title: Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma.
abstract: OBJECTIVE
  Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.
  
  
  METHODS
  The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation.In vitroexperiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis.
  
  
  RESULTS
  The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2,CRIM1,TXNIP,DPYSL2, andCRMP1) that may confer an oncologic effect afterHOXA11suppression were identified.
  
  
  CONCLUSIONS
  The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Young-Bem
authors.initials: YB
authors.lastname: Se
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ja Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yun-Sik
authors.initials: YS
authors.lastname: Dho
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jin Wook
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yong Hwy
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Hyun Goo
authors.initials: HG
authors.lastname: Woo
authors.affiliation: Department of Neurosurgery, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Se-Hyuk
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Korea University College of Medicine, Seoul, Korea.
authors.forename: Shin-Hyuk
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hak Jae
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seung Hong
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Il Han
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.|Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dong Gyu
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.|Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D011379:Prognosis; D034622:RNA Interference; D059467:Transcriptome
chemical_list: C484298:HOXA11 protein, human; D018398:Homeodomain Proteins
keywords: Glioblastoma; HOXA11; Homeobox genes; Treatment resistance