Inhibition of the Cancer Stem Cells-Like Properties by Arsenic Trioxide, Involved in the Attenuation of Endogenous Transforming Growth Factor Beta Signal

Li, Yuan; Jiang, Fei; Shen, Jian; Wang, Xingxing; Zhong, Li; Zhang, Jianping; Lü, Xiang

doi:10.1093/toxsci/kfu218

Cited by 23 publications

(14 citation statements)

References 39 publications

(59 reference statements)

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“… 50 , 51 Consistent with this observation, blocking TGF signaling with arsenic trioxide (As2O3) attenuates the expression of CD133 in HCC. 52 Our study identified the involvement of repressive histone modification in p53-mediated CD133 suppression. Growing evidence demonstrates that there is crosstalk between the DNA methylation and histone modification pathways.…”

Section: Discussionmentioning

confidence: 72%

Transcriptional repression of cancer stem cell marker CD133 by tumor suppressor p53

et al. 2015

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Novel therapeutic strategies are needed to overcome cancer recurrence, metastasis, and resistance to chemo- and radiotherapy. Cancer stem cells (CSCs) are major contributors to the malignant transformation of cells due to their capacity for self-renewal. Although various CSC markers have been identified in several types of tumors, they are primarily used as cancer-prediction markers and for the isolation of CSC populations. CD133, one of the best-characterized CSC markers in distinct solid tumor types, was shown to be correlated with CSC tumor-initiating capacity; however, the regulation of CD133 expression and its function in cancer are poorly understood. Here, we show that CD133 expression is negatively regulated by direct binding of the p53 tumor suppressor protein to a noncanonical p53-binding sequence in the CD133 promoter. Binding of p53 recruits Histone Deacetylase 1 (HDAC1) to the CD133 promoter and subsequently suppresses CD133 expression by reducing histone H3 acetylation. Furthermore, CD133 depletion suppresses tumor cell proliferation, colony formation, and the expression of core stemness transcription factors including NANOG, octamer-binding transcription factor 4 (OCT4), SOX2, and c-MYC. Critically, the anti-proliferative effects of p53 are antagonized by rescue of CD133 expression in a p53 overexpressing cell line, indicating that the tumor suppressive activity of p53 might be mediated by CD133 suppression. Taken together, our results suggest that p53-mediated transcriptional regulation of CD133 is a key underlying mechanism for controlling the growth and tumor-initiating capacity of CSCs and provide a novel perspective on targeting CSCs for cancer therapy.

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Section: Discussionmentioning

confidence: 72%

Transcriptional repression of cancer stem cell marker CD133 by tumor suppressor p53

et al. 2015

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“…TGF-β induces the epithelial-mesenchymal transition via the SMAD signaling pathway, and sometimes the Ras signaling pathway (27). Numerous studies have suggested that TGF-β modulates the expression of c-myc via the classical SMAD signaling pathway, in order to regulate the proliferation of cells (28). The results of the present study demonstrated that miR-193b inhibitors significantly promoted the protein expression of TGF-β in SW620 cells.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of miR-193b affects the growth of colon cancer cells via transforming growth factor-β and regulation of the SMAD3 pathway

Zhao

et al. 2017

Oncology Letters

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MicroRNA-193b (miRNA-193b) is often differentially expressed and is an important regulator of gene expression in colon cancer. The aim of the present study was to determine whether miRNA-193b affects cell growth in colon cancer and to investigate the potential underlying mechanisms. Patients with colorectal cancer (CRC; n=20) and healthy volunteers (n=10) were enrolled from the Department of Gastrointestinal Surgery Center, First Affiliated Hospital of Sun Yat-Sen University (Guangzhou, China). Western blot analysis was used to evaluate the protein expression of SMAD3 and transforming growth factor-β (TGF-β) in the patient samples. It was determined that miRNA-193b expression was markedly elevated in the CRC tissue samples. Furthermore, silencing of miRNA-193bin SW620 CRC cells by specific inhibitors significantly reduced the cell proliferation and induced apoptosis. In addition, the downregulation of miRNA-193b significantly activated the protein expression of SMAD3 and TGF-β, and promoted caspase-3 activity in SW620 cells. The results of the present study suggested that the deregulation of miRNA-193b may affect cell growth in colon cancer via the TGF-β and SMAD3 signaling pathways.

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“…In vivo studies, a dose range from 0.5 to 5.0 mg/kg of ATO and the i.p. route were used in the mouse model to determine the effects of arsenic trioxide on the EMT, metastasis, invasion, and angiogenesis of several cancers [34–37]. …”

Section: Discussionmentioning

confidence: 99%

Induction of the mesenchymal to epithelial transition by demethylation-activated microRNA-125b is involved in the anti-migration/invasion effects of arsenic trioxide on human chondrosarcoma

Bao

Ren

Huang

et al. 2016

J Exp Clin Cancer Res

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BackgroundIn addition to treating acute promyelocytic leukemia, arsenic trioxide (ATO) suppresses other solid tumors, including chondrosarcoma. However, the effects of ATO on metastasis in chondrosarcoma cells, and the underlying molecular mechanisms remain unclear.MethodsThe effects of ATO on the migratory and invasive capacities of chondrosarcoma cells were investigated by Wound healing, Transwell and EMT assays. The expression of miR-125b in human chondrosarcoma tissues and cell lines was detected by real-time PCR analysis. Bisulfite sequencing analysis (BSP) was used to detect the effects of ATO on the expression of miR-125b. The gain-of-function and loss-of-function experiments were performed on chondrosarcoma cell lines to investigate the effects of miR-125b on chondrosarcoma invasion, and to determine whether signal transducer and activator of transcription 3(Stat3) mediates these effects. Dual-luciferase reporter assay was used to identify whether Stat3 is a direct target of miR-125b.ResultsMiR-125b was significantly downregulated in human metastatic chondrosarcoma tissues and cell lines but not in non-metastatic chondrosarcoma tissues. ATO up-regulates the expression of miR-125b by the demethylation of DNA. ATO induces MET and attenuates the invasive capacities of chondrosarcoma cells through miR-125b. Stat3 was verified as a direct target of miR-125b, which is involved in ATO regulating EMT-associated traits.ConclusionsThese findings, for the first time, provides evidence that the miR-125b-mediated inhibition of Stat3 is involved in the ATO-induced attenuation of metastasis in chondrosarcoma cells.

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Inhibition of the Cancer Stem Cells-Like Properties by Arsenic Trioxide, Involved in the Attenuation of Endogenous Transforming Growth Factor Beta Signal

Cited by 23 publications

References 39 publications

Transcriptional repression of cancer stem cell marker CD133 by tumor suppressor p53

Transcriptional repression of cancer stem cell marker CD133 by tumor suppressor p53

Deregulation of miR-193b affects the growth of colon cancer cells via transforming growth factor-β and regulation of the SMAD3 pathway

Induction of the mesenchymal to epithelial transition by demethylation-activated microRNA-125b is involved in the anti-migration/invasion effects of arsenic trioxide on human chondrosarcoma

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