title: MicroRNA-4656 is a prognostic factor and tumor suppressor in human pancreatic cancer through a downstream target of TrkA.
abstract: BACKGROUND
  In the present study, we investigated the expression profile and functional mechanism of microRNA-4656 in human pancreatic cancer (PC).
  
  
  METHODS
  MiR-4656 expression in PC tumors was examined using a quantitative reverse transcriptase-polymerase chain reaction in 134 patients. Associations between tumorous miR-4656 expression and clinicopathological parameters of patients, as well as overall survival, were analyzed. MiR-4656 expression was also examined in PC in vitro cell lines. In Capan-1 and AsPC-1 PC cells, lentivirus-induced miR-4656 overexpression or downregulation was applied to investigate its functional regulations on PC in vitro proliferation and invasion, as well as in vivo transplant growth. The association of miR-4656 and its downstream target, the tropomyosin receptor kinase A (TrkA) gene, was investigated in both cell line and clinical pancreatic tumors. In miR-4656-overerxpressed PC cells, TrkA was overexpressed with the aim of investigating its role in miR-4656-induced functional regulation in PC.
  
  
  RESULTS
  MiR-4656 was downregulated in PC. Low tumorous miR-4656 expression was associated with a poor prognosis and overall survival of patients. MiR-4656 was also found to be downregulated in PC cell lines. MiR-4656 overexpression in Capan-1 and AsPC-1 cells significantly inhibited cancer proliferation and invasion in vitro, as well as explant growth in vivo, whereas miR-4656 downregulation had no effect on cancer development. The TrkA gene was directly bound by miR-4656, and reversely expressed in PC tumors as miR-4656. TrkA overexpression reversed the inhibitory effect of miR-4656-overexpression on PC proliferation and invasion.
  
  
  CONCLUSIONS
  MiR-4656 is expressed to a low extent and is a potential biomarker in PC. Overexpressing miR-4656 has tumor suppressive effects on PC development both in vitro and in vivo, likely through its downstream target of the TrkA gene.
authors.affiliation: Second Department of Surgical Oncology, People's Liberation Army General Hospital, Beijing, China.
authors.forename: Xianglong
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Hepatobiliary, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Lv
authors.affiliation: Second Department of Surgical Oncology, People's Liberation Army General Hospital, Beijing, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Second Department of Surgical Oncology, People's Liberation Army General Hospital, Beijing, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Second Department of Surgical Oncology, People's Liberation Army General Hospital, Beijing, China.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: Second Department of Surgical Oncology, People's Liberation Army General Hospital, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Second Department of Surgical Oncology, People's Liberation Army General Hospital, Beijing, China.
authors.forename: Minggen
authors.initials: M
authors.lastname: Hu
keywords: TrkA; biomarker; invasion; miR-4656; overall survival; pancreatic cancer; proliferation; transplant