MiR-23a regulates TGF-β-induced epithelial-mesenchymal transition by targeting E-cadherin in lung cancer cells

Cao, Ming; Seike, Masahiro; Soeno, Chie; Mizutani, Hideaki; Kitamura, Kazuhiro; Minegishi, Yuji; Noro, Rintaro; Yoshimura, Akinobu; Cai, Li; Gemma, Akihiko

doi:10.3892/ijo.2012.1535

Cited by 154 publications

(124 citation statements)

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“…f Thirty minutes after incubated with EtBr, the content of LDH in the culture medium was measured as described in "Materials and methods". Values are means±SE (n=4) PC-9 cells is low [25], the Smad-dependent canonical TGF-β1 signaling pathway might be aberrant in PC-9 cells. We also found that the motile activity of PC-9 cells was suppressed by treatment with ecto-nucleotidase or P2X7 antagonists, suggesting that constitutive activation of P2X7 receptor is involved in the motility of these cells.…”

Section: Discussionmentioning

confidence: 99%

Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells

Takai

Tsukimoto

Hishida

et al. 2014

Purinergic Signalling

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Extracellular nucleotides, such as ATP, are released from cells and play roles in various physiological and pathological processes through activation of P2 receptors. Here, we show that autocrine signaling through release of ATP and activation of P2X7 receptor influences migration of human lung cancer cells. Release of ATP was induced by stimulation with TGF-β1, which is a potent inducer of cell migration, in human lung cancer H292 cells, but not in noncancerous BEAS-2B cells. Treatment of H292 cells with a specific antagonist of P2X7 receptor resulted in suppression of TGF-β1-induced migration. PC-9 human lung cancer cells released a large amount of ATP under standard cell culture conditions, and P2X7 receptor-dependent dye uptake was observed even in the absence of exogenous ligand, suggesting constitutive activation of P2X7 receptor in this cell line. PC-9 cells showed high motile activity, which was inhibited by treatment with ecto-nucleotidase and P2X7 receptor antagonists, whereas a P2X7 receptor agonist enhanced migration. PC-9 cells also harbor a constitutively active mutation in epidermal growth factor receptor (EGFR). Treatment with EGFR tyrosine kinase inhibitor AG1478 suppressed both cell migration and P2X7 receptor expression in PC-9 cells. Compared to control PC-9 cells, cells treated with P2X7 antagonist exhibited broadened lamellipodia around the cell periphery, while AG1478-treated cells lacked lamellipodia. These results indicate that P2X7-mediated signaling and EGFR signaling may regulate migration of PC-9 cells through distinct mechanisms. We propose that autocrine ATP-P2X7 signaling is involved in migration of human lung cancer cells through regulation of actin cytoskeleton rearrangement.

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Section: Discussionmentioning

confidence: 99%

Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells

Takai

Tsukimoto

Hishida

et al. 2014

Purinergic Signalling

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“…miR-24 also regulates the processing of the pre-TGF-b1 isoform via furin (Luna et al, 2011), such that reduced miR-24 expression would lead to elevated furin-mediated TGF-b1 processing. TGF-b1 induces miR-23 but not miR-24 expression in A549 cells and suppresses miR-24 in myocytes, both in a Smad3-dependent manner (Cao et al, 2012).In summary, this study identifies for the first time, to the best of our knowledge, a mechanism by which RSV NS1 suppresses the expression of miR-24 and induces KLF6 expression to promote TGF-b-mediated cell cycle arrest and RSV replication. miR-24 may prove to be a viable antiviral target, as the induction of miR-24 may overcome RSV-induced cell cycle arrest and inhibition of apoptosis, thus improving viral clearance from infected cells.…”

mentioning

confidence: 63%

Section: Discussionmentioning

confidence: 98%

“…Based on this evidence, it was hypothesized that RSV NS1 induces cell cycle arrest by promoting These data demonstrate a mechanism by which RSV induces cell cycle arrest in infected cells via TGF-b expression, which is promoted by NS1-mediated inhibition of miR-24 and elevation of KLF6 expression. Inhibition of miR-24 has also been shown to deregulate the cell cycle in A549 cells (Cao et al, 2012;Cheng et al, 2005) by inhibiting the anti-apoptotic factor XIAP (X-linked inhibitor of apoptosis), a protein induced during RSV persistence (Nakamura-Ló pez et al, 2011). However, cellular processes other than cell cycle arrest are also affected by inhibition of miR-24.…”

Section: Discussionmentioning

confidence: 99%

“…TGF-b treatment has been shown to increase RSV replication in A549 as well as primary NHBE cells (Gibbs et al, 2009). TGF-b has also been shown to inhibit miR-24 expression in other cell types (Cao et al, 2012;Sun et al, 2008) …”

Section: Silencing Klf6 Induces Mir-24 and Tgf-b Treatment Repressesmentioning

confidence: 99%

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Human respiratory syncytial virus non-structural protein NS1 modifies miR-24 expression via transforming growth factor-β

Bakre

Hiscox

et al. 2015

Journal of General Virology

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Human respiratory syncytial virus (RSV) is a major health challenge in the young and elderly owing to the lack of a safe and effective vaccine and proven antiviral drugs. Understanding the mechanisms by which viral genes and proteins modulate the host response to infection is critical for identifying novel disease intervention strategies. In this study, the RSV non-structural protein NS1 was shown to suppress miR-24 expression during infection. Lack of NS1 was linked to increased expression of miR-24, whilst NS1 overexpression suppressed miR-24 expression. NS1 was found to induce Kruppel-like factor 6 (KLF6), a transcription factor that positively regulates the transforming growth factor (TGF)-b pathway to induce cell cycle arrest. Silencing of KLF6 led to increased miR-24 expression via downregulation of TGF-b. Treatment with exogenous TGF-b suppressed miR-24 expression and induced KLF6. Confocal microscopy showed co-localization of KLF6 and RSV NS1. These findings indicated that RSV NS1 interacts with KLF6 and modulates miR-24 expression and TGF-b, which facilitates RSV replication. Received 23 March 2015Accepted 6 August 2015 INTRODUCTIONHuman respiratory syncytial virus (RSV) is a ubiquitous negative-sense ssRNA virus that can cause severe lung disease following infection (CDC, 2013;Hall et al., 2009;Nair et al., 2010). RSV is a member of the genus Pneumovirus, family Paramyxoviridae with a non-segmented genome that encodes 10 genes and 11 proteins (NS1, NS2, N, P, M, SH, G, F, M2-1, M2-2 and L). The two non-structural proteins (NS1 and NS2), which are not part of the intact virion, are transcribed and translated during infection (Moore et al., 2008).RSV infection rates are high and by age 2 years the majority of young children have experienced at least one infection (CDC, 2008(CDC, , 2013Hall et al., 2009;Mori et al., 2014;Nair et al., 2010;Stockman et al., 2012; Zhou et al., 2012). RSV infection in high-risk individuals, such as infants, young children, immunocompromised adults and the elderly, can manifest as serious pulmonary inflammatory disease including bronchiolitis and pneumonia (Hoffman et al., 2004;Moore et al., 2013;Openshaw & Chiu, 2013;Oshansky et al., 2009b;Psarras et al., 2004;Vicencio, 2010). There is also substantial evidence that early RSV infection can mediate airway remodelling, a feature that predisposes individuals to asthma development and exacerbation (Fong et al., 2000;Foronjy et al., 2014;Hirakawa et al., 2013;Hotard et al., 2015;Liesman et al., 2014;Meng et al., 2014;Piedimonte, 2002Piedimonte, , 2003Tan et al., 2008;Wu et al., 2011). Transforming growth factor (TGF)-b is expressed during RSV infection of lung epithelial cells (Gibbs et al., 2009;McCann & Imani, 2007;Mgbemena et al., 2011) and several studies indicate that it plays an important role in asthma development (de Faria et al., 2008;Fong et al., 2000;Gagliardo et al., 2013;Hoshino et al., 1998;Howell & McAnulty, 2006; Pelaia et al., 2007;Sharma et al., 2009). TGF-b also regulates aspects of the inflammatory cytokine r...

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Clinical impact of epithelial–mesenchymal transition for cancer therapy

Mukerjee,

Nag,

Bhattacharya

et al. 2024

Clinical and Translational Dis

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The epithelial–mesenchymal transition (EMT) represents a pivotal frontier in oncology, playing a central role in the metastatic cascade of cancer—a leading global health challenge. This comprehensive review delves into the complexities of EMT, a process where cancer cells gain exceptional mobility, facilitating their invasion into distant organs and the establishment of secondary malignancies. We thoroughly examine the myriad of factors influencing EMT, encompassing transcription factors, signalling pathways, metabolic alterations, microRNAs, long non‐coding RNAs, epigenetic changes, exosomal interactions and the intricate dynamics of the tumour microenvironment. Particularly, the review emphasises the advanced stages of EMT, crucial for the development of highly aggressive cancer phenotypes. During this phase, cancer cells penetrate the vascular barrier and exploit the bloodstream to propagate life‐threatening metastases through the mesenchymal–epithelial transition. We also explore EMT's significant role in fostering tumour dormancy, senescence, the emergence of cancer stem cells and the formidable challenge of therapeutic resistance. Our review transcends a mere inventory of EMT‐inducing elements; it critically assesses the current state of EMT‐focused clinical trials, revealing both the hurdles and significant breakthroughs. Highlighting the potential of EMT research, we project its transformative impact on the future of cancer therapy. This exploration is aimed at paving the way towards an era of effectively managing this relentless disease, positioning EMT at the forefront of innovative cancer research strategies.

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MiR-23a regulates TGF-β-induced epithelial-mesenchymal transition by targeting E-cadherin in lung cancer cells

Cited by 154 publications

References 41 publications

Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells

Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells

Human respiratory syncytial virus non-structural protein NS1 modifies miR-24 expression via transforming growth factor-β

Clinical impact of epithelial–mesenchymal transition for cancer therapy

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