title: Epithelial-mesenchymal transition is necessary for acquired resistance to cisplatin and increases the metastatic potential of nasopharyngeal carcinoma cells.
abstract: Radiotherapy and adjuvant cisplatin (DDP) chemotherapy are standard approaches used in the treatment of nasopharyngeal carcinoma (NPC). However, resistance to chemotherapy has recently become more common, resulting in the failure of this combination therapy for NPC. The aim of the present study was to assess the cellular morphology, motility and molecular changes in DDP-resistant NPC cells in relation to epithelial-mesenchymal transition (EMT). CNE2 cells were continuously exposed to increasing doses of DDP to establish a stable cell line resistant to DDP (CNE2/DDP cells). The human NPC cell lines, HNE1, CNE2, HNE1/DDP and CNE2/DDP, were used to examine the association between chemoresistance and the acquisition of an EMT-like phenotype of cancer cells. The DDP-resistant cells were less sensitive than the HNE1 cells to treatment with DDP, and were shown by a cell viability assay, western blot analysis and qRT-PCR to have acquired chemoresistance. The HNE1/DDP cells examined by wound healing and Transwell Boyden chamber assays exhibited an increased migration and invasion potential. The DDP-resistant cells exhibited morphological and molecular changes consistent with EMT, as observed by western blot analysis and qRT-PCR. These changes included becoming more spindle-like in shape, a loss of polarity and formation of pseudopodia, the downregulation of E-cadherin and β-catenin and the upregulation of vimentin, ﬁbronectin and matrix metalloproteinase (MMP)-9. Moreover, the levels of the EMT-related transcription factors, Snail, Slug, Twist and zinc finger E-box binding homeobox 1 (ZEB1), were higher in the DDP‑resistant NPC cells. These data suggest that the development of DDP resistance of NPC cells is accompanied by inducible EMT-like changes with an increased metastatic potential in vitro. Further elucidation of the association between resistance to DDP and EMT may facilitate the future development of novel therapeutic approaches for the treatment of chemoresistant tumors.
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Xia
authors.forename: Qian Wen
authors.initials: QW
authors.lastname: Zhang
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Zhen Hua
authors.initials: ZH
authors.lastname: Chao
authors.forename: Zhi Wen
authors.initials: ZW
authors.lastname: Jiang
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D009362:Neoplasm Metastasis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D005353:Fibronectins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D014746:Vimentin; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D002945:Cisplatin