Zhong Yun PhD
Associate Professor of Therapeutic Radiology
Molecular and cancer biology; Stem cell biology, hypoxia; microRNA, tumor microenvironment; Obesity and metabolic syndromes
My lab focuses on two main areas of research with a goal to provide pertinent insights for the mechanistic understanding of human diseases. First, we are trying to understand the mechanisms by which stem cell maintenance and differentiation are regulated by environmental factors such as oxygen or by epigenetic mechanisms involving microRNAs. We are particularly interested in regulation of cancer stem cell functions. The second area of our research concerns the role of oxygen-sensing pathway in the regulation of energy homeostasis, in the pathological progression of obesity, and in obesity-associated metabolic syndromes including type 2 diabetes and cardiovascular diseases.
Extensive Research Description
Oxygen is essential to all aerobic life forms on earth. In addition to its role in energy
metabolism, oxygen has broad biological impact from embryogenesis to
adulthood. This notion is strongly
supported by the fact that mammalian embryos develop in a low oxygen or hypoxic
environment (approximately 3% O2 or less) during the first trimester. Furthermore, recent studies from us and
other laboratories have shown that oxygen can directly regulate the
differentiation of stem/precursor cells, and may participate in the maintenance
of stem cells in the stem cell niche.
Our overall research interest is to investigate the mechanisms by which tissue microenvironment, especially hypoxia, regulates the important biological processes including cellular differentiation, metabolism, tumor progression and tumor response to therapy. Our current focuses are (1) the role of hypoxia in the regulation of stem cell maintenance and differentiation, (2) the effects of hypoxia on cancer cell differentiation, malignant progression and response to therapy, (3) the role of HIF pathway in adipocytes and myocytes, especially in the regulation of energy homeostasis, and the pathogenesis of obesity and/or type 2 diabetes.
The oxygen-sensing pathway and regulation of cancer stem cell functions.
Nearly all of solid tumors contain areas of hypoxia. Tumor hypoxia is strongly correlated with advanced disease stage and poor clinical outcome. Increasing amounts of evidence suggest that hypoxic tumor cells tend to be poorly differentiated. We hypothesize that hypoxia inhibits cancer cell differentiation and thus arrests tumor cells in their undifferentiated state, which represents a novel approach to the understanding of tumor progression under hypoxic conditions. Poorly differentiated tumor cells are almost always more tumorigenic and more malignant than their more differentiated counterparts. The extensive proliferative potentials and long lifespan will allow the undifferentiated tumor cells to accumulate stable genetic and epigenetic changes that eventually confer the malignant phenotype. Therefore, hypoxia-mediated differentiation arrest of tumorigenic cells provides a platform that allows continuous accumulation and perpetuation of both genetic and epigenetic changes that result in tumor malignancy. Currently, we are using several tumor model systems to test this hypothesis. These studies will have the potentials to provide new approaches toward effective therapy for solid tumors, e.g. by specifically targeting the undifferentiated cancer stem cell population in the hypoxic regions.
The oxygen-sensing pathway and metabolism: Implications in obesity and diabetes.
Obesity has become a world wide epidemic and is associated with more than 30 human diseases including type 2 diabetes, cardiovascular disease, and cancer. Adipose tissue plays a critical role in the development of obesity and other metabolic syndromes. It has been shown that obesity results in adipose tissue hypoxia, suggesting that the oxygen-sensing pathway would play a key role in the pathological progression of obesity and its related diseases.
We were the first to investigate the mechanisms by which HIF-1 regulates the adipogenic differentiation. We have found that HIF-1 is both necessary and sufficient to inhibit the adipogenic differentiation of preadipocytes. Furthermore, hypoxia arrests preadipocytes in their stem/precursor state. We have generated a genetic mouse model to test the hypothesis that HIF plays an important role in the development and functions of adipose tissue, as well as in the pathogenesis of obesity and related metabolic syndromes including diabetes and cardiovascular diseases.