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ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.

ABSTRACT: ING5 belongs to the Inhibitor of Growth (ING) candidate tumor suppressor family, whose functions have been involved in the regulation of chromatin remodeling, cell cycle progression, proliferation and apoptosis. Our previous study has shown that ING5 overexpression inhibits lung cancer aggressiveness via suppressing epithelial to mesenchymal transition (EMT). However, the mechanisms remain largely unknown. In the current study, by Phospho-Kinase array and western blot, we have defined significantly upregulated EGFR/PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways in ING5 knockdown A549 cells, which could be downregulated by ING5 overexpression. PI3K inhibitor ZSTK474 or STAT3 inhibitor Niclosamide not only abolished ING5 knockdown-promoted proliferation, colony formation, migration and invasion of lung cancer A549 cells, but also impaired ING5 knockdown-stimulated metastasis of cancer cells in mouse xenograft models with tail vein injection of A549 cells. Furthermore, treatment with ZSTK474 or Niclosamide decreased protein level of EGFR, p-Akt, IL-6 and p-STAT3, and reversed ING5 knockdown-promoted EMT, as indicated by downregulated expression of EMT marker E-cadherin, an epithelial marker, increased expression of N-cadherin, a mesenchymal marker, and EMT-related transcription factors including Snail, Slug, Smad3 and Twist. Taken together, these results demonstrate that loss of ING5 enhances aggressiveness of lung cancer cells by promoting EMT via activation of EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.

SUBMITTER: Liu XL

PROVIDER: S-EPMC5589578 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.

Liu Xin-Li XL Zhang Xu-Tao XT Meng Jin J Zhang Hong-Fei HF Zhao Yong Y Li Chen C Sun Yang Y Mei Qi-Bing QB Zhang Feng F Zhang Tao T

Oncotarget 20170421 33

ING5 belongs to the Inhibitor of Growth (ING) candidate tumor suppressor family, whose functions have been involved in the regulation of chromatin remodeling, cell cycle progression, proliferation and apoptosis. Our previous study has shown that ING5 overexpression inhibits lung cancer aggressiveness via suppressing epithelial to mesenchymal transition (EMT). However, the mechanisms remain largely unknown. In the current study, by Phospho-Kinase array and western blot, we have defined significan ...[more]

PMID: 28903339

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Project description:Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, and poor prognosis of HCC patients are still lacking. Methods: Immunohistochemistry (IHC) was performed on HCC tissues (n = 325), and the correlations between MST4 expression of the clinical HCC tissues, the clinicopathologic features, and survival were further evaluated. The effects of MST4 on HCC cell migratory and invasive properties in vitro were evaluated by Transwell and Boyden assays. The intrahepatic metastasis mouse model was established to evaluate the HCC metastasis in vivo. The PI3K inhibitor, LY294002, and a specific siRNA against Snail1 were used to investigate the roles of PI3K/AKT pathway and Snail1 in MST4-regulated EMT, migration, and invasion of HCC cells, respectively. Results: In this study, by comprehensively analyzing our clinical data, we discovered that low MST4 expression is highly associated with the advanced progression of HCC and serves as a prognostic biomarker for HCC patients of clinical-stage III-IV. Functional studies indicate that MST4 inactivation induces epithelial-to-mesenchymal transition (EMT) of HCC cells, promotes their migratory and invasive potential in vitro, and facilitates their intrahepatic metastasis in vivo, whereas MST4 overexpression exhibits the opposite phenotypes. Mechanistically, MST4 inactivation elevates the expression and nuclear translocation of Snail1, a key EMT transcription factor (EMT-TF), through the PI3K/AKT signaling pathway, thus inducing the EMT phenotype of HCC cells, and enhancing their invasive and metastatic potential. Moreover, a negative correlation between MST4 and p-AKT, Snail1, and Ki67 and a positive correlation between MST4 and E-cadherin were determined in clinical HCC samples. Conclusions: Our findings indicate that MST4 suppresses EMT, invasion, and metastasis of HCC cells by modulating the PI3K/AKT/Snail1 axis, suggesting that MST4 may be a potential prognostic biomarker for aggressive and metastatic HCC.

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ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.

Publications

ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.

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