title: Pim-1 kinase is a target of miR-486-5p and eukaryotic translation initiation factor 4E, and plays a critical role in lung cancer.
abstract: BACKGROUND
  Pim-1 kinase is a proto-oncogene and its dysregulation contributes to tumorigenesis and progression of a variety of malignancies. Pim-1 was suggested as a therapeutic target of cancers. The functional relevance of Pim-1 and the mechanism underlying its dysregulation in lung tumorigenesis remained unclear. This study aimed to investigate if Pim-1 has important functions in non-small-cell lung cancer (NSCLC) by: 1) evaluating the clinicopathologic significance of Pim-1 through analysing its expression in 101 human NSCLCs tissues using quantitative PCR, Western Blot and immunohistochemical studies, 2) determining its role in NSCLC and drug resistance using in vitro assays, and 3) investigating the regulatory mechanism of Pim-1 dysregulation in lung tumorigenesis.
  
  
  RESULTS
  Pim-1 was upregulated in 66.2% of the lung tumor tissues and its expression was significantly related to advanced stage (P = 0.019) and lymph node metastasis (P = 0.026). Reduced Pim-1 expression suppressed NSCLC cell growth, cell cycle progression and migration in vitro. Pim-1 was a novel target of miR-486-5p determined by luciferase report assay, and ectopic miR-486-5p expression in cancer cells reduced Pim-1 expression. Furthermore, eukaryotic translation initiation factor 4E (eIF4E) controlled the synthesis of Pim-1 in NSCLC cells, and its expression was positively associated with that of Pim-1 in NSCLC tissue specimens (r = 0.504, p < 0.001). The downregulated miR-486-5p and upregulated eIF4E in NSCLC cells led to the overexpression of Pim-1 by relieving the inhibitory effect of the 3'-UTR or 5'-UTR of Pim-1 mRNA, respectively. Moreover, Pim-1 knockdown sensitized NSCLC cells to cisplatin and EGFR tyrosine kinase inhibitor, gefitinib.
  
  
  CONCLUSIONS
  Pim-1 kinase could be a critical survival signaling factor in NSCLC, and regulated by miR-486-5p and eIF4E. Pim-1 kinase may provide a potential target for diagnosis and treatment for lung cancer.
authors.forename: Wenshuai
authors.initials: W
authors.lastname: Pang
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.forename: Fan
authors.initials: F
authors.lastname: Bai
authors.forename: Ruiyu
authors.initials: R
authors.lastname: Han
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Haitao
authors.initials: H
authors.lastname: Shen
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
authors.forename: Yueping
authors.initials: Y
authors.lastname: Liu
authors.forename: Xia
authors.initials: X
authors.lastname: Yan
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China. xinglingxiao@hotmail.com.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xing
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D014176:Protein Biosynthesis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C000715470:MAS1 protein, human; C560945:MIRN486 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D051573:Proto-Oncogene Proteins c-pim-1; D002945:Cisplatin; D000077156:Gefitinib