Our Science – Kimura Website
Shioko Kimura, Ph.D.
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.
(1-1) 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 is attracting a great deal of attention, in which subset microcolonies of cancer cells having stem cells 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 and/or thyroid cells obtained from wild-type as well as NKX2-1-heterozygous and thyroid-conditional knockout mice. The latter two mouse lines are used to study the role of NKX2-1 in the maintenance of stem/progenitor cell populations.
(1-2) Mouse model of thyroid cancer.
About 1/5 of NKX2-1-thyroid-conditional knockout mice develop spontaneous adenomas in their thyroids. When treated with a genotoxic mutagen, almost all of mice develop thyroid adenomas as compared to 0-8% in wild-type or NKX2-1 heterozygous mice. The results suggest a role for NKX2-1 in thyroid carcinogenesis. In order to prove this hypothesis, NKX2-1-conditional knockout mice were crossed with HrasG12V knock-in mice in which the oncogenic HrasG12V is activated upon follicular cell specific Cre expression using TPO-Cre mice (TPO: a follicular cell specific thyroid peroxidase promoter). The incidence of spontaneous adenomas increases in NKX2-1;HrasG12V mice is currently under investigation. We are also in the process of establishing a radiation-induced thyroid carcinogenesis model mouse.
(2-1) Another research project is to characterize secretoglobin (SCGB) 3A2, formerly called uteroglobin-related protein (UGRP) 1, and its homologue SCGB3A1, formerly called UGRP2. 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. Our recent studies demonstrated that SCGB3A2 is over-expressed in lung carcinomas, in particularly adenocarcinomas in humans. On the other hand, SCGB3A1 is a known tumor suppressor. In order to further understand the physiological roles of SCGB3A1 and SCGB3A2 in lung and/or lung diseases including lung cancer, we have produced a knockout mouse line for both genes. These knockout mice are being characterized to identify additional roles for SCGB3A1 and/or SCGB3A2 in lung. Our research further focuses on the identification of SCGB3A2 and/or SCGB3A1 receptors and associated signal transduction pathways that lead to various activities as described above.
This page was last updated on 11/26/2013.