title: Downregulation of Insulin-like growth factor binding protein 6 is associated with ACTH-secreting pituitary adenoma growth.
abstract: BACKGROUND
  Adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome, called Cushing disease, is caused by a corticotroph tumor of the pituitary gland. Insulin-like growth factor binding protein 6 (IGFBP6), which regulates insulin-like growth factor (IGF) activity and inhibits several IGF2-dependent cancer growths, plays a pivotal role in the tumorigenesis of malignancy, but its roles in ACTH-secreting pituitary adenomas remain unclear.
  
  
  OBJECTIVE
  To investigate IGFBP6 expression in ACTH-secreting pituitary adenomas, and its involvement in tumor growth.
  
  
  METHODS
  Sporadic ACTH-secreting pituitary adenomas specimens (n = 41) and adjacent non-tumorous pituitary tissues (n = 9) were collected by transphenoidal surgery. IGFBP6 expression was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and validated by Western blotting. Associations of IGFBP6 expression with maximum tumor diameter or Ki-67 labeling index were evaluated in ACTH-secreting pituitary adenomas.
  
  
  RESULTS
  IGFBP6 mRNA and protein expression were both decreased in ACTH-secreting pituitary adenomas, compared to adjacent non-tumorous pituitary tissues (P < 0.01). IGFBP6 expression was correlated inversely with maximum tumor diameter (Rho = -0.53, P < 0.0001) and Ki-67 levels (Rho = -0.52, P < 0.05). Moreover, IGFBP6 downregulation activated PI3 K-AKT-mTOR pathway in ACTH-secreting pituitary adenomas.
  
  
  CONCLUSIONS
  IGFBP6 attenuation in ACTH-secreting pituitary adenomas is associated with tumor growth, through activation of PI3K-AKT-mTOR pathway. The finding underlies IGFBP6 roles in Cushing disease and would potentially provide a novel target of medical therapies.
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
authors.forename: Yakun
authors.initials: Y
authors.lastname: Yang
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Sheng
authors.forename: Fengming
authors.initials: F
authors.lastname: Huang
authors.forename: Dechao
authors.initials: D
authors.lastname: Bu
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Yao
authors.forename: Congxin
authors.initials: C
authors.lastname: Dai
authors.forename: Bowen
authors.initials: B
authors.lastname: Sun
authors.forename: Jindong
authors.initials: J
authors.lastname: Zhu
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jiao
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Wei
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zhu
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Chengyu
authors.initials: C
authors.lastname: Jiang
authors.forename: Renzhi
authors.initials: R
authors.lastname: Wang
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000378:metabolism*; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000096:biosynthesis*; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D018976:Insulin-Like Growth Factor Binding Protein 6; D019394:Ki-67 Antigen; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases