EMX2 is epigenetically silenced and suppresses growth in human lung cancer

Okamoto, Junichi; Hirata, Tomomi; Chen, Z; Hm, Zhou; Mikami, Iwao; H, Li; Yagui-Beltrán, Adam; Johansson, Magnus; Coussens, LM; Clément, Geneviève; Shi, Yuankai; Zhang, F; Koizumi, Kiyoshi; Shimizu, Kazuo; Jablons, David M.; He, Bei-Bei

doi:10.1038/onc.2010.330

Cited by 51 publications

(56 citation statements)

References 36 publications

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“…Cisplatin-resistant NSCLC cells had increased expression of Wnt pathway genes. An exposure of these cells to a Wnt inhibitor led to an inhibited cell proliferation and sensitized NSCLC cells to chemotherapeutic agent docetaxel [74] and cisplatin [75], along with a downregulated expression of Wnt signaling target genes. In this study, we showed that a blockage of Wnt/PKC signaling could increase the baseline apoptosis and cisplatin-induced apoptosis in NSCLC A549 cells and cisplatin-resistant A549/DDP cells, suggesting that targeting Wnt/PKC noncanonical Wnt signaling may be a potential therapeutic strategy to circumvent chemoresistance in lung cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Yang

Zhang

et al. 2016

Stem Cells International

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The development of chemoresistance to cisplatin regimens causes a poor prognosis in patients with advanced NSCLC. The role of noncanonical Wnt signaling in the regulation of properties of lung cancer stem cells and chemoresistance was interrogated, by accessing capacities of cell proliferation, migration, invasion, and clonogenicity as well as the apoptosis in A549 cell lines and cisplatin-resistant A549 cells treated with Wnt5a conditional medium or protein kinase C (PKC) inhibitor GF109203X. Results showed that the noncanonical Wnt signaling ligand, Wnt5a, could promote the proliferation, migration, invasion, and colony formation in A549 lung adenocarcinoma cells and cisplatin-resistant A549/DDP cells and increase the fraction of ALDH-positive cell in A549/DDP cells. An exposure of cells to Wnt5a led to a significant reduction of A549/DDP cell apoptosis but not A549 cells. An addition of GF109203X could both strikingly increase the baseline apoptosis and resensitize the Wnt5a-inhibited cell apoptosis. Interestingly, an inhibition of Wnt/PKC signaling pathway could reduce properties of lung cancer stem cells, promote cell apoptosis, and resensitize cisplatin-resistant cells to cisplatin via a caspase/AIF-dependent pathway. These data thus suggested that the Wnt5a could promote lung cancer cell mobility and cisplatin-resistance through a Wnt/PKC signaling pathway and a blockage of this signaling may be an alternative therapeutic strategy for NSCLC patients with resistance to chemotherapies.

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Section: Discussionmentioning

confidence: 99%

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Yang

Zhang

et al. 2016

Stem Cells International

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“…Furthermore, several groups reported an inverse correlation between EMX2 expression levels and malignancy of a number of non neural tumors [10–14]. These findings led us to hypothesize employing Emx2 as a tool to suppress highly proliferating glioblastoma multiforme tumors (GBM).…”

Section: Introductionmentioning

confidence: 99%

Emx2as a novel tool to suppress glioblastoma

et al. 2016

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Glioblastoma is a devastating CNS tumour for which no cure is presently available. We wondered if manipulation of Emx2, which normally antagonizes cortico-cerebral astrogenesis by inhibiting proliferation of astrocyte progenitors, may be employed to counteract it. We found that Emx2 overexpression induced the collapse of seven out of seven in vitro tested glioblastoma cell lines. Moreover, it suppressed four out of four of these lines in vivo. As proven by dedicated rescue assays, the antioncogenic activity of Emx2 originated from its impact on at least six metabolic nodes, which accounts for the robustness of its effect. Finally, in two out of two tested lines, the tumor culture collapse was also achieved when Emx2 was driven by a neural stem cell-specific promoter, likely active within tumor-initiating cells. All that points to Emx2 as a novel, promising tool for therapy of glioblastoma and prevention of its recurrencies.

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“…Connection to epigenetic modification and Wnt pathway activation has been demonstrated in the literature not just for cisplatin [47][48][49] but for other drugs including paclitaxel, doxorubicin and gemcitabine [50,51]. Further studies, however, needed to reveal the step-by-step biochemical mechanism and to identify molecular targets for intervention.…”

Section: A) B)mentioning

confidence: 99%

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

et al. 2017

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Background: Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno-(AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in-depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. Methods: Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n = 90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune-fluorescent staining and transport function analysis. Results: Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity.

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EMX2 is epigenetically silenced and suppresses growth in human lung cancer

Cited by 51 publications

References 36 publications

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Emx2as a novel tool to suppress glioblastoma

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

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