title: Up-regulation of NEK2 by microRNA-128 methylation is associated with poor prognosis in colorectal cancer.
abstract: BACKGROUND
  NIMA-related kinase 2 (NEK2), an enzyme involved in the development and progression of cancer, is abnormally expressed in a wide variety of human cancers, including colorectal cancer (CRC), and is known to have roles in cell division and mitotic regulation through centrosome splitting. We investigated the clinical significance of NEK2 in CRC. In particular, we examined miR-128 expression, which is thought to target NEK2.
  
  
  METHODS
  We measured NEK2 mRNA and miR-128 levels in clinical samples by quantitative reverse transcription real-time PCR and analyzed the associations between NEK2 levels, miR-128 levels, clinicopathological factors, and prognoses. Furthermore, we performed in vitro assays using a pre-miR-128 precursor and conducted miR-128 methylation analyses.
  
  
  RESULTS
  MiR-128 inhibited NEK2 expression and cancer cell proliferation via cell cycle arrest. Moreover, miR-128 was silenced by DNA methylation. Increased NEK2 expression was associated with serosal invasion, lymphatic invasion, and peritoneal dissemination. Patients with high NEK2 expression also had significantly poorer prognoses. Multivariate analysis indicated that high NEK2 expression was an independent prognostic factor for survival. Patients with high miR-128 expression had significantly lower NEK2 expression and lower recurrence rates than those with low miR-128 expression.
  
  
  CONCLUSIONS
  NEK2 may be an independent prognostic factor for CRC and was regulated by miR-128, a microRNA that was subjected to epigenetic regulation. Thus, this miR-128/NEK2 pathway may be a prospective therapeutic target for patients with CRC.
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, Beppu, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwaya
authors.forename: Genta
authors.initials: G
authors.lastname: Sawada
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.forename: Tae
authors.initials: T
authors.lastname: Matsumura
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Uchi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueo
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takano
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.forename: Tomoya
authors.initials: T
authors.lastname: Sudo
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D000072379:NIMA-Related Kinases; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases