Graduate School of Medicine „ Human Science
„ Obstetrics and Gynecology

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Professor: Tanri Shiozawa, MD, PhD.
Associate Professor: Akiko Horiuchi, MD, PhD. Tsutomu Miyamoto, MD, PhD.
Assistant Professor: Kenji Oka, MD. Satoshi Ohira, MD. Hiroyasu Kashima, MD, PhD. Norihiko Kikuchi, MD, PhD. Akihisa Suzuki, MD. Ryota Tachibana, MD.

Summary of Activity
The main thesis of our research group is to clarify the molecular mechanisms of tumorigenetic, as well as metastatic process of endometrial and ovarian carcinomas. Based on these findings, we are searching new molecular targets for the treatment of gynecologic malignancies.


Research Projects

  1. Impaired mismatch repair (MMR) is reportedly crucial in the early stages of endometrial carcinogenesis. Estrogen exposure is considered an important risk factor for endometrial carcinoma, however, the relationship between estrogen and mismatch repair (MMR) activity remains undetermined. Therefore, we investigated the effect of estrogen on MMR activity in normal and malignant endometrial cells. E2 induced MMR activity in endometrial cells, which is suggesting that high estrogen levels act as an intrinsic defense against endometrial carcinogenesis.
  2. We have investigated the growth-regulatory mechanism through the cell-cycle related molecules in normal endometrium and endometrial cancer. Among the cell-cycle related molecules, cyclin A is poor prognostic factor of endometrial cancer patients. Therefore, we examined the effect of cyclin A2 on the development of resistance to chemotherapeutic drugs. Our results indicate cyclin A2 involved in the acquisition of aggressive behavior of tumor cells through the activation of PI3K by cyclin A2-induced periplakin, and to be a promising therapeutic target.
  3. Epithelial ovarian carcinomas progress mainly via disseminated metastasis into the peritoneal cavity, and more than half of the patients are diagnosed at the advanced stage of disease. Since the tumor cells detach from the primary lesion and become independent of the blood supply during the peritoneal dissemination, the hypoxic environment is considered important in ovarian cancer progression. We have investigated the effect of hypoxia on angiogenesis, proliferation, adhesion and invasiveness of ovarian carcinoma cells. From the data gathered, we propose the hypothesis that the ability of ovarian cancer cells to survive under hypoxia may involve changing the expression of hypoxia-inducible factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), E-cadherin and cell cycle-related molecules. These findings suggest that hypoxia plays an important role in the functional transformation of ovarian cancer cells into the gmetastatic phenotypeh
Selected References

1. Hayashi A, Horiuchi A, Kikuchi N, Hayashi T, Fuseya C, Suzuki A, Konishi I, Shiozawa T. (2010) Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin. Int J Cancer 127: 1332-1346.

2. Fakhry H, Miyamoto T, Kashima H, Suzuki A, Ke H, Konishi I, Shiozawa T. (2010) Immunohistochemical detection of histone deacetylases in endometrial carcinoma: involvement of histone deacetylase 2 in the proliferation of endometrial carcinoma cells. Hum Pathol 41: 848-858.

3. Suzuki A, Horiuchi A, Ashida T, Miyamoto T, Kashima H, Nikaido T, Konishi I, Shiozawa T. (2009) Cyclin A2 confers cisplatin resistance to endometrial carcinoma cells via up-regulation of an Akt-binding protein, periplakin. J Cell Mol Med. 2009 Jul 6.

4. Kashima H, Shiozawa T, Miyamoto T, Suzuki A, Uchikawa J, Kurai M, Konishi I. (2009) Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E. Endocr Relat Cancer 16:113-22.

5. Miyamoto T, Shiozawa T, Kashima H, Feng YZ, Suzuki A, Kurai M, Nikaido T, Konishi I. (2006) Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells. Endocrinology 147:4863-70.

6. Horiuchi A, Kikuchi N, Osada R, Wang C, Hayashi A, Nikaido T, Konishi I. (2008) Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer. Cancer Sci. 99:2532-9.

7. Osada R, Horiuchi A, Kikuchi N, Yoshida J, Hayashi A, Ota M, Katsuyama Y, Melillo G, Konishi I. (2007) Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel-Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma. Hum Pathol. 38:1310-20.

8. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T, Konishi I. (2003) Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol. 163:1437-47.