title: Blocking PI3K/Akt signaling attenuates metastasis of nasopharyngeal carcinoma cells through induction of mesenchymal-epithelial reverting transition.
abstract: In the present study, we evaluated the role of phosphatidylinositol-3 OH kinase/protein kinase B (PI3K/Akt) signaling on changes to epithelial-to-mesenchymal reverting transition (EMrT) in nasopharyngeal carcinoma (NPC). Protein expression levels of p-Akt (Ser473), and the epithelial‑to-mesenchymal transition (EMT) markers E-cadherin, vimentin, α smooth muscle actin (α-SMA), were examined in clinical samples from 130 cases of undifferentiated non-keratinizing NPC, and 20 cases of benign nasopharyngitis. The relationship between protein expression levels and the statue of NPC lymph node metastasis was analyzed. The poorly‑differentiated NPC cell line CNE2Z was treated with various concentrations of the PI3K inhibitor, LY294002, and western blotting and quantitative polymerase chain reaction assays were used to analyze the activation of PI3K/Akt signaling and expression of E-cadherin, vimentin and α-SMA. The ability of cellular migration and invasion was assessed using Transwell assays. The in vivo effects of LY294002 on metastasis and expression of EMT markers in CNE2Z cells was evaluated using tumor xenograft experiments. The expression levels of p-Akt (Ser473) in NPC samples were higher than those in nasopharyngitis. There were reduced levels of membrane E-cadherin protein expression, and increased cytosol vimentin and α-SMA expression levels in NPC samples compared with those in nasopharyngitis samples. High expression levels of p-Akt (Ser473), vimentin, and α-SMA, and low expression levels of E-cadherin were positively associated with lymph node metastasis of NPC cells. Treating CNE2Z cells with LY294002 inhibited p-Akt (Ser473), vimentin and α-SMA expression but upregulated E-cadherin expression, leading to significantly attenuated cell invasion and migration. Administration of mice with LY294002 resulted in upregulation of membrane E-cadherin, and downregulation of vimentin and α-SMA in CNE2Z xenografts, with reduced pulmonary metastasis. Our findings suggest that inhibiting the PI3K/Akt pathway using LY294002 attenuated NPC metastasis via induction of EMrT.
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Hanguo
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Botao
authors.initials: B
authors.lastname: Luo
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Rujia
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Ranran
authors.initials: R
authors.lastname: Ding
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Ha
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Zhenliang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology, School of Basic Medicine Science, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jie
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage* / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014746:Vimentin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000199:Actins; D015820:Cadherins; D002867:Chromones; C549075:LY 290042; D009025:Morpholines; D014746:Vimentin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt