Wnt/β‐Catenin Signaling Activates Expression of the Bone‐Related Transcription Factor RUNX2 in Select Human Osteosarcoma Cell Types

Vega, Oscar A.; Lucero, Claudia; Araya, Héctor; Jerez, Sofía; Tapia, Julio C.; Antonelli, Marcelo; Salazar‐Onfray, Flavio; Heras, Facundo Las; Thaler, Roman; Riester, Scott M.; Stein, Gary S.; Wijnen, André J. van; Galindo, Mario

doi:10.1002/jcb.26011

Cited by 47 publications

(39 citation statements)

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“…Mechanical stimulation sensed by cells must be translated into biochemical changes in signaling events such as phosphorylation, transcription factor translocation, or alterations of gene expression. Consequently, the present study focused on the Akt/β‐catenin signaling pathway, an important signaling pathway implicated in the control of cell differentiation and cellular adaption (Duan and Bonewald, 2016), whose regulatory effect on Runx‐2 expression and activity has been demonstrated by several studies (Hamidouche et al, 2008; Haxaire et al, 2016; Vega et al, 2017). β‐catenin is the central, critical molecule in the canonical Wnt/β‐catenin pathway, which plays a key role in osteoblast differentiation and proliferation (Duan and Bonewald, 2016).…”

Section: Discussionmentioning

confidence: 99%

Fluid shear stress induces Runx‐2 expression via upregulation of PIEZO1 in MC3T3‐E1 cells

Song

Liu

et al. 2020

Cell Biology International

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Mechanically induced biological responses in bone cells involve a complex biophysical process. Although various mechanosensors have been identified, the precise mechanotransduction pathway remains poorly understood. PIEZO1 is a newly discovered mechanically activated ion channel in bone cells. This study aimed to explore the involvement of PIEZO1 in mechanical loading (fluid shear stress)‐induced signaling cascades that control osteogenesis. The results showed that fluid shear stress increased PIEZO1 expression in MC3T3‐E1 cells. The fluid shear stress elicited the key osteoblastic gene Runx‐2 expression; however, PIEZO1 silencing using small interference RNA blocked these effects. The AKT/GSK‐3β/β‐catenin pathway was activated in this process. PIEZO1 silencing impaired mechanically induced activation of the AKT/GSK‐3β/β‐catenin pathway. Therefore, the results demonstrated that MC3T3‐E1 osteoblasts required PIEZO1 to adapt to the external mechanical fluid shear stress, thereby inducing osteoblastic Runx‐2 gene expression, partly through the AKT/GSK‐3β/β‐catenin pathway.

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Section: Discussionmentioning

confidence: 99%

Fluid shear stress induces Runx‐2 expression via upregulation of PIEZO1 in MC3T3‐E1 cells

Song

Liu

et al. 2020

Cell Biology International

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“…β-catenin is a scaffold protein linking the cytoplasmic tail of classical cadherins of the endothelium to the actin cytoskeleton. Upregulation of β-catenin may cause tumor metastasis (27). Cyclin D1 is a cell cycle-related factor associated with G1/S stage transition.…”

Section: Discussionmentioning

confidence: 99%

Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression

2018

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Colon cancer is characterized by invasion and migration. DNA methylation of CpG islands in tumor suppressor genes is considered to be an epigenetic mechanism underlying cancer development. Epigenetic silencing of a gene may be reversed by drugs, including genistein. The present study aimed to determine the effect of genistein on Wnt inhibitory factor 1 (WIF1) and invasion, and migration of colon cancer cells. The viability of HT29 colon cancer cells was suppressed by genistein in a dose dependent manner. Following 72 h of treatment with 10, 20 and 60 µmol/l genistein, increased demethylation of WIF1 was induced in a dose‑dependent manner. Additionally, the invasive/migratory abilities of cells treated with genistein decreased in a dose‑dependent manner. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were performed to identify the mRNA and protein expression levels of invasion/migration‑associated factors. Following treatment with genistein, matrix metalloproteinase (MMP) 2 and MMP9 expression levels decreased, whereas the expression of metalloproteinase inhibitor 1 and E‑cadherin increased significantly. In addition, the expression levels of proto‑oncogene Wnt‑1 (Wnt‑1)/β‑catenin pathway‑associated factors, β‑catenin, c‑Myc proto‑oncogene protein and cyclin D1 decreased in a dose‑dependent manner following treatment with genistein. The invasive/migratory abilities of cells transfected with WIF1‑small interfering (si) RNA, and those transfected with WIF1‑siRNA and treated with genistein, increased notably compared with the control group. The present study demonstrated that genistein was able to inhibit the cell invasion and migration of colon cancer cells by inducing demethylation, and recovering the activity of WIF1 by altering the expression of invasion‑associated factors, and components of the Wnt signaling pathway.

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“…Previous studies have shown that the Wnt/β-catenin pathway regulates the expression and activity of Runx2. 46,47 Thus, decreased activation of this pathway could potentially attenuate the expression of Runx2 in OS. From our results, we Mechanistically, we elucidated that the cell apoptosis caused by blockage of HSP90 was attributed by the suppression of AKT and the decease of p-GSK-3β (Ser9)/GSK-3β ratio, which in turn led to the down-regulation of β-catenin expression in OS cells.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK‐3β/β‐catenin signaling

Liang

Liu

et al. 2017

J of Cellular Biochemistry

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Osteosarcoma (OS) is the most malignant primary bone tumor in children and adolescents with limited treatment options and poor prognosis. Recently, aberrant expression of Runx2 has been found in OS, thereby contributing to the development, and progression of OS. However, the upstream signaling molecules that regulate its expression in OS remain largely unknown. In the present study, we first confirmed that the inhibition of HSP90 with 17-AAG caused significant apoptosis of OS cells via a caspase-3-dependent mechanism, and that inhibition or knockdown of HSP90 by 17-AAG or siRNAs significantly suppressed mRNA and protein expression of Runx2. Furthermore, we provided evidence that Runx2 was transcriptionally regulated by HSP90 when using MG132 and CHX chase assay. We also demonstrated that β-catenin was overexpressed in OS tissue, and that knockdown of β-catenin induced pronounced apoptosis of OS cells in the presence or absence of 17-AAG.Interestingly, this phenomenon was accompanied with a significant reduction of Runx2 and Cyclin D1 expression, indicating an essential role of Runx2/Cyclin D1 in 17-AAG-induced cells apoptosis. Moreover, we demonstrated that the apoptosis of OS cells induced by 17-AAG did require the involvement of the AKT/GSK-3β/ β-catenin signaling pathway by using pharmacological inhibitor GSK-3β (LiCl) or siGSK-3β. Our findings reveal a novel mechanism that Runx2 is transcriptionally

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Wnt/β‐Catenin Signaling Activates Expression of the Bone‐Related Transcription Factor RUNX2 in Select Human Osteosarcoma Cell Types

Cited by 47 publications

References 100 publications

Fluid shear stress induces Runx‐2 expression via upregulation of PIEZO1 in MC3T3‐E1 cells

Fluid shear stress induces Runx‐2 expression via upregulation of PIEZO1 in MC3T3‐E1 cells

Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression

Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK‐3β/β‐catenin signaling

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