Androgen dependency of hepatocarcinogenesis in TGFalpha transgenic mice.
OBJECTIVE
Sex difference has been shown to play a major role in susceptibility to the development of hepatocellular carcinoma in humans and rodents. In order to clarify the necessity of androgens in hepatic tumorigenesis in transgenic mice overexpressing transforming growth factor (TGF) alpha (MT42), androgen supplement after castration and the LH-RH analogue, leuprolerin acetate, were tested in an experimental model in MT42.


METHODS
Male MT42 mice were castrated and supplemented with dihydrotestosterone (DHT) every three months up to 15 months and hepatic tumorigenesis was observed. Leuprolerin acetate was administered to both male and female MT42 mice once a month from 2 months after birth to 15 months to observe the effect on hepatic tumorigenesis. Northern hybridization was performed to detect messenger RNA (mRNA) of TGFalpha expression and the rate of proliferative cell nuclear antigen (PCNA) staining compared with the castrated and non-treated mice.


RESULTS
Castration tended to decrease both body and liver weight in MT42 mice which was then restored by DHT. Untreated MT42 males developed 11 liver tumors in 6 mice. Hormonal treatment including castration and DHT supplementation did not change the expression of TGFalpha-mRNA. Castrated transgenic mice developed 2 liver tumors in 2 out of 6 mice and DHT supplementation after castration restored the number of liver tumors to 9 in 5 of 6 mice. PCNA labelling indexes of liver tumors and adjacent non-tumorous-liver were 7.1% (p<0.05): 0.6% in untreated MT42, 3.2%: 0.2% in castrated MT42 and 10.1% (p<0.05): 0.5% in MT42 with castration and DHT supplementation (significant difference compared with castrated mice). Leuprolerin acetate-treated MT42 males developed one liver tumor in 6 mice compared to MT42 administered with saline as a vehicle control in which group 7 liver tumors in 6 male MT42 were observed. Tumors in castrated-MT42 and leuprolerin treated-MT42 were smaller than those in control MT42 mice.


CONCLUSIONS
TGFalpha related hepatocarcinogenesis and hepatocyte proliferation are increased by androgenic stimulation. Suppression of androgens may be useful for the treatment of TGFalpha related liver tumors.
Matsumoto
T
T
The First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Takagi
H
H
Mori
M
M
D000818:Animals; D015152:Blotting, Northern; D001835:Body Weight / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D013196:Dihydrotestosterone / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020249:Hormone Replacement Therapy; D016729:Leuprolide / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012727:Sex Characteristics; D013739:Testosterone / Q000097:blood; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D013196:Dihydrotestosterone; D013739:Testosterone; D016729:Leuprolide