Our research interest is to understand the mechanisms of differentiation, function and maintenance of homeostasis of the thyroid and lung, dysregulation of which results in various diseases, including cancer. We have been particularly interested in a homeodomain transcription factor NKX2-1, also called TTF1, TITF1 or T/EBP. NKX2-1 is expressed in the thyroid, lung, and ventral forebrain during early embryogenesis and plays a role in genesis of these organs. NKX2-1 regulates the expression of thyroid and lung-specific genes, and the proteins encoded by these genes are essential for the function and homeostasis of the thyroid and lung. Thus, NKX2-1 is considered as a master regulator in the thyroid and lung. In lung cancers, NKX2-1 acts as a lineage-specific oncogene in a subset of adenocarcinomas while in most cases, NKX2-1 plays a role in lineage-specific differentiation program. We have used NKX2-1 knockout and thyroid-specific conditional knockout mice to study the role of NKX2-1 in the thyroid. Based on results obtained using these mice, we currently focus on the following research aims to understand the role of NKX2-1 in the thyroid.

(1) Identification and characterization of thyroid stem/progenitor cells.
The studies with the mouse models suggested the presence of stem/progenitor cells in the thyroid, which has long been suggested, however, only recently has data supporting this notion emerged. Our main aim is to characterize stem/progenitor cells of mouse thyroid. In recent years, the cancer stem cell theory has attracted a great deal of attention, in which subset microcolonies of cancer cells having stem cell characteristics with tumor-initiating ability are thought to be the main culprits for cancer recurrence and metastasis. Our understanding of thyroid stem/progenitor cells is critical to better understand thyroid cancers and the involvement of thyroid stem cells in thyroid carcinogenesis. To this end, we use side population (SP) cells as a source for stem/progenitor cells that have the ability to efflux the vital dye Hoechst 33342 due to expression of the ABCG2 transporter, since no thyroid stem/progenitor cell-specific surface markers are known. Our studies demonstrated that thyroid SP cells possess stem/progenitor cell-like characteristics and that NKX2-1 may be involved in maintaining this population of cells. We employ various techniques to demonstrate that thyroid stem/progenitor cells are indeed present within the SP fraction of cells. These techniques include partial thyroidectomy, primary thyroid cell culture, and xenografting of cells to immunocompromised mice. The experiments are carried out using thyroids, thyroid cells, and/or thyroid tumor cells obtained from wild-type as well as Nkx2-1-thyroid-conditional knockout mice that are subjected to chemical carcinogenesis model. The latter mouse line is used to study the role of NKX2-1 in the maintenance of stem/progenitor cell populations, and in thyroid carcinogenesis.

(2) Characterization of SCGB3A2.
Another research project is to characterize a cytokine-like molecule, secretoglobin (SCGB) 3A2, formerly called uteroglobin-related protein (UGRP) 1. SCGB3A2 was originally identified as an NKX2-1 downstream target in lung using Nkx2-1 knockout mice. SCGB3A2 is highly expressed in the epithelial cells of the trachea, bronchus and bronchioles. SCGB3A2 exhibits anti-inflammatory function, growth factor activity responsible for fetal lung development, and anti-fibrotic activity. SCGB3A2 can also be a marker for lung carcinomas, particularly adenocarcinomas in humans. Our most recent findings demonstrate that SCGB3A2 possesses anti-cancer activity using Lewis lung carcinoma cells lung metastasis model. A Scgb3a2 knockout mouse line was produced in order to understand the mechanisms and/or additional roles for SCGB3A2 in lung and lung diseases, particularly lung cancer. Our research further focuses on the identification of a SCGB3A2 receptor and the associated signal transduction pathway that leads to various activities as described above.