Different Effects of the Liver Mitogens Triiodo-Thyronine and Ciprofibrate on the Development of Rat Hepatocellular Carcinoma

Abstract

Previous work has shown that treatment with thyroid hormone (T3) decreased the incidence of rat hepatocellular carcinoma (HCC). The present study was designed to determine whether the inhibitory effect of T3 on HCC development was limited to early steps of the carcinogenetic process or, whether a similar effect could also be exerted by starting T3 treatment at later stages. Hepatic nodules were induced in Fischer rats by a single dose of DENA, followed by a 2-week exposure of the animals to 2-AAF and partial hepatectomy. Rats were then divided into 3 groups: group 1 was maintained on basal diet: group 2 was fed a diet containing 4 mg/kg T3 for a week, every month/7 months, starting 9 weeks after DENA administration: group 3 was exposed to cycles of T3 starting 8 months after initiation. Results demonstrate that inhibition of HCC development was essentially similar in rats exposed to T3 starting either 9 weeks or 8 months after initiation (50% inhibition compared to control rats). We have previously shown that T3-induced nodule regression and HCC inhibition occurred in spite of its mitogenic effect. Therefore, we next wished to determine whether a similar antitumoral effect could be exerted by other liver mitogens, such as peroxisome proliferators. Rats exposed to the initiation-promotion protocol described previously, were subjected to 11 cycles of a T3 or a ciprofibrate-supplemented diet, each cycle consisting of 7 days/month: the incidence of HCC and lung metastases was determined 13.5 months after initiation. Results showed that although treatment with T3 strongly inhibited HCC development (only 31% of T3+ rats showed HCC vs 91% of controls), rats given ciprofibrate developed the same number of HCC as T3-untreated rats. In conclusion, the results of this study showed that the anticarcinogenic effect of T3 is maintained also when treatment begins late in the process, and its antitumoral property appears to be specific and may not be shared by other liver mitogens.

Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway

“…38, 39, 40 Previous studies using the DEN-induced HCC animal model have suggested that T 3 serves as a hepatomitogenic factor to stimulate liver cell growth but without associated cell death, consequently leading to decreased preneoplastic hepatic lesions. 10, 11 However, in advanced HCC cells, the TH may exert a pro-survival function, causing chemotherapeutic drug resistance. The mitogenic effect of TH may promote malignant hepatic tumor progression or chemoresistance but requires further investigation.…”

“…In the diethylnitrosamine (DEN)-induced HCC animal model, 10, 11 T 3 has been identified as a potent inhibitor of HCC development, although significant associated mitogenic effects on hepatocytes are reported. Conversely, in chemotherapy-resistant populations of advanced HCC cells, TH/TR has been shown to promote tumor cell metastasis via upregulation of several extracellular matrix (ECM) proteases, such as matrix metalloproteinase (MMP)-2, -7 and -9.…”

Molecular Functions of Thyroid Hormones and Their Clinical Significance in Liver-Related Diseases

“…However, instead of promoting liver growth with a typical pattern of liver regeneration, T 3 has been reported to act as a hepatomitogenic factor to stimulate liver cell growth without associated cell loss/death. Moreover, experiments using the DEN-induced HCC animal model have shown that hepatocyte proliferation induced by T 3 is associated with a decrease in HCC development [119, 121, 122]. By contrast, T 3 not only reduced the size of hepatic preneoplastic nodules of rats suffering from HCC, it also suppressed aberrant cellular growth by controlling the expression of cell-cycle regulators, such as PTTG1, ppRb, CDK2, and cyclin E in hepatoma cell lines [24, 125, 160].…”

“…Moreover, T 3 acts as a mitogenic factor to induce hepatocyte proliferation without causing cell death; the resulting acceleration of proliferation rate is associated with anticancer effects, including nodule regression, in the carcinogen-induced HCC model [119–122]. A recent epidemiological study suggested that long-term hypothyroidism is associated with the incidence of HCC, independent of other HCC risk factors [123].…”

Hypothyroidism Enhances Tumor Invasiveness and Metastasis Development

“…On the other hand, it has been reported that hypothyroidism might be a possible risk factor for liver cancer in humans [31], and thyroid hormone administration also influences hepatocarcinoma progression in experimental animals. Thus, T3 treatment in rats, despite causing liver hyperplasia, induces a rapid regression of carcinogen-induced hepatic nodules and reduces the incidence of hepatocarcinoma and lung metastasis [32]–[34].…”