Snail promotes an invasive phenotype in lung carcinoma

Merikallio, Heta; Turpeenniemi‐Hujanen, Taina; Pääkkö, Paavo; Mäkitaro, Riitta; Kaarteenaho, Riitta; Salo, Sirpa; Salo, Tuula; Harju, Terttu; Soini, Ylermi

doi:10.1186/1465-9921-13-104

Cited by 42 publications

(33 citation statements)

References 23 publications

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“…Upregulation of mesenchymal biomarkers and Met activation have both been associated separately with prognosis in several tumor types (6,(31)(32)(33) and coexistence of both markers with stemness (34). One could hypothesize that the presence of a subset of cells with these markers in SCLC at diagnosis could predict the enrichment of this chemoresistant population at progression after chemotherapy and, therefore, explain the poor prognosis of these patients in our study.…”

Section: Discussionmentioning

confidence: 62%

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Cañadas

Rojo

Taus

et al. 2014

Clinical Cancer Research

111

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Purpose: Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/ Met-mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models.Experimental Design: SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N ¼ 87) and relapse (N ¼ 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome.Results: We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease.Conclusion: These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease. Clin Cancer Res; 20(4); 938-50. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 62%

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Cañadas

Rojo

Taus

et al. 2014

Clinical Cancer Research

111

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“…Several transcription factors such as Slug, Snail, are normally considered repressors for E-cadherin [36,39,40,41]. In A549 cells, the knockdown of RhoGDI2 significantly decreased the expression of E-cadherin, whereas overexpressing RhoGDI2 increased the expression of E-cadherin (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Down-regulation of E-cadherin decreases cell adhesion strength and promotes motility, hence it is considered the fundamental hallmark of EMT in cancer [5,6,36,37,38]. It is widely accepted that E-cadherin represses cell invasion and metastasis [5,6,37,38], and its activity can be regulated by several transcription factors e.g., Slug and Snail especially in lung carcinoma [36,39,40,41]. Down-regulation of E-cadherin is usually caused by the expression of transcription factors such as Slug, Snail, Zeb1, E47 [36].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of RhoGDI2 Mediated Lung Cancer Epithelial-Mesenchymal Transition Suppression

Huang¹,

Wu²,

Jiang³

et al. 2014

Cell Physiol Biochem

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Background: The aim of this study was to evaluate the function of RhoGDI2 in lung cancer epithelial-mesenchymal transition (EMT) process and to illustrate the underlying mechanisms that will lead to improvement of lung cancer treatment. Methods: The RhoGDI2 knock-down and overexpressing A549 cell lines were first constructed. The influence of RhoGDI2 on cytoskeleton in A549 cells was studied using two approaches: G-LISA-based Rac1 activity measurement and immunostaining-based F-actin distribution. The expression levels of key EMT genes were analyzed using real time quantitative polymerase chain reaction (RT-qPCR), western blot and immunostaining in untreated and RhoGDI2 knock-down or overexpressing A549 cells in both in vivo and in vitro experimental settings. Results: Our study showed that the activity of Rac1, a key gene that is crucial for the initiation and metastasis of human lung adenocarcinoma, causing the redistribution of F-actin with partial loss of cell-cell adhesions and stress fibers, was significantly suppressed by RhoGDI2. RhoGDI2 promoted the expression of EMT marker gene E-cadherin and repressed EMT promoting genes Slug, Snail, α-SMA in both A549 cells and lung and liver organs derived from the mouse models. Knocking-down RhoGDI2 induced abnormal morphology for lung organs. Conclusion: These findings indicate that RhoGDI2 repressed the activity of Rac1 and may be involved in the rearrangement of cytoskeleton in lung cancer cells. RhoGDI2 suppresses the metastasis of lung cancer mediated through EMT by regulating the expression of key genes such as E-cadherin, Slug, Snail and α-SMA in both in vivo and in vitro models.

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“…In our study, we found that DLL3 promoted SCLC‐cell migration and invasion by modulating Snail expression, despite our observation of no significant alterations in E‐cadherin or VIM levels. The zinc‐finger transcription factor Snail is upregulated in some solid malignancies, such as SCLC, and is associated with risks of metastasis and poor survival . Snail is involved in EMT by downregulating the levels of epithelial molecules, such as E‐cadherin, Occludin and Claudins .…”

Section: Discussionmentioning

confidence: 99%

DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail

et al. 2019

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Delta‐like protein 3 ( DLL 3) is a ligand of Notch signaling, which mediates cell‐fate decisions and is tumor‐suppressive or oncogenic depending on the cellular context. Previous studies show that DLL 3 is highly expressed in small cell lung cancer ( SCLC ) but not in normal lung tissue, suggesting that DLL 3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL 3 in tumorigenesis in SCLC , we performed loss‐of‐function and gain‐of‐function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL 3 knockdown reduced migration and invasion of SCLC cells, whereas DLL 3 overexpression increased these activities. In addition, DLL 3 positively regulated SNAI 1 expression and knockdown of SNAI 1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL 3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL 3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI 1/Snail.

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Snail promotes an invasive phenotype in lung carcinoma

Cited by 42 publications

References 23 publications

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Mechanisms of RhoGDI2 Mediated Lung Cancer Epithelial-Mesenchymal Transition Suppression

DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail

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