WT1 Promotes Invasion of NSCLC via Suppression of CDH1

Wu, Chen; Zhu, Weiyou; Qian, Ji; He, Shasha; Wu, Changping; Chen, Yijiang; Shu, Yongqian

doi:10.1097/jto.0b013e31829f6a5f

Cited by 36 publications

(35 citation statements)

References 39 publications

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“…Furthermore, overexpression of WT1 enhanced proliferation through upregulation of cyclin D1 and p-pRb in NSCLC cells [12]. WT1 suppressed the expression of E-cadherin through directly binding its promoter to enhance the invasion [15]. Thus, WT1 plays an important role in promoting proliferation and invasion in NSCLC cells.…”

Section: Introductionmentioning

confidence: 99%

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Pathologically decreased expression of miR-193a contributes to metastasis by targeting WT1-E-cadherin axis in non-small cell lung cancers

Chen

Gao

Wang

et al. 2016

J Exp Clin Cancer Res

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BackgroundThe metastatic cascade is a complex and multistep process with many potential barriers. Recently, miR-193a has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-oncogenic activity in non-small cell lung cancers (NSCLC) is not fully elucidated.MethodsThe expressions of miR-193a (miR-193a-5p) in human lung cancer tissues and cell lines were detected by real-time PCR. Dual-luciferase reporter assay was used to identify the direct target of miR-193a. Cell proliferation, apoptosis, and metastasis were assessed by CCK-8, flow cytometry, and Transwell assay, respectively.ResultsThe expression of miR-193a in lung cancer tissues was decreased comparing to adjacent non-tumor tissues due to DNA hypermethylation in lung cancer tissues. Ectopic expression of miR-193a inhibited cell proliferation, colony formation, migration, and invasion in A549 and H1299 cells. Moreover, overexpression of miR-193a partially reversed tumor growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) in NSCLC cells. Mechanistically, miR-193a reduced the expression of WT1, which negatively regulated the protein level of E-cadherin, suggesting that miR-193a might prevent EMT via modulating WT1-E-cadherin axis. Importantly, knockdown of WT1 resembled the anti-cancer activity by miR-193a and overexpression of WT1 partially reversed miR-193a-induced anti-cancer activity, indicating that WT1 plays an important role in miR-193a-induced anti-cancer activity. Finally, overexpression of miR-193a decreased the growth of tumor xenografts in mice.ConclusionCollectively, our results have revealed an important role of miR-193a-WT1-E-cadherin axis in metastasis, demonstrated an important molecular cue for EMT, and suggested a therapeutic strategy of restoring miR-193a expression in NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0450-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

“…However, whether miR-193a can regulate E-cadherin expression is not determined. Because WT1 is implicated in the metastasis of NSCLC through inhibiting the expression of E-cadherin [15], we hypothesized that one mechanism of anti-metastasis activity of miR-193a might perform by modulating WT1-E-cadherin axis.…”

Section: Introductionmentioning

confidence: 99%

Pathologically decreased expression of miR-193a contributes to metastasis by targeting WT1-E-cadherin axis in non-small cell lung cancers

Chen

Gao

Wang

et al. 2016

J Exp Clin Cancer Res

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“…Finally, they concluded that low WT1 expression predicted poor prognosis in patients with NSCLC. On the other hand, two recently published papers from the same group determined that WT1 promotes the invasion of NSCLC via the suppression of E-cadherin, and it increases cell proliferation in NSCLC cell lines through upregulation of cyclin D1 and pRb [43], [44]. Therefore, the exact role of WT1 in NSCLC is a current matter of debate, and more prospective studies are required to confirm its importance.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Androstane Receptor Ligands Modulate the Anti-Tumor Efficacy of Paclitaxel in Non-Small Cell Lung Cancer Cells

et al. 2014

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BackgroundLung tumors are the leading cause of cancer deaths worldwide and paclitaxel has proven to be useful for patients with lung cancer, however, acquired resistance is a major problem. To overcome this problem, one promising option is the use of Constitutive Androstane Receptor (CAR) ligands in combination with chemotherapeutics against cancer cells. Therefore, we wish to elucidate the effects of CAR ligands on the antineoplastic efficacy of paclitaxel in lung cancer cells.Methodology/Principal FindingsOur results from cell viability assays exposing CAR agonist or inverse-agonist to mouse and human lung cancer cells modulated the antineoplastic effect of paclitaxel. The CAR agonists increased the effect of Paclitaxel in 6 of 7 lung cancer cell lines, whereas the inverse-agonist had no effect on paclitaxel cytotoxicity. Interestingly, the mCAR agonist TCPOBOP enhanced the expression of two tumor suppressor genes, namely WT1 and MGMT, which were additively enhanced in cells treated with CAR agonist in combination with paclitaxel. Also, in silico analysis showed that both paclitaxel and CAR agonist TCPOBOP docked into the mCAR structure but not the inverse agonist androstenol. Paclitaxel per se increases the expression of CAR in cancer cells. At last, we analyzed the expression of CAR in two public independent studies from The Cancer Genome Atlas (TCGA) of Non Small Cell Lung Cancer (NSCLC). CAR is expressed in variable levels in NSCLC samples and no association with overall survival was noted.Conclusions/SignificanceTaken together, our results demonstrated that CAR agonists modulate the antineoplastic efficacy of paclitaxel in mouse and human cancer cell lines. This effect was probably related by the enhanced expression of two tumor suppressor genes, viz. WT1 and MGMT. Most of NSCLC cases present CAR gene expression turning it possible to speculate the use of CAR modulation by ligands along with Paclitaxel in NSCLC therapy.

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“…By in vitro experiments, we showed that WT1 can promote NSCLC invasion through direct binding to the CDH1 promoter [19]. Furthermore, WT1 was found to promote NSCLC cell proliferation by upregulating Cyclin Dl and p-pRb expression in vitro and in vivo [20] .…”

Section: Introductionmentioning

confidence: 99%

WT1 Enhances Proliferation and Impedes Apoptosis in KRAS Mutant NSCLC via Targeting cMyc

Wang

et al. 2015

Cell Physiol Biochem

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Background: A novel link between oncogenic KRAS signalling and WT1 was recently identified. We sought to investigate the role of WT1 and KRAS in proliferation and apoptosis. Methods: KRAS mutations and WT1 (cMyc) expression were detected using Sanger sequencing and real-time PCR in 77 patients with non-small cell lung cancer (NSCLC). Overexpression and knockdown of WT1 were generated with plasmid and siRNA via transient transfection technology in H1299 and H1568 cells. MTT assay for detection of cell proliferation, and TUNEL assay and proteomic profiler assay for apoptosis evaluation were carried out. Dual luciferase reporter assay and ChIP-PCR were performed to validate the effect of WT1 on the cMyc promoter. Results: KRAS mutations showed a negative impact on overall survival (OS). High expressions of WT1 and cMyc were associated with poor OS in KRAS mutant subgroup. The potential mechanisms that WT1 promotes proliferation and impedes apoptosis through affecting multiple apoptosis-related regulators in KRAS mutant NSCLC cells were identified. WT1 could activate cMyc promoter directly in KRAS mutant cells. Conclusion: The results suggest that WT1 and c-MYC expression is important for survival in KRAS mutant tumors as opposed to KRAS wild-type tumors. For treatment of KRAS mutant NSCLC, targeting WT1 and cMyc may provide alternative therapeutic strategies.

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WT1 Promotes Invasion of NSCLC via Suppression of CDH1

Abstract: WT1 expression was correlated with clinical stage, metastasis, and survival rate in 159 NSCLC patients. Via direct binding to the promoter, WT1 could suppress CDH1 and promote NSCLC invasion.

Cited by 36 publications

References 39 publications

Pathologically decreased expression of miR-193a contributes to metastasis by targeting WT1-E-cadherin axis in non-small cell lung cancers

Pathologically decreased expression of miR-193a contributes to metastasis by targeting WT1-E-cadherin axis in non-small cell lung cancers

Constitutive Androstane Receptor Ligands Modulate the Anti-Tumor Efficacy of Paclitaxel in Non-Small Cell Lung Cancer Cells

WT1 Enhances Proliferation and Impedes Apoptosis in KRAS Mutant NSCLC via Targeting cMyc

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