• Contact
  • Access
  • English
  • Japanese

HOME > Departments > Pathophysiology



Name Pathophysiology
Chairman 顔写真

Naoko Ohtani
Contact Phone:+81-6-6645-3711
Website http://www.rs.tus.ac.jp/ohtani-lab/ link
http://www.med.osaka-cu.ac.jp/physiol/ link

Over the past several decades, obesity has become more prevalent in most developed countries, and is increasingly recognized as a major risk factor for several common types of cancers. Although several events are proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Recently, we found that cellular senescence and senescence-associated secretory phenotype (SASP) have crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Therefore, we are currently focusing on the role and mechanisms of SASP in cancer development in an obesity-associated HCC mouse model in vivo. We found that myofibroblasts in the tumor microenvironment of obesity-associated liver cancer showed tumor-promoting SASP. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut microbial metabolite known to cause DNA damage. The enterohepatic circulation of DCA produces the SASP phenotype in hepatic stellate cells (HSCs), which in turn secrete various inflammatory and tumor-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogens. Notably, blocking DCA production or reducing gut microbiota efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has a key role in obesity-associated HCC development. Moreover, signs of SASP were also observed in HSCs from HCC patients with non-alcoholic steatohepatitis (NASH), indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. We are continuing to conduct clinical studies on the relationship between gut microbial metabolites and human obesity-associated HCC.

We have been studying how cellular senescence, an irreversible arrest of cell proliferation is provoked by oncogenic impulses that cause DNA damage. Cellular senescence is thought to be a fail-safe mechanism preventing the proliferation of abnormal cells that might transform into cancer cells. Unlike apoptotic cells, senescent cells do not die immediately, and survive for a long time. Recently, it has been shown that senescent cells have the potential to secrete inflammatory cytokines, chemokines, matrix remodeling factors and growth factors. This phenotype of cellular senescence is called senescence-associated secretory phenotype (SASP) and is sometimes beneficial or deleterious depending on the biological context. We focus on the role of SASP in vivo.

As mentioned, senescent cells secrete inflammatory cytokines, chemokines, matrix remodeling factors and growth factors called SASP factors. However, the precise mechanisms of how a variety of SASP factors concurrently upregulate senescent cells are still unknown. We are currently conducting research to elucidate these mechanisms.


Acdemic Departments

Preventive Medicine and Environmental Health
Under construction(都市環境医学)
Exercise environmental physiology
Toneyama Institute for Tuberculosis Research
Immunology and Genomics(ゲノム免疫学)
Under construction(生体機能解析学)
Under construction(遺伝子制御学)
Vascular Medicine
Molecular Oncology and Therapeutics
Under construction(分子制御学)
Radiation Oncology
Under construction(診断病理・病理病態学)
Oral and Maxillofacial Surgery
Women’s Life Care Medicine
Pathophysiology of Gynecologic Oncology
Department of Medical Genetics
Under construction(上気道機能病態学)
Plastic and Reconstructive Surgery
Medical Quality and Safety Science
Medical Informatics