What Is the Role of Thyroid Hormone Receptors during Oncogenesis?

Recently, Hassan et al. reported a significantly elevated risk for the association between hypothyroidism and hepatocellular carcinoma (HCC) in women, which was independent of established HCC risk factors. Additionally, hypothyroidism and low-normal free T4 are related with an increased risk of breast cancer in postmenopausal women. Martínez-Iglesias also reported that hypothyroidism enhances tumor invasiveness and the development of metastasis. These data indicate that thyroid hormone receptors (TRs) may play a tumor-suppressor role in normal physiological conditions. TRs possibly lose their suppressor function in the hypothyroidism condition (without T3), thus inducing cancer. In contrast, in the WNT-activated condition, TR1 plays a tumor promoter role in the intestine. Therefore, questions arise pertaining to the role of TRs during tumorigenesis and the nature of the underlying mechanism. We propose five specific aims to test our hypothesis. Specific Aim 1: To determine the role of TRs, an oligo microarray will be analyzed to identify genes that are downregulated in HCC tissues, but stimulated by T3 in HCC cell lines. Alternatively, oncogenes that are upregulated in HCC tissues and suppressed by T3 will be selected for study. The TR target genes will be divided into two groups based on their function, i.e., oncogenes or suppressor genes. We hypothesize that, in the absence of T3 (hypothyroidism), TR loses its suppressor function and induces cancer. However, in normal physiological conditions, wild-type TRs play a suppressor role by inhibiting oncogene expression and stimulating suppressor genes. Specific Aim 2: Characterization of the regulation mechanism of target genes that are regulated by T3 in hepatoma cells. Specific Aim 3: (A) Functional study of the role of TRs in HCC cells. We will establish TR-overexpressing or TR-knockdown HCC cell lines. The function (tumorigenic, proliferative, or invasive) of these cells will be determined. (B) Functional study of the role of TR target genes in tumor cells. If we confirm that genes are regulated by TRs, the function of these genes will be studied using an overexpression or knockdown strategy to determine their role in HCC cells. Specific Aim 4: To determine the expression levels of TR target genes in clinical specimens. The clinical significance of TRs or TR target genes will be determined in hepatoma specimens. The data will be analyzed statistically to determine the role of TRs or TR target genes in these cells. Specific Aim 5: Establishment of a transgenic mouse model to confirm the suppressor role of TRs. Finally, a transgenic mouse carrying the hepatitis B virus X (HBX) gene with various T3 conditions will be established, to elucidate the critical role of TR during carcinogenesis.

Project ID:PC10008-0590
External Project ID:NSC100-2320-B182-029-MY3