catenin$ expression were assessed using the Chi-square test. Logistic regression analysis was used to assess any relation of the pattern of ${\beta}-catenin$ expression with the pathological response. Results: Cytoplasmic ${\beta}-catenin$ expression was detected in 34% of BCs. Among our cases, 52% were hormonal receptor (HR)-positive, 24% were HER2-positive, 74% were clinical stage III and 74% received both anthracycline and taxane-based chemotherapy. Patients with cytoplasmic expression were more commonly younger than 40 years at diagnosis (cytoplasmic, 41.2% vs. no cytoplasmic expression, 12.1%, p=0.03). By doing t-test, cytoplasmic ${\beta}-catenin$ expression was linked with a higher body mass index compared to membranous-only expression ($mean{\pm}SD$ $33.0{\pm}4.47$ vs. $29.6{\pm}6.01$, respectively, p=0.046). No significant associations were found between ${\beta}-catenin$ expression and other parameters such as HR and HER2 status, or clinical stage. Complete pathological response (pCR) rate was twice as great in patients with membranous expression but without statistical significance (membranous-only, 33.3% vs. cytoplasmic, 17.6%, OR= 2.3, 95% CI= 0.55-9.87, p=0.24). Conclusions: This study suggests that cytoplasmic ${\beta}-catenin$ expression may be linked with lower probability of achieving pCR after neoadjuvant chemotherapy. These data need to be validated in a larger cohort of patients.

• BMB Reports
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• v.42 no.6
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• pp.338-343
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• 2009

The Wnt/$\beta$-catenin signaling pathway alters adipocyte differentiation by inhibiting adipogenic gene expression. $\beta$-catenin plays a central role in the Wnt/$\beta$-catenin signaling pathway. In this study, we revealed that tumour necrosis factor-$\alpha$ (TNF-$\alpha$), a potential negative regulator of adipocyte differentiation, inhibits porcine adipogenesis through activation of the Wnt/$\beta$-catenin signaling pathway. Under the optimal concentration of TNF-$\alpha$, the intracellular $\beta$-catenin protein was stabilized. Thus, the intracellular lipid accumulation of porcine preadipocyte was suppressed and the expression of important adipocyte marker genes, including peroxisome proliferator-activated receptor-$\gamma$ (PPAR$\gamma$) and CCAAT/enhancer binding protein-$\alpha$ (C/EBP$\alpha$), were inhibited. However, a loss of $\beta$-catenin in porcine preadipocytes enhanced the adipogenic differentiation and attenuated TNF-$\alpha$ induced anti-adipogenesis. Taken together, this study indicated that TNF-$\alpha$ inhibits adipogenesis through stabilization of $\beta$-catenin protein in porcine preadipocytes.