RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway

Sun, Jikui; Li, Banban; Jia, Zhifan; Zhang, Anling; Wang, Guangxiu; Chen, Zhijuan; Shang, Zhende; Zhang, Chaocai; Cui, Jian; Yang, Weidong

doi:10.1007/s11060-018-2927-0

Cited by 32 publications

(25 citation statements)

References 27 publications

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“…It has been shown that RUNX3 is able to constrain the Wnt pathway signaling even when this pathway is aberrantly activated due β-catenin activation [ 28 ]. Our results confirm previous studies showing that RUNX3 binds to β-catenin [ 28 , 30 ], suggesting that the downregulation of RUNX3 in the CTNNB1 S45F mutants (and not an inhibition of binding to β-catenin) might play a role in the impairment of apoptosis observed in these cells. RUNX3 expression has been shown to be lost or downregulated in several tumors, including gastric, breast and colorectal cancers [ 41 – 43 ].…”

Section: Discussionsupporting

confidence: 92%

“…Studies of the mechanisms that regulate β-catenin transcriptional activity have become of great interest, given that nuclear localization of β-catenin is key to Wnt/β-catenin signaling. In this context, RUNX3 has emerged as a novel protein that interacts with transcriptional complex components and regulates β-catenin transcriptional activity [ 28 – 30 ]. It has been shown that RUNX3 forms a complex with β-catenin and TCF4, and that this interaction attenuates the DNA-binding activity of β-catenin/TCF4 [ 28 , 30 ]; however, to the best of our knowledge, this study is the first to show that a specific β-catenin mutation can regulate RUNX3 levels.…”

Section: Introductionmentioning

confidence: 99%

“…In this context, RUNX3 has emerged as a novel protein that interacts with transcriptional complex components and regulates β-catenin transcriptional activity [ 28 – 30 ]. It has been shown that RUNX3 forms a complex with β-catenin and TCF4, and that this interaction attenuates the DNA-binding activity of β-catenin/TCF4 [ 28 , 30 ]; however, to the best of our knowledge, this study is the first to show that a specific β-catenin mutation can regulate RUNX3 levels. Here, we demonstrate that S45F mutant β-catenin has deregulated expression of several genes involved in apoptosis, resulting in the impairment of this cell death mechanism; moreover, this impairment is specific to the S45F mutation per se and not to the cell model utilized.…”

Section: Introductionmentioning

confidence: 99%

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β-catenin S45F mutation results in apoptotic resistance

et al. 2020

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Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3 , thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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β-catenin S45F mutation results in apoptotic resistance

et al. 2020

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“…Furthermore, the present study revealed that FA-2-b-β suppressed the expression of β-catenin as well as the protein products of Wnt target genes; c-myc, c-Jun and cyclin D1 in the G 1 transition. Subsequently, FA-2-b-β treatment contributed to cell cycle arrest during the G 1 phase and this observation is supported by a previous study ( 52 ). In the absence of Wnt signaling, β-catenin remains low through the degradation of cytoplasmic β-catenin, which prevents induction of the transcription of a number of proliferation-associated genes, including; cyclin D1, c-myc and fibronectin.…”

Section: Discussionsupporting

confidence: 87%

<em>Agaricus blazei</em> extract (FA‑2‑b‑β) induces apoptosis in chronic myeloid leukemia cells

Sun

Cheng

et al. 2020

Oncol Lett

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Agaricus blazei Murill (AbM) is a mushroom belonging to the Basidiomycetes family, which is believed to have antitumor and antioxidative activities. Proteoglycans and ergosterol are considered the key compounds of AbM for antitumor properties and so are used in complementary and alternative medicine as an anticancer drug. AbM is used to avoid serious side effects that would inevitably affect patients. Currently, the efficacy of AbM against chronic myeloid leukemia (CML) has not been established. The present study aimed to investigate the antitumor activities of the acidic RNA protein complex, FA-2-b-β, extracted from wild edible AbM. The CML K562 cells or primary CML bone marrow (BM) cells were treated with FA-2-b-β at different concentrations and time points. CML cell line proliferation and apoptosis were determined using the CCK-8 assay or Annexin V/propidium iodide (PI) labeling, RT-qPCR and western blotting was performed to determine the involvement of the Wnt/β-catenin-associated apoptotic pathway. The results of the present study demonstrated that FA-2-b-β has a high anti-proliferative potency and strong pro-apoptotic effects. Thus, daily intake of mushrooms containing FA-2-b-β may be an adequate source as an alternative medicine in the management of CML, and may provide useful information for the development of a novel therapeutic target in this area.

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“…RUNX3 can directly bind to the effector molecule Smad3 of transforming growth factor β, a signal pathway to participate in the process of cell growth inhibition [20]. RUNX3 can also form complexes with transcription factor 4 (TCF4) and B-catenin, the key effectors of the Wnt pathway, to inhibit the binding of TCF4β-catenin to target DNA, thus weakening the transcription of target genes [21]. In addition, RUNX3 is involved in the regulation of epithelial-mesenchymal transition (EMT) by Evidence-Based Complementary and Alternative Medicine directly regulating the transcription of blocking protein-1, thus inhibiting tumor invasion and metastasis by protecting nesting apoptosis [22].…”

Section: Discussionmentioning

confidence: 99%

RUNX3 Inhibits the Invasion and Metastasis of Human Colon Cancer HT-29 Cells by Upregulating MMP-2/9

Xue

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Objective. To investigate the effect of Runt-associated transcription factor 3 (RUNX3) on the invasion and metastasis of human colon cancer HT-29 cells and to preliminarily explore the mechanism of its anticancer effect. Methods. e RUNX3 plasmid vector was transfected into human colon cancer HT-29 cells by liposome-mediated transfection, while the empty vector and the blank group were used as the control group. After Geneticin (G418) screening, HT-29 cells with stable expression of RUNX3 gene were obtained. e expressions of mRNA and proteins of RUNX3 and metalloproteinases (MMP)-2/9 were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Cell proliferation was determined by MTT assay. e effect of RUNX3 on invasion and metastasis of HT-29 cells was evaluated by scratch injury assay, Transwell chamber, and Matrigel invasion model. Results. RUNX3 was expressed stably in HT-29 cells after transfection. e expressions of RUNX3 mRNA and proteins in the experimental group were significantly higher than those in the blank/empty vector groups. Meanwhile, the expressions of MMP-2/9 mRNA and proteins in the observation group were significantly lower than those in the blank group and the empty vector group. e proliferation and migration ability in the experimental group was significantly lower than blank/ empty vector groups from the third day. Transwell chamber experiment and Matrigel invasion assay showed that the number of Transwell cells was decreased significantly than blank/empty vector groups, but no difference was found between the blank group and the empty vector group. Conclusion. RUNX3 can inhibit the invasion and metastasis of human colon cancer HT-29 cells, and the mechanism may be related to decreased expression of MMP-2 and MMP-9.

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RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway

Abstract: RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.

Cited by 32 publications

References 27 publications

β-catenin S45F mutation results in apoptotic resistance

β-catenin S45F mutation results in apoptotic resistance

<em>Agaricus blazei</em> extract (FA‑2‑b‑β) induces apoptosis in chronic myeloid leukemia cells

RUNX3 Inhibits the Invasion and Metastasis of Human Colon Cancer HT-29 Cells by Upregulating MMP-2/9

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RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway

Abstract: RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.

Cited by 32 publications

References 27 publications

β-catenin S45F mutation results in apoptotic resistance

β-catenin S45F mutation results in apoptotic resistance

<em>Agaricus blazei</em> extract (FA‑2‑b‑&beta;) induces apoptosis in chronic myeloid leukemia cells

RUNX3 Inhibits the Invasion and Metastasis of Human Colon Cancer HT-29 Cells by Upregulating MMP-2/9

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<em>Agaricus blazei</em> extract (FA‑2‑b‑β) induces apoptosis in chronic myeloid leukemia cells