Epigenetic regulation of IQGAP2 promotes ovarian cancer progression via activating Wnt/β-catenin signaling

Deng, Zhuo; Wang, Lijie; Hou, Huilian; Zhou, Jiancheng; Xu, Li

doi:10.3892/ijo.2015.3228

Cited by 37 publications

(38 citation statements)

References 32 publications

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“…This is in agreement with a previous study, which demonstrated that targeted depletion of 14-3-3β reduces lung cancer cell migration and invasion (31). Activation of Wnt/β-catenin signaling promotes the invasive activities of several types of cancer cells (32,33), while suppression of Wnt/β-catenin signaling inhibits cancer cell invasion (34,35). In the present study, 14-3-3β inhibited β-catenin expression, as well as osteosarcoma cell invasion, suggesting that 14-3-3β may regulate cell invasion through the canonical Wnt signaling pathway.…”

Section: -3-3β Knockdown Suppresses the Expression Of β-Catenin Cysupporting

confidence: 93%

Downregulation of 14-3-3β inhibits proliferation and migration in osteosarcoma cells

Jun

Fan

et al. 2017

Mol Med Report

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The 14-3-3 protein isoform β (14‑3‑3β), which is an intracellular adaptor protein that exists in all eukaryotic organisms, is highly expressed in many cancer tissues, including glioma, lung carcinoma and breast cancer. However, 14‑3‑3β expression and function in osteosarcoma progression remain unknown. In the present study, the endogenous expression of 14‑3‑3β was assessed in osteosarcoma samples and the effect of 14‑3‑3β knockdown was examined in human osteosarcoma MG63 cells using small interfering RNA (siRNA). mRNA and protein expression levels for 14‑3‑3β were detected by reverse transcription‑quantitative polymerase reaction and western blotting, respectively. The results demonstrated that endogenous 14‑3‑3β mRNA and protein were highly expressed in human osteosarcoma tissues and osteosarcoma cell lines (U2OS, MG63 and SaOs‑2), but not in normal bone tissues or normal osteoblast hFOB1.19 cells. These data suggested that increased expression of 14‑3‑3β may be significantly associated with the development and progression of osteosarcoma. Therefore, the effect of 14‑3‑3β knockdown in MG63 cells was further examined in vitro. Knockdown of 14‑3‑3β by siRNA significantly decreased cell viability, and inhibited cell proliferation and invasion. In addition, 14‑3‑3β knockdown significantly decreased the protein expression levels of β‑catenin, cyclin D1, v‑myc avian myelocytomatosis viral oncogene homolog and matrix metallopeptidase 9 in osteosarcoma MG63 cells. These results suggested that the anticancer effects of 14‑3‑3β knockdown in MG63 cells might be mediated by the inhibition of the Wnt/β‑catenin signaling pathway. In summary, 14‑3‑3β knockdown decreased proliferation and invasion in MG63 cells, which suggests a potential therapeutic application for 14‑3‑3β as a novel target for the treatment of osteosarcoma patients.

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Section: -3-3β Knockdown Suppresses the Expression Of β-Catenin Cysupporting

confidence: 93%

Downregulation of 14-3-3β inhibits proliferation and migration in osteosarcoma cells

Jun

Fan

et al. 2017

Mol Med Report

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“…Our results show that pyrvinium at 100 and 500 nM, which effectively targeted growth and survival, did not affect ATP level in ovarian cancer cells, whereas pyrvinium at 1000 nM slightly decreased ATP level (Supplementary Figure 1), suggesting that pyrvinium does not act on ovarian cancer cells through mitochondrial function inhibition. As Wnt/β-catenin signaling plays an important role in the development of ovarian cancer [5,16,17], we next tested whether pyrvinium acts on ovarian cancer cells through inhibiting Wnt/β-catenin signaling.…”

Section: Resultsmentioning

confidence: 99%

Targeting of Wnt/β-Catenin by Anthelmintic Drug Pyrvinium Enhances Sensitivity of Ovarian Cancer Cells to Chemotherapy

Zhang

et al. 2017

Med Sci Monit

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BackgroundAberrant activation of Wnt/β-catenin has been shown to promote ovarian cancer proliferation and chemoresistance. Pyrvinium, an FDA-approved anthelmintic drug, has been identified as a potent Wnt inhibitor. Pyrvinium may sensitize ovarian cancer cells to chemotherapy.Material/MethodsThe effect of pyrvinium alone and its combination with paclitaxel in ovarian cancer was investigated using an in vitro culture system and in vivo xenograft models. The mechanisms of its action were also analyzed, focusing on the Wnt/β-catenin pathway.ResultsPyrvinium inhibited growth and induced apoptosis of paclitaxel- and cisplatin-resistant epithelial ovarian cancer cell lines A2278/PTX and SK-OV-3. Its combination with paclitaxel was synergistic in targeting ovarian cancer cells in vitro. In 3 independent ovarian xenograft mouse models, pyrvinium alone inhibited tumor growth. More importantly, we observed significant inhibition of tumor growth throughout the treatment when using pyrvinium and paclitaxel combined. Mechanistically, pyrvinium increased the Wnt-negative regulator axin and decreased the β-catenin levels in ovarian cancer cells. In addition, pyrvinium suppressed Wnt/β-catenin-mediated transcription, as shown by the decreased mRNA levels of MYC, cyclin D, and BCL-9. In contrast, the inhibitory effects of pyrvinium were reversed by β-catenin stabilization or overexpression, demonstrating that pyrvinium acted on ovarian cancer cells via targeting the Wnt/β-catenin signaling pathway.ConclusionsWe demonstrated that the anthelmintic drug pyrvinium targets ovarian cancer cells through suppressing Wnt/β-catenin signaling. Our work highlights the therapeutic value of inhibiting Wnt/β-catenin in ovarian cancer.

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“…IQGAP1 and IQGAP3 have been found to be upregulated in many cancers and promote tumor growth and metastasis [11][12][13][14][15], whereas the role of IQGAP2 is not fully understood in cancers. Most of the reports showed a reduced expression of IQGAP2 in HCC, prostate, gastric and ovary cancer [16][17][18][19], suggesting it to be a tumor suppressor but in couple of studies it was found to be an oncogene too [20,21]. Our previous work also showed reduced expression level of IQGAP2 in breast cancer, using Oncomine data analysis [22].…”

Section: Introductionmentioning

confidence: 87%

IQGAP2 acts as a tumor suppressor in breast cancer and its reduced expression promotes cancer growth and metastasis by MEK/ERK signalling pathways

Kumar

Hassan

Pattanaik³

et al. 2019

Preprint

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IQGAP2 is a member of IQGAPs scaffolding protein family. It has been reported as a tumor suppressor in various cancers, as well as, an oncogene in some cancers, suggesting organ specific role. Need to identify therapeutic targets which function in ER/PR independent way, prompted us to explore role of IQGAP2 in molecular mechanism in breast cancer, which was completely unknown. In vitro studies in estrogen receptor positive breast cancer cell line (MCF7) showed that low IQGAP2 expression results in increased cell proliferation, migration and invasion of cells whereas an opposite effect was observed with ectopic expression of IQGAP2. Triple negative breast cancer cell line (MDA-MB-468), with IQGAP2 depletion showed similar effect, supporting its role in ER/PR independent manner. Furthermore, we found that reduced IQGAP2 expression induces the expression of EMT markers; twist and Ncadherin and decreases the expression of MET marker, E-cadherin via the MEK/ERK pathway but not via AKT pathway. Validation of findings in patients showed a reduced IQGAP2 expression in breast cancer tissues compared to normal tissue. Patients with low levels of IQGAP2 showed correlation with higher tumor stage. Our results suggest that IQGAP2 acts as a tumor suppressor and its down regulation results in cell growth, cell invasion and EMT through the MEK/ERK signalling pathways and it hence may be a potential therapeutic target in breast cancer.

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Epigenetic regulation of IQGAP2 promotes ovarian cancer progression via activating Wnt/β-catenin signaling

Cited by 37 publications

References 32 publications

Downregulation of 14-3-3β inhibits proliferation and migration in osteosarcoma cells

Downregulation of 14-3-3β inhibits proliferation and migration in osteosarcoma cells

Targeting of Wnt/β-Catenin by Anthelmintic Drug Pyrvinium Enhances Sensitivity of Ovarian Cancer Cells to Chemotherapy

IQGAP2 acts as a tumor suppressor in breast cancer and its reduced expression promotes cancer growth and metastasis by MEK/ERK signalling pathways

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