PMID- 22719055
OWN - NLM
STAT- MEDLINE
DCOM- 20121001
LR  - 20120723
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 153
IP  - 8
DP  - 2012 Aug
TI  - Suppression of hydatidiform molar growth by inhibiting endogenous brain-derived 
      neurotrophic factor/tyrosine kinase B signaling.
PG  - 3972-81
LID - 10.1210/en.2012-1167 [doi]
AB  - Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) receptor 
      signaling promotes trophoblast growth in normal and abnormal pregnancy. It also 
      regulates the growth of malignant trophoblastic, choriocarcinoma cells. However, 
      possible involvement of this signaling system in hydatidiform mole, another major 
      gestational trophoblastic disease, has not been determined. Here, we found the 
      expression of BDNF in syncytiotrophoblasts and its receptor, TrkB, in 
      cytotrophoblasts of hydatidiform mole using real-time RT-PCR and immunoassays. In 
      molar explant cultures, treatment with soluble TrkB ectodomain or a Trk receptor 
      inhibitor K252a inhibited trophoblast outgrowth as well as decreased 
      cytotrophoblast proliferation and cellular viability based on histopathological 
      analyses and glucose metabolism monitoring. These inhibitors also increased 
      apoptosis and caspase-3/7 activities. In an in vivo model of hydatidiform molar 
      growth based on xenotransplantation of molar tissues into kidney capsules of SCID 
      mice, treatment with K252a suppressed molar growth as reflected by decreased 
      trophoblast proliferation and their invasion into mouse kidney, reduced tissue 
      levels of chorionic gonadotropin-beta, and increased apoptosis. Based on PCR array 
      analyses to identify changes in expression profiles of cell cycle- and 
      apoptosis-related genes in cultured molar explants, suppression of endogenous 
      TrkB signaling led to decreases in key cell cycle-stimulatory and checkpoint 
      genes together with the down-regulation of different antiapoptotic genes. Our 
      findings demonstrate the importance of paracrine signaling by the BDNF/TrkB 
      system in the proliferation and survival of molar trophoblasts. Inhibition of 
      BDNF/TrkB signaling could provide a novel medical treatment for hydatidiform 
      mole.
FAU - Kawamura, Kazuhiro
AU  - Kawamura K
AD  - Department of Obstetrics and Gynecology, Akita University Graduate School of 
      Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. kawamura@yf7.so-net.ne.jp
FAU - Kawamura, Nanami
AU  - Kawamura N
FAU - Kawagoe, Yuta
AU  - Kawagoe Y
FAU - Kumagai, Jin
AU  - Kumagai J
FAU - Fujimoto, Toshio
AU  - Fujimoto T
FAU - Terada, Yukihiro
AU  - Terada Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120619
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Carbazoles)
RN  - 0 (Indole Alkaloids)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0 (neurotrophin 4(5) receptor)
RN  - 97161-97-2 (staurosporine aglycone)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/genetics/*metabolism
MH  - Carbazoles/therapeutic use
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Humans
MH  - Hydatidiform Mole/drug therapy/*metabolism
MH  - Indole Alkaloids/therapeutic use
MH  - Mice
MH  - Mice, SCID
MH  - Pregnancy
MH  - Receptor, trkB/antagonists & inhibitors/genetics/*metabolism
MH  - Receptors, Nerve Growth Factor/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2012/06/22 06:00
MHDA- 2012/10/02 06:00
CRDT- 2012/06/22 06:00
PHST- 2012/06/22 06:00 [entrez]
PHST- 2012/06/22 06:00 [pubmed]
PHST- 2012/10/02 06:00 [medline]
AID - en.2012-1167 [pii]
AID - 10.1210/en.2012-1167 [doi]
PST - ppublish
SO  - Endocrinology. 2012 Aug;153(8):3972-81. doi: 10.1210/en.2012-1167. Epub 2012 Jun 
      19.