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The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling.

ABSTRACT: Paired-box 6 (PAX6) is an important transcription factor required for the function of human neuroectodermal epithelial tissues. Previous studies have suggested that it is also expressed in several types of tumors and has an oncogenic role. However, little is known about its role in non-small cell lung cancer (NSCLC). Here, we found that PAX6 expression levels were upregulated in human lung cancer tissues and correlated with poor clinical outcomes. PAX6 overexpression significantly promoted NSCLC epithelial-to-mesenchymal transition (EMT) and metastasis, whereas its knockdown inhibited these processes. PAX6 is commonly correlated with EMT-mediated stem cell transformation, thereby inducing cisplatin resistance. Using the RT² Profiler PCR Array, we found that WNT5A, EGFR, and ZEB2 were differentially regulated in response to PAX6 modulation. In addition, PAX6 directly bound to the promoter region of ZEB2. ZEB2 knockdown significantly reduced the expression and function of PAX6. ZEB2 was upregulated upon PAX6 overexpression and downregulated upon PAX6 knockdown, whereas E-cadherin expression negatively correlated with PAX6 levels. Moreover, p-PI3K and p-AKT were significantly enhanced by PAX6, which was reversed by the addition of the PI3K-AKT inhibitor, LY294002. These data suggest that PAX6 can mediate E-cadherin downregulation through the PI3K/AKT signaling pathway by directly binding the promoter region of ZEB2, thereby mediating cell migration, stem cell transformation, and cisplatin resistance; and ultimately, affecting survival in NSCLC patients.

SUBMITTER: Wu DM

PROVIDER: S-EPMC6483988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:While phosphatidylethanolamine-binding protein 4 (PEBP4) is a key factor in the malignant proliferation and metastasis of tumor cells, the exact regulatory network governing its roles remains unclear. This study was designed to investigate the effect of PEBP4 on PI3K/Akt/mTOR pathway and explore its molecular network that governs the proliferation and metastasis of tumor cells. METHODS:After the recombinant plasmid pcDNA3.1-PEBP4 was constructed, the recombinant plasmid pcDNA3.1-PEBP4 and PEBP4-targeting siRNA were transfected into lung cancer HCC827 cell line. The expressions of PI3K/Akt/mTOR pathway components in HCC827 cells in each group were determined using Western blotting. In the HCC827 cells, the effect of PI3K pathway inhibitor LY294002 on the expressions of PI3K/Akt/mTOR pathway components under the effect of PEBP4 was determined using Western blotting, and the effects of LY294002 on the cell viability, proliferation, and migration capabilities under the overexpression of PEBP4 were determined using MTT method, flow cytometry, and Transwell migration assay. Furthermore, the effect of mTOR inhibitor rapamycin (RAPA) on the expressions of PI3K/Akt/mTOR pathway components under the effect of PEBP4 was determined using Western blotting, and the effects of RAPA on the cell viability, proliferation, and migration capabilities under the overexpression of PEBP4 were determined using MTT method, flow cytometry, and Transwell migration assay. RESULTS:As shown by Western blotting, the protein expressions of p-Akt and phosphorylated mTOR (p-mTOR) were significantly higher in the pcDNA3.1-PEBP4-transfected group than in the normal control group and PEBP4 siRNA group (P<0.05); furthermore, the protein expressions of p-Akt and p-mTOR significantly decreased in the PEBP4 targeting siRNA-transfected group (P<0.05). Treatment with LY294002 significantly inhibited the protein expressions of p-Akt and p-mTOR in HCC827 cells (P<0.05). In contrast, treatment with RAPA only significantly inhibited the protein expression of p-mTOR (P<0.05). As shown by MTT, flow cytometry, and Transwell migration assay, both LY294002 and RAPA could significantly lower the viability of HCC827 cells and inhibit their proliferation and invasion (P<0.05); meanwhile, they could reverse the effect of PEBP4 in promoting the proliferation and migration of HCC827 cells (P<0.05). CONCLUSIONS:The overexpression of PEBP4 increases the phosphorylation levels of Akt and mTOR in lung cancer cells. The PI3K/Akt/mTOR signaling axis may be a key molecular pathway via which PEBP4 promotes the proliferation and invasion of non-small cell lung cancer (NSCLC) cells; also, it may serve as a potential therapeutic target.

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The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling.

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