Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model.
Tumor recurrence after liver transplantation still remains a significant problem in patients with hepatocellular carcinoma. The small GTPase Rho/Rho-associated kinase (ROCK) pathway is involved in the motility and invasiveness of cancer cells. We investigated whether tacrolimus activated the Rho/ROCK signal pathway to promote the invasiveness of rat hepatocellular carcinoma cells. We also investigated whether the ROCK inhibitor Y-27632 suppressed tumor recurrence after experimental liver transplantation in a rat hepatocellular carcinoma model. Orthotopic liver transplantation was performed in hepatocellular carcinoma cell line McA-RH7777-bearing rats. Tacrolimus was administered to liver transplant rats and these rats were divided into two groups: the Y-27632-treated (10 mg/kg, for 28 days) group and the Y-27632-untreated group. Tacrolimus enhanced the cancer cell migration and stimulated phosphorylation of the myosin light chain (MLC), a downstream effector of Rho/ROCK signaling. Y-27632 suppressed the cancer cell migration and tacrolimus-induced MLC phosphorylation. Suppression of tumor recurrence after liver transplantation and significant prolongation of survival were observed in the Y-27632-treated rats in comparison with theY-27632-untreated rats. Tacrolimus stimulates the Rho/ROCK signal pathway to enhance the invasiveness of hepatocellular carcinoma, and the ROCK inhibitor Y-27632 can be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.
Ogawa
T
T
Second Department of Surgery, Faculty of Medicine, Hirashima University, Hiroshima, Japan.
Tashiro
H
H
Miyata
Y
Y
Ushitora
Y
Y
Fudaba
Y
Y
Kobayashi
T
T
Arihiro
K
K
Okajima
M
M
Asahara
T
T
D000577:Amides / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology* / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000503:physiopathology* / Q000628:therapy; D016031:Liver Transplantation; D008297:Male; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009364:Neoplasm Recurrence, Local / Q000503:physiopathology / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011915:Rats, Inbred BUF; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D016559:Tacrolimus