Shioko Kimura, Ph.D.
- Center for Cancer Research
- National Cancer Institute
- Building 37, Room 3112B
- Bethesda, MD 20892
Dr. Kimura’s research focuses on understanding the role of homeodomain transcription factor NKX2-1, a marker for lung adenocarcinoma in humans, and its downstream target, a novel cytokine, secretoglobin (SCGB) 3A2, in development, homeostasis, physiology, and pathogenesis of diseases, particularly cancers of the thyroid and lung. Dr. Kimura uses cell culture and mouse models, and various genetically engineered mouse lines to investigate these problems. Her recent studies have suggested that SCGB3A2 has anti-cancer activity, and her group is currently extensively involved in uncovering the mechanism.
Areas of Expertise
1) NKX2-1, 2) SCGB3A2, 3) thyroid and lung carcinogenesis, 4) mouse model, 5) genetically engineered mice
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.
Secretoglobin superfamily protein SCGB3A2 deficiency potentiates ovalbumin-induced allergic pulmonary inflammation
Shioko Kimura, Ph.D.
Dr. Kimura obtained her Ph.D. in chemistry at Hokkaido University, Sapporo, Japan. After postdoctoral studies at Queen's University, Kingston, Ontario and the National Institute of Child Health and Human Development as a visiting fellow, she moved to the Laboratory of Molecular Carcinogenesis, NCI. Since 1996, she has been head of the Endocrinology Section, Laboratory of Metabolism.
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Co-expression of Achaete-Scute Homologue-I and Calcitonin Gene-Related Peptide during NNK-Induced Pulmonary Neuroendocrine Hyperplasia and Carcinogenesis in Hamsters
Cover: Co-expression of Achaete-Scute Homologue-I and Calcitonin Gene-Related Peptide during NNK-Induced Pulmonary Neuroendocrine Hyperplasia and Carcinogenesis in Hamsters
Abstract: Achaete-scute homologue-1 or ASCL1 (MASH1, hASH1) plays roles in neural development and pulmonary neuroendocrine (NE) differentiation, and it is expressed in certain lung cancers. This study was aimed to assess whether and/or how ASCL1 plays a role in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced pulmonary NE hyperplasia and carcinogenesis in hamsters. Hamsters were injected 3 times weekly with either NNK or solvent alone (control) for treatment periods of 6 and 24 weeks, both without and with 6-week recovery. Immunohistochemical analysis was carried out to examine the expressions of ASCL1, CGRP (calcitonin gene-related peptide), secretoglobin SCGB1A1 (club [Clara] cell specific 10 kD protein, CC10, CCSP), synaptophysin (SYP), and PCNA (proliferating cell nuclear antigen). The number of ASCL1-expressing NE foci per airway increased from 0.8 in controls to 1.6 and 2.0 during NNK exposure for 6 and 24 weeks, respectively, and the number of cells per foci doubled after NNK exposure. Most ASCL1-expressing cells in NEBs (neuroepithelial bodies) were also CGRP immunoreactive; NNK enhanced this co-expression with CGRP, a NE marker with known proliferation-promoting properties. NNK also increased PCNA expression within NE foci. NNK-induced tumors showed no immunoreactivity for NE markers. This study confirms ASCL1 as an excellent marker for pulmonary NE cells and demonstrates CGRP co-expression in ASCL1-positive NEB cells participating in NNK-induced NE hyperplasia.
Co-expression of Achaete-Scute Homologue-1 and Calcitonin Gene-Related Peptide during NNK-Induced Pulmonary Neuroendocrine Hyperplasia and Carcinogenesis in
Hamsters. Naizhen X, Linnoila RI, Kimura S. J Cancer. 7(14): 2124-2131, 2016.