Abstract: The Impact of Thyroid Hormone Receptor Mutations on the Development of Hepatocellular Carcinoma

The thyroid hormone receptor (TR) is a nuclear receptor that is essential for the proper regulation of metabolism and development as it regulates gene expression. The amino acid sequence of TR contains nuclear localization signals (NLSs) and nuclear export signals (NESs) that allow for TR transport into and out of the nucleus, respectively. Previous research has shown that nuclear import, nuclear retention, and nuclear export of TR is associated with modulation of gene expression, the alteration of which can lead to various diseases, including Resistance to Thyroid Hormone (RTH) Syndrome, type II diabetes mellitus, and several types of cancer.

Since the summer of 2016, I have been examining a TR mutant that consists of four changes in its amino acid sequence (S40T, K136R, L251P, V390A) that were observed in a patient with hepatocellular carcinoma, and are associated with NLSs and NESs of TRa1. While wild-type TR has a primarily nuclear localization with a smooth distribution in human cells grown in culture, the experiments that I have conducted revealed that the mutant TR is localized throughout the cell often as aggregates. Such distribution of this mutant TR appears to be similar to the distribution of caveolin-1, a protein that is associated with tumor suppression. Observing fluorescently-tagged mutant TR and caveolin-1 by fluorescence microscopy has shown that they may be colocalized. I will work to confirm colocalization of the mutant TR and caveolin-1 through confocal microscopy to improve understanding of the impact of TR mislocalization on the development of hepatocellular carcinoma. This improved understanding could lead to novel strategies for discovering therapies for TR-related illnesses.