VCU Philips Institute of Oral and Craniofacial Molecular Biology

Image of Hiroshi Miyazaki, M.D., Ph.D.

Hiroshi Miyazaki, M.D., Ph.D.

  • Assistant Professor of Oral and Craniofacial Molecular Biology

Office Location: Wood Building, Room 424
P.O. Box: 980566
Phone: (804) 827-1766
Fax: (804) 828-0150
E-mail: hmiyazaki@vcu.edu

Research Interests

Head and neck cancer comprises malignancies of the head and neck region, including the nasal cavity, sinuses, lips, mouth, salivary glands, pharynx and/or larynx. Generally more than 90% of these tumors arise in the squamous mucosal epithelium and, therefore, are referred to as squamous cell carcinomas (HNSCC). The 5-year survival rate when the cancer remains localized may be as high as 81%, but when it spreads (metastasizes) to distant sites, patient survival decreases dramatically to around 16%. Current treatments can be harsh and may impair the patient's quality of life. Thus, we need to address the early detection of cancer, improve treatment outcomes and design new therapies. To achieve this, we believe detection and prevention of metastasis in early stage is the best approach to seek. In this regard, my laboratory is pursuing two themes: metastasis and the role of chemokines.

Metastasis

Metastasis is the uncontrolled spreading of cancer cells from their primary origin to a distant location(s). In order for the cancer cells to undergo metastasis they must undergo a series of biological changes induced by atypical molecular expression profiles. First, they must migrate from the primary site, invade the lymphatic or circulatory system, transport through the vessels, attach to the inner wall of the vessel and exit the vessel at the secondary site. Finally, the cells must acquire the ability to survive at the distant site and establish metastatic tumor deposits. To accomplish this, the cancer cells must alter their own biological characteristics by modifying their gene expression profiles through a process known as epithelial-to-mesenchymal transition (EMT). Work from our laboratory and others has documented alteration of molecular signals involved in EMT in metastatic cells compared to primary tumor cells. We are currently dissecting the molecular mechanisms responsible for EMT and their contribution to oral cancer metastasis.

Chemokines

Chemokines are key regulators of cell migration and have been shown to be involved in tumor progression, serving as chemoattractants that enhance cell movement, as well as shaping the tumor microenvironment, and ensuring survival and proliferation of metastasized cells. Chemokines transduce their signals through G-protein coupled receptors (GPCRs). It has been shown by others that specific chemokine receptor expression is responsible for directing organ specific metastasis of tumor cells. Thus, it is suggested that receptors present on the surface of migratory cancer cells enable targeting to ligands secreted by cells at the site of metastasis. So far, there are around 50 human chemokines and 20 chemokine receptors characterized. It is well recognized that the family of ELR(+) CXC chemokines plays a critical role in enhancing the tumor blood supply, by acting as chemoattractants for vascular endothelial cells and thereby promoting angiogenesis. The binding of chemokines to chemokine receptors sequentially induces activation of a number of intracellular signaling pathways, including Akt, Erk1/2 and NFκB, eventually leading to transcription of specific target genes whose protein products are involved in regulating cell survival, proliferation and cell cycle progression (Fig. 1). However, these signaling pathways are complex and are often cell dependent. Our laboratory is currently exploring pathways activated by chemokine signaling and associated alterations in gene expression.

Fig. 1. Schematic representation of signaling pathways activated by binding of chemokine ligands to their "seven transmembrane" G-protein coupled receptors.

Funded Research

  • A.D. Williams Award: Role of ELR+CXC chemokine CXCL5 in tumor development

Selected Publications

  1. Wang H, Patel V, Miyazaki H, Gutkind JS, Yeudall WA. Role for EPS8 in squamous carcinogenesis. Carcinogenesis. 2009 30:165-74.
  2. Paccione RJ, Miyazaki H, Patel V, Waseem A, Gutkind JS, Zehner ZE, Yeudall WA.Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility. Mol Cancer Ther. 2008 7:2894-903.
  3. Christofakis EP, Miyazaki H, Rubink DS, Yeudall WA. Roles of CXCL8 in squamous cell carcinoma proliferation and migration. Oral Oncol. 2008 44:920-6.
  4. Yeudall WA, Miyazaki H. Chemokines and squamous cancer of the head and neck: targets for therapeutic intervention? Expert Rev Anticancer Ther. 2007 7:351-60.
  5. Kehat I, Heinrich R, Ben-Izhak O, Miyazaki H, Gutkind JS, Aronheim A. Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation. Cardiovasc Res. 2006 70:543-54.
  6. Fukumoto S, Miner JH, Ida H, Fukumoto E, Yuasa K, Miyazaki H, Hoffman MP, Yamada Y. Laminin alpha 5 is required for dental epithelium growth and polarity and the development of tooth bud and shape. J Biol Chem. 2006 281:5008-16.
  7. He J, Miyazaki H, Anaya C, Yu F, Yeudall WA, Lewis JP. Role of Porphyromonas gingivalis FeoB2 in metal uptake and oxidative stress protection. Infect Immun. 2006 74:4214-23.
  8. Miyazaki H, Patel V, Wang H, Edmunds RK, Gutkind JS, Yeudall WA. Down-regulation of CXCL5 inhibits squamous carcinogenesis. Cancer Res. 2006 66:4279-84.
  9. Miyazaki H, Patel V, Wang H, Ensley JF, Gutkind JS, Yeudall WA. Growth factor-sensitive molecular targets identified in primary and metastatic head and neck squamous cell carcinoma using microarray analysis. Oral Oncol. 2006 42:240-56.
  10. Yeudall WA, Miyazaki H, Ensley JF, Cardinali M, Gutkind JS, Patel V. Uncoupling of epidermal growth factor-dependent proliferation and invasion in a model of squamous carcinoma progression. Oral Oncol. 2005 41:698-708.
  11. Nishio M, Fukumoto S, Furukawa K, Ichimura A, Miyazaki H, Kusunoki S, Urano T, Furukawa K. Overexpressed GM1 suppresses nerve growth factor (NGF) signals by modulating the intracellular localization of NGF receptors and membrane fluidity in PC12 cells. J Biol Chem. 2004 279:33368-78.
  12. Vazquez-Prado J, Miyazaki H, Castellone MD, Teramoto H, Gutkind JS. Chimeric G alpha i2/G alpha 13 proteins reveal the structural requirements for the binding and activation of the RGS-like (RGL)-containing Rho guanine nucleotide exchange factors (GEFs) by G alpha 13. J Biol Chem. 2004 279:54283-90.