The Biological Significance of Hormone-Regulated Non-Coding Rnas

Our previous reports indicates that thyroid hormone (TH) suppresses cell proliferation through endoglin-mediated promotion of p21 stability or stimulates transforming growth factor β (TGFβ) overexpression. Thyroid hormone receptors (TRs) play a suppressor role by reducing pituitary tumor-transforming gene 1 (PTTG1) expression. Further, TH/TR enhances a suppressor gene-Dickkopf 4 (DKK4) expression. DKK4 expression and inhibits the Wnt signaling cascade leading to suppression of proliferation/migration of hepatocellular carcinoma (HCC) cells, thus supporting a tumor suppressor role of TR. Currently, we raised the question of whether TH mediated long non-coding RNAs to prevent the progression of HCC. Long non-coding RNAs (lncRNAs) regulate gene expression and are involved in many biological processes or in carcinogenesis. However, the mechanism/clinical significance of such regulation in HCC remain largely unknown. In the present study, we will identify and determine the biological significance of critical TH-regulated lncRNAs that may participate in the prevention of HCC progression. Six aims are proposed based on the clinical analysis and preliminary results. Aim 1: To identify/select the TH-regulated lncRNAs related to HCC proliferation and progression. To select the candidate lncRNAs correlated with HCC malignancy as well as suppressed by thyroid hormone, two datasets will be used. Aim 2: To determine the expression levels of TH-regulated lncRNAs in clinical specimens. The clinical significance of TH-regulated lncRNAs genes will be determined in HCC specimens. Aim 3: To study whether TH-regulated lncRNAs is associated with epithelial-mesenchymal transition. We will establish lncRNAs-overexpression or -depletion in HCC cell lines. The functions of these cells will be determined in vitro/in vivo. Aim 4: To study whether TH-regulated lncRNAs are associated with autophagy. Recent studies have suggested that T3 regulates lipid metabolism or tumor prevention via autophagy. Here we attempted to explore the roles of T3 triggered autophagy in tumor suppression. Aim 5: To identify the lncRNAs associated/interacted proteins. The role of lncRNAs genes in the biological significance of TH-mediated regulation is currently unknown. However, how lncRNAs affects downstream gene expression? This can be studied by its interaction proteins/genes. Aim 6: Identification of candidate lncRNAs-regulated genes by affymetrix microarray analysis. Affymetrix microarray profiling will be performed using lncRNA-depletion or overexpression cells. Significance of the proposal: 1) To offer an opportunity to identify TH regulated lncRNAs in liver cancer and 2) To provide fundamental knowledge to explore the biological roles of lncRNAs in liver cancer. 3) To unravel TH-regulated lncRNAs. Finally, the molecular mechanisms of the action or therapeutic potential of lncRNAs in liver carcinogenesis and cancer progression can be established.

Project ID:PC10907-0939
External Project ID:MOST109-2320-B182-011