title: Methylation status of insulin-like growth factor-binding protein 7 concurs with the malignance of oral tongue cancer.
abstract: BACKGROUND
  Aberrant insulin-like growth factor-binding protein 7 (IGFBP-7) expression has been found in various cancers such as prostate, breast, and colon. IGFBP-7 induced the apoptosis of tumor and potentially predicted the clinical outcome in some cancers is further demonstrated. This study investigates the causes and underlying mechanisms of aberrant IGFBP-7 expression in unravelling head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  A total of 47 oral tongue cancer patient samples were primarily analyzed for the methylation status in 5' region of IGFBP-7 by methylation-specific PCR (MS-PCR). Subsequently the invasion, overexpression, and knockdown of IGFBP-7 in the HNSCC A253 invasive subpopulation were employed to examine the effect of IGFBP-7. The epithelial-mesenchymal transition (EMT) marker genes and AKT/GSK3β/β-catenin signaling were further evaluated by Western blot for the understanding the role of aberrant IGFBP-7 expression and thereof putative mechanism.
  
  
  RESULTS
  EMT expressed in the invasive subpopulation of HNSCC cell lines (A253 and RPMI 2650) was contemporary with the down-regulation of IGFBP-7. After treatment with 5-AZA-2' deoxycytidine, the de-methylated CpG sites in the 5' region of IGFBP-7 were observed and IGFBP-7 mRNA expression was also restored. Accordingly, re-expression IGFBP-7 in invasive subpopulation of A253 could induce the mesenchymal-epithelial transition (MET) and concurrently inhibited the cell invasion. Moreover, IGFBP-7 methylation status of 47 oral tongue tumors showed a positive correlation to invasive depth of the tumor, loco-regional recurrence, and cancer sequence.
  
  
  CONCLUSIONS
  IGFBP-7 can alter EMT relative marker genes and suppress cell invasion in A253 cell through AKT/GSK3β/β-catenin signaling. The epigenetic control of IGFBP-7 in the invasion and metastasis of HNSCC was reported, suggesting that IGFBP-7 could be a prognostic factor for the probability of invasion and a therapeutic remedy.
authors.affiliation: Department of Life Science and the Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan. lhc.ndhu@gmail.com.|Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. lhc.ndhu@gmail.com.
authors.forename: Li-Hsuen
authors.initials: LH
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. dwliu5177@yahoo.com.tw.|School of Medicine, Tzu Chi University, Hualien, Taiwan. dwliu5177@yahoo.com.tw.
authors.forename: Dai-Wei
authors.initials: DW
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan. junn9liang@yahoo.com.tw.|Department of Biomedical Engineering, Ming Chuan University, Taoyuan, Taiwan. junn9liang@yahoo.com.tw.
authors.forename: Junn-Liang
authors.initials: JL
authors.lastname: Chang
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. cprong@ms3.hinet.net.|Department of Otolaryngology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. cprong@ms3.hinet.net.
authors.forename: Peir-Rong
authors.initials: PR
authors.lastname: Chen
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. ent.sleepy@msa.hinet.net.|Department of Otolaryngology, Buddhist Taichung Tzu Chi Hospital, Taichung, Taiwan. ent.sleepy@msa.hinet.net.
authors.forename: Lee-Ping
authors.initials: LP
authors.lastname: Hsu
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. doc31221@gmail.com.|Department of Radiation Oncology, Buddhist Dalin Tzu Chi Hospital, Chia-Yi, Taiwan. doc31221@gmail.com.
authors.forename: Hon-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. yufuchou@yahoo.com.tw.|Department of Otolaryngology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. yufuchou@yahoo.com.tw.
authors.forename: Yu-Fu
authors.initials: YF
authors.lastname: Chou
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. e430013@yahoo.com.tw.|Department of Otolaryngology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. e430013@yahoo.com.tw.
authors.forename: Chia-Fong
authors.initials: CF
authors.lastname: Lee
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. yangmiaochun@yahoo.com.tw.|Department of Otolaryngology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. yangmiaochun@yahoo.com.tw.
authors.forename: Miao-Chun
authors.initials: MC
authors.lastname: Yang
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. hatsuyuki2001@yahoo.com.tw.|Department of Otolaryngology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. hatsuyuki2001@yahoo.com.tw.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Wen
authors.affiliation: Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. hwl@tzuchi.com.tw.|School of Medicine, Tzu Chi University, Hualien, Taiwan. hwl@tzuchi.com.tw.
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Department of Life Science and the Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan. cfweng@mail.ndhu.edu.tw.
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Weng
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014062:Tongue Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D047368:Tumor Burden
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3