Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia

Zhang, Xie; Ma, Wanhong; Cui, Jiantao; Hu, Yao; Zhou, Haixia; Ge, Yaojun; Xiao, Liying; Hu, Xin; Liu, Baohua; Yang, Jing; Li, Yuanyuan; Chen, S; Eaves, Connie J.; Wu, Di; Zhao, Yifan

doi:10.1038/onc.2014.241

Cited by 27 publications

(23 citation statements)

References 57 publications

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“…In order to investigate whether circMTO1 exerts its antitumor effect through sponge activity of miR‐9, we examined the expression of tumor suppressor p21, the target of miR‐9 . Both silencing of circMTO1 or transfection of miR‐9 mimic significantly reduced mRNA and protein expression levels of p21 in HCC cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Circular RNA circMTO1 acts as the sponge of microRNA‐9 to suppress hepatocellular carcinoma progression

et al. 2017

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Section: Resultsmentioning

confidence: 99%

Circular RNA circMTO1 acts as the sponge of microRNA‐9 to suppress hepatocellular carcinoma progression

et al. 2017

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“…These data suggested a role of TIMP-1 in promoting AML cell cycle progression. In order to confirm this observation, we analyzed the effect of TIMP-1 on expression of p21 WAF1/CIP1 , a cell cycle inhibitor [33] (Figure 3B). Interestingly, the normalized mean fluorescence intensity (nMFI) of p21 expression was significantly reduced in leukemic cells after exposure to TIMP-1 for 24 hours as compared with untreated cells (nMFI: 3.1±1.1 vs 4.5±1.5, respectively; p ≤ 0.05; data not shown).…”

Section: Resultsmentioning

confidence: 99%

The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

et al. 2016

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We and others have shown that the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), a member of the inflammatory network exerting pleiotropic effects in the bone marrow (BM) microenvironment, regulates the survival and proliferation of different cell types, including normal hematopoietic progenitor cells. Moreover, TIMP-1 has been shown to be involved in cancer progression. However, its role in leukemic microenvironment has not been addressed. Here, we investigated the activity of TIMP-1 on Acute Myelogenous Leukemia (AML) cell functions. First, we found that TIMP-1 levels were increased in the BM plasma of AML patients at diagnosis. In vitro, recombinant human (rh)TIMP-1 promoted the survival and cell cycle S-phase entry of AML cells. These kinetic effects were related to the downregulation of cyclin-dependent kinase inhibitor p21. rhTIMP-1 increases CXCL12-driven migration of leukemic cells through PI3K signaling. Interestingly, activation of CD63 receptor was required for TIMP-1's cytokine/chemokine activity. Of note, rhTIMP-1 stimulation modulated mRNA expression of Hypoxia Inducible Factor (HIF)-1α, downstream of PI3K/Akt activation. We then co-cultured AML cells with normal or leukemic mesenchymal stromal cells (MSCs) to investigate the interaction of TIMP-1 with cellular component(s) of BM microenvironment. Our results showed that the proliferation and migration of leukemic cells were greatly enhanced by rhTIMP-1 in presence of AML-MSCs as compared to normal MSCs. Thus, we demonstrated that TIMP-1 modulates leukemic blasts survival, migration and function via CD63/PI3K/Akt/p21 signaling. As a “bad actor” in a “bad soil”, we propose TIMP-1 as a potential novel therapeutic target in leukemic BM microenvironment.

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“…Consistent with this notion is a report by Zhang et al . (), showing that in acute myeloid leukemia (AML) in around 30% of examined cases hypermethylation of TWIST2 occurred leading to reduced expression of both TWIST2 and the cyclin‐dependent kinase inhibitor p21. TWIST2 activates p21 expression among other tumor suppressor genes and suppresses oncogenic activity.…”

Section: Mt In Hematological Malignanciesmentioning

confidence: 97%

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

2017

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The epithelial‐to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment‐derived stimuli that provoke EMT‐like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal‐to‐epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets.

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Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia

Cited by 27 publications

References 57 publications

Circular RNA circMTO1 acts as the sponge of microRNA‐9 to suppress hepatocellular carcinoma progression

Circular RNA circMTO1 acts as the sponge of microRNA‐9 to suppress hepatocellular carcinoma progression

The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

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