Thyroid Hrmones Sppress Ras Oncogene Induced Hepatic Tumor Development

Objective: To investigate the effects of thyroid hormones on ras oncogene induced hepatic tumorigenesis and development.Methods:1.The liver tissues and serum samples of 3,5,7,9-month-age non-transgenic and H-ras12 V transgenic male mice were collected.The liver/body weight ratio and levels of total and free serum T3,T4 was detected.2.The liver tissues of 9-month-age non-transgenic male mice(Wt)and the tumor tissues(T)and peri-tumor tissues(P)of 9-month-age H-ras12 V transgenic male mice were collected.Pathological analysis was performed and total proteins and total RNAs were extracted.Application of Western blotting to detect the protein levels of cyclin D1?p-RXR??ERK and p-ERK in tissue samples.RT-q PCR was used to detect the m RNA levels of TBG,Dio1,cyclin D1 in tissue samples.3.36 SPF-grade 3-month-age transgenic male mice were randomly divided into control group,hyperthyroidism group(feeding thyroid tablets),and hypothyroidism group(feeding propylthiouracil tablets),12 each group,and treated for 4 months and sampled at 7-month-age.The levels of total serum T3,T4,liver / body weight ratio,number and size of liver tumors were detected.4.12 SPF-grade 9-month-age transgenic male mice were randomly divided into control group,ERK inhibition group,6 each group,and treated for 15 days by using PD184352.The tumor tissues(T)and peri-tumor tissues(P)of 9-month-age transgenic male mice were collected.Total proteins and total RNAs were extracted.Detection of inhibitors on the protein levels of cyclin D1 and p-RXR.Results:1.The liver / body weight ratio of 3,5,7,9-month-age transgenic male mice were gradually increased along with aging and significantly higher than that of age-matched non-transgenic male mice(P < 0.01).Serum ELISA detection results showed,compared to the non-transgenic male mice,levels of total serum T3,T4 of9-month-age transgenic male mice increased significantly(P < 0.01),but free serum T3,T4 levels had not significantly changed.2.RT-PCR test results showed,compared to the liver tissues of 9-month-age non-transgenic male mice and the peri-tumor tissues of transgenic male mice,the m RNA levels of TBG and cyclin D1 significantly increased in liver tumor tissues(P <0.05),the m RNA levels of Dio1 significantly decreased(P < 0.05).Western blot test results showed,compared to the liver tissues of non-transgenic male mice and the peri-tumor tissues of transgenic male mice,the protein levels of cyclin D1?p-RXR??ERK and p-ERK significantly increased in liver tumor tissues.3.Thyroid tablets(hyperthyroidism)and methimazole(hypothyroidism)processing experimental results show,compared to the control group,serum T3 and T4 levels in hyperthyroid group increased significantly(P < 0.05)and in hypothyroidism group decreased significantly(P < 0.05).Compared to the control group,the liver/body weight ratio and total number of liver tumors of hyperthyroid group decreased significantly(P < 0.05).Compared to control group and hypothyroidism group,the number of liver tumors more than 2 mm in hyperthyroid group significantly decreased(P < 0.05),but there was no significant difference in the number of liver tumors less than 2 mm.4.Inhibition experiments in vivo showed that the level of cyclin D1 and p-RXR?gradually decreased by using PD184352 in the tumor tissues of transgenic male mice,however,the peri-tumor tissues of the male mice were unchanged.Conclusions: Thyroid hormones have significant suppression effects on ras oncogene induced hepatic tumor development,but not tumorigenesis.ERK signaling pathway may be one of the important molecular mechanisms of Ras oncogene-induced liver cancer that regulating THs / TR signaling pathway.