Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation.
Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf(+/-) mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-beta signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.
Kitisin
K
K
Department of Surgical Sciences, School of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Ganesan
N
N
Tang
Y
Y
Jogunoori
W
W
Volpe
E A
EA
Kim
S S
SS
Katuri
V
V
Kallakury
B
B
Pishvaian
M
M
Albanese
C
C
Mendelson
J
J
Zasloff
M
M
Rashid
A
A
Fishbein
T
T
Evans
S R T
SR
Sidawy
A
A
Reddy
E P
EP
Mishra
B
B
Johnson
L B
LB
Shetty
K
K
Mishra
L
L
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D056741:Cyclin D; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013049:Spectrin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
D002352:Carrier Proteins; D056741:Cyclin D; D016213:Cyclins; D008840:Microfilament Proteins; D018125:Receptors, Transforming Growth Factor beta; D013049:Spectrin; D053781:Transforming Growth Factor beta2; D025521:Tumor Suppressor Proteins