Faculty Profiles - HIRASAWA Akira

beta-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation

M. Villacorte, K. Suzuki, A. Hirasawa, Y. Ohkawa, M. Suyama, T. Maruyama, D. Aoki, Y. Ogino, S. Miyagawa, T. Terabayashi, Y. Tomooka, N. Nakagata, G. Yamada

ONCOGENE 32 ( 29 ) 3477 - 3482 2013.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The Wnt/beta-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated beta-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/beta-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of beta-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that beta-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that beta-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that beta-catenin regulates Foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation. Altogether, the augmented expression levels of beta-catenin and Foxa2 are essential features during the formation of endometrial hyperplasia.

DOI： 10.1038/onc.2012.376

beta-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation Reviewed

M. Villacorte, K. Suzuki, A. Hirasawa, Y. Ohkawa, M. Suyama, T. Maruyama, D. Aoki, Y. Ogino, S. Miyagawa, T. Terabayashi, Y. Tomooka, N. Nakagata, G. Yamada

ONCOGENE 32 ( 29 ) 3477 - 3482 2013.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

DOI： 10.1038/onc.2012.376

Experience of risk-reducing salpingo-oophorectomy for a BRCA1 mutation carrier and establishment of a system performing a preventive surgery for hereditary breast and ovarian cancer syndrome in Japan: our challenges for the future. International journal

Akira Hirasawa, Kenta Masuda, Tomoko Akahane, Tomohiko Tsuruta, Kouji Banno, Kazuya Makita, Nobuyuki Susumu, Hiromitsu Jinno, Yuko Kitagawa, Kokichi Sugano, Kenjiro Kosaki, Daisuke Aoki

Japanese journal of clinical oncology 43 ( 5 ) 515 - 9 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

BACKGROUND: Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan. METHODS: We developed the first system in Japan for performing risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008. RESULTS: The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan. CONCLUSIONS: Recent treatment guidelines for breast cancer in Japan recommended risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingo-oophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future.

DOI： 10.1093/jjco/hyt036

Experience of Risk-reducing Salpingo-oophorectomy for a BRCA1 Mutation Carrier and Establishment of a System Performing a Preventive Surgery for Hereditary Breast and Ovarian Cancer Syndrome in Japan: Our Challenges for the Future

Akira Hirasawa, Kenta Masuda, Tomoko Akahane, Tomohiko Tsuruta, Kouji Banno, Kazuya Makita, Nobuyuki Susumu, Hiromitsu Jinno, Yuko Kitagawa, Kokichi Sugano, Kenjiro Kosaki, Daisuke Aoki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 43 ( 5 ) 515 - 519 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan.
We developed the first system in Japan for performing risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008.
The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan.
Recent treatment guidelines for breast cancer in Japan recommended risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingo-oophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future.

DOI： 10.1093/jjco/hyt036

高用量黄体ホルモン療法後に妊娠に至った若年性子宮体癌および複雑型子宮内膜異型増殖症43例の妊娠予後と分娩後のサーベイランス Reviewed

山上亘, 進伸幸, 市川義一, 桑波田美智子, 野村弘行, 平沢晃, 峰岸一宏, 冨永英一郎, 宮越敬, 阪埜浩司, 青木大輔, 吉村泰典

日本産科婦人科学会雑誌 65 ( 2 ) 574 - 574 2013.2

The origin of stroma surrounding epithelial ovarian cancer cells. International journal

Tomoko Akahane, Akira Hirasawa, Hiroshi Tsuda, Fumio Kataoka, Sadako Nishimura, Hideo Tanaka, Eiichiro Tominaga, Hiroyuki Nomura, Tatsuyuki Chiyoda, Yoko Iguchi, Wataru Yamagami, Nobuyuki Susumu, Daisuke Aoki

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 32 ( 1 ) 26 - 30 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Cancer stroma is thought to play an important role in tumor behavior, including invasion or metastasis and response to therapy. Cancer stroma is generally thought either to be non-neoplastic cells, including tissue-marrow or bone-marrow-derived fibroblasts, or to originate in epithelial mesenchymal transition of cancer cells. In this study, we evaluated the status of the p53 gene in both the cancer cells and the cancer stroma in epithelial ovarian cancer (EOC) to elucidate the origin of the stroma. Samples from 16 EOC patients were included in this study. Tumor cells and adjacent nontumor stromal cells were microdissected and DNA was extracted separately. We analyzed p53 sequences (exons 5-8) of both cancer and stromal tissues in all cases. Furthermore, we examined p53 protein expression in all cases. Mutations in p53 were detected in 9 of the 16 EOCs: in 8 of these cases, the mutations were detected only in cancer cells. In 1 case, the same mutation (R248Q) was detected in both cancer and stromal tissues, and p53 protein expression was detected in both the cancer cells and the cancer stroma. Most cancer stroma in EOC is thought to originate from non-neoplastic cells, but some parts of the cancer stroma might originate from cancer cells.

DOI： 10.1097/PGP.0b013e3182518533

MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer. Reviewed International journal

Koichiro Saito, Koji Inagaki, Takahiro Kamimoto, Yoko Ito, Toshiaki Sugita, Satoko Nakajo, Akira Hirasawa, Arifumi Iwamaru, Takashi Ishikura, Hideki Hanaoka, Keisuke Okubo, Tokio Onozaki, Takeru Zama

PloS one 8 ( 8 ) e71480 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

BACKGROUND: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary. METHODOLOGY/PRINCIPAL FINDINGS: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model. CONCLUSIONS/SIGNIFICANCE: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

DOI： 10.1371/journal.pone.0071480

Establishment of a system for performing risk-reducing salpingo-oophorectomy for BRCA1 or BRCA2 mutation carriers in Japan: Our challenges for the future. Reviewed

Hirasawa A, Masuda K, Akahane T, Tsuruta T, Banno K, Makita K, Susumu N, Sugano K, Kosaki K, Aoki D

Jpn J Clin Oncol 43 ( 5 ) 515-519 2013

遺伝性乳癌・卵巣癌に対する婦人科の取り組み Invited

平沢晃, 青木大輔

化療ニュース 22 ( 2 ) 13 - 19 2013

子宮体がんとエストロゲン Invited Reviewed

進伸幸, 山上亘, 二宮委美, 桑波田美智子, 片岡史夫, 平沢晃, 阪埜浩司, 青木大輔

産婦人科の実際 62 ( 9 ) 1181 - 1187 2013

ホルモンによるがんの化学予防 Invited Reviewed

平沢晃, 鶴田智彦, 青木大輔

産科と婦人科 80 ( Sup ) 164 - 168 2013

遺伝性乳癌・卵巣癌女性への遺伝カウンセリング Invited Reviewed

平沢晃, 青木大輔

産科と婦人科 80 ( 11 ) 1465 - 1472 2013

当科健康維持外来患者からみためまいの現状 Invited

牧田和也, 橫田めぐみ, 堀場裕子, 平沢晃, 小川真里子, 弟子丸亮太, 柳本茂久, 高松潔, 青木大輔, 吉村泰典

日本女性医学学会雑誌 21 ( 1 ) 54 - 59 2013

子宮峡部癌の臨床病理学的特徴とLynch症候群との関連 Invited Reviewed

増田健太, 阪埜浩司, 矢野倉恵, 小林佑介, 辻浩介, 木須伊織, 植木有紗, 野村弘行, 平沢晃, 進伸幸, 青木大輔

家族性腫瘍 13 ( 1 ) 1 - 5 2013

Lobular endocervical glandular hyperplasia and peritoneal pigmentation associated with Peutz-Jeghers syndrome due to a germline mutation of STK11

A. Hirasawa, T. Akahane, T. Tsuruta, Y. Kobayashi, K. Masuda, K. Banno, T. Fujii, N. Susumu, T. Itsubo, K. Kameyama, K. Sugano, D. Aoki

ANNALS OF ONCOLOGY 23 ( 11 ) 2990 - 2992 2012.11

Relationship of lower uterine segment cancer with Lynch syndrome: a novel case with an hMLH1 germline mutation. Reviewed International journal

Kenta Masuda, Kouji Banno, Akira Hirasawa, Megumi Yanokura, Kosuke Tsuji, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Hiroyuki Nomura, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki

Oncology reports 28 ( 5 ) 1537 - 43 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) had cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

DOI： 10.3892/or.2012.2008

Relationship of lower uterine segment cancer with Lynch syndrome: A novel case with an hMLH1 germline mutation

Kenta Masuda, Kouji Banno, Akira Hirasawa, Megumi Yanokura, Kosuke Tsuji, Yusuke Kobayashi, Iori Kisu, Arisa Ueki, Hiroyuki Nomura, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki

ONCOLOGY REPORTS 28 ( 5 ) 1537 - 1543 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) :lad cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

DOI： 10.3892/or.2012.2008

Lobular endocervical glandular hyperplasia and peritoneal pigmentation associated with Peutz-Jeghers syndrome due to a germline mutation of STK11 Reviewed

A. Hirasawa, T. Akahane, T. Tsuruta, Y. Kobayashi, K. Masuda, K. Banno, T. Fujii, N. Susumu, T. Itsubo, K. Kameyama, K. Sugano, D. Aoki

ANNALS OF ONCOLOGY 23 ( 11 ) 2990 - 2992 2012.11

Blood-direct InvaderPlus® as a new method for genetic testing. International journal

Akira Hirasawa, Tomoko Akahane, Yusuke Tanigawara, Daisuke Aoki

Personalized medicine 9 ( 6 ) 657 - 663 2012.8

Language：English Publishing type：Research paper (scientific journal) Publisher：FUTURE MEDICINE LTD

AIM: This study compared the efficiency of Blood-direct InvaderPlus® with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. MATERIALS & METHODS: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. RESULTS: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A1*6, *27, *28, *60, VKORC1 -1639G>A, VKORC1 1173T>C and CYP2C9 *2 and *3 much faster than the conventional methods. CONCLUSION: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms.

DOI： 10.2217/pme.12.71