Regulation of selection of liver nodules initiated with N‐nitrosodiethylamine and promoted with nodularin injections in Fischer 344 male rats by reciprocal expression of transforming growth factor‐β1 and its receptors

Abstract

To investigate how glutathione-S-transferase placental form (GST-P)+ hyperplastic nodules (HNs) are selected and to determine the driving force for progression or regression of HNs, changes in transforming growth factor-beta1 (TGF-beta) and its receptors were examined during hepatocarcinogenesis initiated by N-nitrosodiethylamine (DEN) and promoted by nodularin. The induction of TGF-beta1 expression in the GST-P+ HNs was dependent on nodularin injections for 10 wk, which started the third week after DEN initiation. The kinetics of TGF-beta1 induction during carcinogenesis were quite different from that of simple regeneration after partial hepatectomy (PH): hepatocytes initiated with DEN alone induced TGF-beta1 expression for 24 d, and subsequent stimulation by PH on the fourteenth day after DEN initiation super-induced TGF-beta1 mRNA (50 times that of the control level), as opposed to a transient expression for less than 5 d by PH alone. GST-P+ HNs did not express TGF-beta receptors I (RI) and II (RII) during the early stage of carcinogenesis, whereas the surrounding hepatocytes strongly expressed both of these receptors. On cessation of nodularin injection, however, the expression of RI and RII in the HNs changed significantly: RII+ nodules appeared, and the number and area of RII+/- nodules were significantly increased at 10 wk after the cessation. These findings indicate that induction of TGF-beta expression in GST-P+ HNs might be a strong selection pressure that allows outgrowth of RII- nodules during liver carcinogenesis.

Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

“…It is suggested that the cells are capable of ''successfully'' escaping from the TGFb1-induced apoptosis under a ''favorable'' signal such as PTN in this case. Such possibility has earlier been investigated in the chemically induced carcinogenesis in rat liver [21].…”

“…The level of TGFb1 in liver and serum is increased in the chemically induced liver cirrhosis and carcinogenesis in humans as well as rats [21]. Blocking of TGFb1 by TGFb1 type II receptor dominant negative or TGFb1 soluble antibodies inhibits the fibrosis in dimethylnitrosamine-induced liver fibrosis [19,36].…”

“…Blocking of TGFb1 by TGFb1 type II receptor dominant negative or TGFb1 soluble antibodies inhibits the fibrosis in dimethylnitrosamine-induced liver fibrosis [19,36]. Furthermore, the hepatocyte proliferation was enhanced in the absence of TGFb type II receptor in chemically induced hepatocarcinogenesis [21]. Several studies suggest that TGFb1 is a potent activator of hepatocyte apoptosis and the loss of TGFb1 signal activates hepatocyte proliferation and hepatocarcinogenesis.…”

“…The deregulation of apoptosis and the accelerated proliferate activity of hepatocytes have been reported as significant steps for hepatocarcinogenesis [20,21]. During hepatocarcinogenesis, some of the genetically altered hepatocytes progress to apoptosis and some escape from the apoptosis and undergo carcinogenesis [21]. TGFb1 is the most effective apoptotic cytokine during hepatocarcinogenesis [22].…”

“…TGFb1 generated the reactive oxygen species and induced apoptosis of Huh-7 cells and activates first caspase-8, -9, and finally -3 [23,24]. Furthermore, a study on ''the loss of TGFb receptor'' showed that the hepatocytes in diethylnitrosamine and nodularin-induced-hyperplastic liver nodules escaped from the TGFb1-induced apoptosis and continued to proliferate [21].…”