The RNA-binding protein RBM47 inhibits non-small cell lung carcinoma metastasis through modulation of AXIN1 mRNA stability and Wnt/β-catentin signaling

Abstract The phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human cancers, including non-small cell lung carcinoma. The PI3-K/Akt pathway is negatively regulated by the dual-specificity phosphatase and tensin homolog (PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies have shown that PTEN phosphatase activity is inhibited by PREX2, a guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an RNA binding protein, cooperates synergistically with PTEN as a tumor suppressor in multiple cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation, PTEN phosphatase activity is upregulated with CELF2 overexpression. In addition, overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. In an ex vivo study, CELF2 gene delivery could significantly inhibit patient-derived xenografts (PDX) tumor growth. To further investigate the clinical relevance of this finding, we analyzed 87 paired clinical lung adenocarcinoma samples and the results showed that CELF2 protein expression is downregulated in tumor tissues and associated with poor prognosis. The CELF2 gene is located on the chromosome 10p arm, a region frequently lost in human cancers, including breast invasive carcinoma, low-grade glioma and glioblastoma. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in all these cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.

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Small cell lung carcinoma metastasis to palatine tonsils

Brazilian Journal of Otorhinolaryngology ◽

10.5935/1808-8694.20130117 ◽

2013 ◽

Vol 79 (5) ◽

pp. 645 ◽

Cited By ~ 4

Author(s):

Helena Hotz Arroyo ◽

Jefferson Takehara ◽

Allex Itar Ogawa ◽

Ronaldo Frizzarini ◽

Rui Imamura ◽

...

Keyword(s):

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Palatine Tonsils ◽

Carcinoma Metastasis

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The crosstalk between p38 and Akt signaling pathways orchestrates EMT by regulating SATB2 expression in NSCLC cells

Tumor Biology ◽

10.1177/1010428317706212 ◽

2017 ◽

Vol 39 (9) ◽

pp. 101042831770621 ◽

Cited By ~ 4

Author(s):

Hakan Kucuksayan ◽

Hakan Akca

Keyword(s):

Lung Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Binding Protein ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Carcinoma Cells ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Mesenchymal Transition ◽

Lung Carcinoma Cells

Epithelial–mesenchymal transition is a crucial event for metastasis and could be mediated by several pathways such as phosphoinositide 3-kinase/Akt, mitogen-activated protein kinases, as well as many epigenetic regulators. Special AT-rich sequence-binding protein 2 is an epigenetic regulator involved in epithelial–mesenchymal transition and osteoblastic differentiation. It has been reported that the crosstalk between several pathways is responsible for the regulation of epithelial–mesenchymal transition in cancer cells. However, crosstalks between p38 and Akt pathways involved in epithelial–mesenchymal transition are still unknown. We recently reported that there is a crosstalk between p38 and Akt pathways in non-small-cell lung carcinoma cells, and this crosstalk is associated with E-cadherin and special AT-rich sequence-binding protein 2 expressions. Therefore, we aimed to determine whether this crosstalk has a mediator role in the regulation of epithelial–mesenchymal transition in non-small-cell lung carcinoma. Our results showed that inhibition of p38 leads to the disruption of this crosstalk via decreased expression of phosphatase and tensin homolog (PTEN) and subsequently increased activation of Akt in non-small-cell lung carcinoma cells. Then, we found that p38 inhibition upregulated special AT-rich sequence-binding protein 2 expression and reversed epithelial–mesenchymal transition in non-small-cell lung carcinoma cells. Furthermore, special AT-rich sequence-binding protein 2 knockdown abolished the effect of p38 inhibition on epithelial–mesenchymal transition in non-small-cell lung carcinoma cells. In conclusion, our results strongly indicate that the crosstalk between p38 and Akt pathways can determine special AT-rich sequence-binding protein 2 expression and epithelial character of non-small-cell lung carcinoma cells, and special AT-rich sequence-binding protein 2 is a critical epigenetic regulator for epithelial–mesenchymal transition mediated by p38 pathway in non-small-cell lung carcinoma. Our findings will contribute to illuminate the molecular mechanisms of the epithelial–mesenchymal transition process that has a critical significance for lung cancer metastasis.

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