Hiroshi Harada, Ph.D., Professor
Malignant solid tumors contain hypoxic regions due to uncontrolled proliferation of cancer cells and insufficient formation of a vascular network. Accumulating evidence has suggested that hypoxia-inducible factor 1 (HIF-1) functions in not only cellular adaptive response to hypoxia but also malignant progression and chemo-/radio-resistance of cancer cells. However, gene networks responsible for the activation of HIF-1 have not yet been fully elucidated, which makes it difficult to develop novel therapeutic strategies for cancers. We aim at identifying novel HIF-1-related and hypoxia-dependent gene networks and utilizing them as rational targets for cancer therapies.
Research and EducationWe aim at elucidating molecular mechanisms behind malignant progression and chemo-/radio-resistance of cancer cells for the development of innovative strategies for cancer therapy. We are performing a genetic screening experiment to explore novel hypoxia-responsive gene networks underlying malignant progression of cancer cells and are analyzing not only mechanism of action but also functions of them. In addition, we are employing molecular imaging technologies to clarify the intratumoral localizations and dynamics of malignant cancer cells for refinement of precision chemo-/radio-therapy in the future.
Figure 1： Hypoxic tumor cells (green) distant from blood vessels (blue) are resistant to radiation-induced DNA damage (red).
Figure 2： HIF-1-mediated gene networks responsible for both adaptive responses to hypoxia and malignant progression of cancer cells.
- Goto Y, Zeng L, Yeom CJ, Zhu Y, Morinibu A, Shinomiya K, Kobayashi M, Hirota K, Itasaka S, Yoshimura M, Tanimoto K, Torii M, Sowa T, Menju T, Sonobe M, Kakeya H, Toi M, Date H, Hammond EM, Hiraoka M, *Harada H. UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α. Nature Communications. 6: 6153.2015.
- Zeng L, Morinibu A, Kobayashi M, Zhu Y, Wang X, Goto Y, Yeom CJ, Zhao T, Hirota K, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hammond EM, Hiraoka M, *Harada H. Aberrant IDH3alpha expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis. Oncogene. 34:4758-4766. 2015.
- Zhao T, Zhu Y, Morinibu A, Kobayashi M, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hiraoka M, *Harada H. HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs. Scientific Reports. 4:3793. 2014.
- Zhu Y, Zhao T, Itasaka S, Zeng L, Yeom CJ, Hirota K, Suzuki K, Morinibu A, Shinomiya K, Ou G, Yoshimura M, Hiraoka M, *Harada H. Involvement of decreased hypoxia-inducible factor 1 activity and resultant G1-S cell cycle transition in radioresistance of perinecrotic tumor cells. Oncogene. 32:2058-2068. 2013.
- *Harada H, Inoue M, Itasaka S, Hirota K, Morinibu A, Shinomiya K, Zeng L, Ou G, Zhu Y, Yoshimura M, McKenna WG, Muschel RJ, Hiraoka M. Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nature Communications. 3: 783. 2012.
LaboratoryProfessor： Hiroshi Harada, Ph.D.
Associate Professor： Junya Kobayashi, Ph.D.