Details of a Researcher - Chiyoda, Tatsuyuki

Papers - Chiyoda, Tatsuyuki

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Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

Nobusue Hiroyuki, Onishi Nobuyuki, Shimizu Takatsune, Sugihara Eiji, Oki Yoshinao, Sumikawa Yuko, Chiyoda Tatsuyuki, Akashi Koichi, Saya Hideyuki, Kano Koichiro

Nature Communications (NATURE PUBLISHING GROUP) 5 3368 2014

ISSN 2041-1723

Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by dynamics of the actin cytoskeleton. Here we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. Induction of adipocyte differentiation results in disruption of actin stress fibres through downregulation of RhoA-ROCK signalling. The consequent rapid increase in monomeric G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARγ followed by adipogenic differentiation. Moreover, we found that MKL1 and PPARγ act in a mutually antagonistic manner in the adipocytic differentiation programme. Our findings thus provide new mechanistic insight into the relation between the dynamics of cell shape and transcriptional regulation during cellular differentiation.

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Simultaneous analysis of the gene expression profiles of cancer and stromal cells in endometrial cancer

Iguchi Yoko, Ito Yoichi M., Kataoka Fumio, Nomura Hiroyuki, Tanaka Hideo, Chiyoda Tatsuyuki, Hashimoto Shiho, Nishimura Sadako, Takano Masashi, Yamagami Wataru, Susumu Nobuyuki, Aoki Daisuke, Tsuda Hiroshi

Genes Chromosomes and Cancer (WILEY-BLACKWELL) 53 ( 9 ) 725 - 737 2014

ISSN 1045-2257

To address the role of cancer-stroma interactions, we performed gene expression profiling of both cancer and stroma, using matching samples of endometrial cancer (EC), and analyzed the relationship between the gene expression pattern and prognosis in EC. Sixty EC cases were included in this study (38 nonrecurrent and 22 recurrent). Cancer and stroma were separated by performing laser capture microdissection, and microarray analysis was performed separately on cancer and stromal cells. Genes related with progression-free survival (PFS) in cancer and stroma were analyzed using the Cox regression model, and we established a formula, based on the gene expression pattern of cancer and stroma, to predict recurrence using logistic regression. We estimated the accuracy of the formula using the 0.632 method. All cases were classified based on the 79 selected genes of cancer and stroma related to PFS, based on unsupervised clustering. A total of 143 genes in cancer, and 79 genes in stroma were significantly related with PFS. The estimated area under the curve of receiver operating characteristics curve in cancer and stroma to predict recurrence were 0.800 and 0.758, respectively. Based on the 79 genes of cancer, the 22 recurrent cases were divided into two groups, which generally correlated with the histological grade. In contrast, based on the 79 genes of stroma, the 22 recurrent cases displayed homogeneous gene expression, unrelated to the histological grade. We conclude that gene expression profiles of cancer and stroma can predict the recurrence of EC and stromal that gene expression does not depend on the cancer grade.

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腹腔鏡を用いて子宮筋腫を核出した後に子宮肉腫を発症した2例

千代田達幸, 片岡史夫, 野村弘行, 有馬宏和, 橋本志歩, 桑波田美智子, 野上侑哉, 山上亘, 進伸幸, 吉村泰典, 青木大輔

日本産科婦人科内視鏡学会雑誌 ((一社)日本産科婦人科内視鏡学会) 29 ( Suppl.I ) 164 - 164 2013.08

ISSN 1884-9938

Gene scoring model to predict recurrence in low- and intermediate-risk uterine endometrial cancer: Establishment of uterine print

Tatsuyuki Chiyoda, Yoichi M. Ito, Fumio Kataoka, Wataru Yamagami, Hiroyuki Nomura, Hiroshi Tsuda, Hideo Tanaka, Masashi Takano, Sadako Nishimura, Yoko Iguchi, Shiho Hashimoto, Tomoko Yoshihama, Nobuyuki Susumu, Daisuke Aoki

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 31 ( 15 ) 1733 - 1739 2013.05

ISSN 0732-183X

卵巣成熟嚢胞性奇形腫の悪性転化を好中球/リンパ球比(N/L比)で予測できるか

澤野佳子, 千代田達幸, 片岡史夫, 野村弘行, 山上亘, 津田浩史, 井口蓉子, 橋本志歩, 冨永英一郎, 進伸幸, 吉村泰典, 青木大輔

関東連合産科婦人科学会誌 ((一社)関東連合産科婦人科学会) 50 ( 2 ) 334 - 334 2013.05

ISSN 2186-0610

The APC/C activator Cdh1 regulates the G2/M transition during differentiation of placental trophoblast stem cells

Naoe Hideaki, Chiyoda Tatsuyuki, Ishizawa Jo, Masuda Kenta, Saya Hideyuki, Kuninaka Shinji

Biochemical and Biophysical Research Communications 430 ( 2 ) 757 - 762 2013.01

ISSN 0006-291X

Differentiation of placental trophoblast stem (TS) cells to trophoblast giant (TG) cells is accompanied by transition from a mitotic cell cycle to an endocycle. Here, we report that Cdh1, a regulator of the anaphase-promoting complex/cyclosome (APC/C), negatively regulates mitotic entry upon the mitotic/endocycle transition. TS cells derived from homozygous Cdh1 gene-trapped (Cdh1^GT/GT) murine embryos accumulated mitotic cyclins and precociously entered mitosis after induction of TS cell differentiation, indicating that Cdh1 is required for the switch from mitosis to the endocycle. Furthermore, the Cdh1^GT/GT TS cells and placenta showed aberrant expression of placental differentiation markers. These data highlight an important role of Cdh1 in the G2/M transition during placental differentiation.

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The origin of stroma surrounding epithelial ovarian cancer cells

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

International Journal of Gynecological Pathology (LIPPINCOTT WILLIAMS & WILKINS) 32 ( 1 ) 26 - 30 2013.01

ISSN 0277-1691

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.

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LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression

Chiyoda Tatsuyuki, Sugiyama Naoyuki, Shimizu Takatsune, Naoe Hideaki, Kobayashi Yusuke, Ishizawa Jo, Arima Yoshimi, Tsuda Hiroshi, Ito Masaaki, Kaibuchi Kozo, Aoki Daisuke, Ishihama Yasushi, Saya Hideyuki, Kuninaka Shinji

Journal of Cell Biology (ROCKEFELLER UNIV PRESS) 197 ( 5 ) 625 - 641 2012.05

ISSN 0021-9525

In the mitotic exit network of budding yeast, Dbf2 kinase phosphorylates and regulates Cdc14 phosphatase. In contrast, no phosphatase substrates of LATS1/WARTS kinase, the mammalian equivalent of Dbf2, has been reported. To address this discrepancy, we performed phosphoproteomic screening using LATS1 kinase. Screening identified MYPT1 (myosin phosphatase- targeting subunit 1) as a new substrate for LATS1. LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1. An MYPT1 mutant (S445A) failed to dephosphorylate Thr 210 of PLK1 (pololike kinase 1), thereby activating PLK1. This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. Consistent with this, LATS1-depleted HeLa cells or fibroblasts from LATS1 knockout mice showed increased PLK1 activity. We also found deoxyribonucleic acid (DNA) damage-induced LATS1 activation caused PLK1 suppression via the phosphorylation of MYPT1 S445. Furthermore, LATS1 knockdown cells showed reduced G2 checkpoint arrest after DNA damage. These results indicate that LATS1 phosphorylates a phosphatase as does the yeast Dbf2 and demonstrate a novel role of LATS1 in controlling PLK1 at the G2 DNA damage checkpoint.

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Induction of ZEB proteins by inactivation of RB protein is key determinant of mesenchymal phenotype of breast cancer

Arima Yoshimi, Hayashi Hidemi, Sasaki Mikako, Hosonaga Mari, Goto Takaaki M., Chiyoda Tatsuyuki, Kuninaka Shinji, Shibata Tatsuhiro, Ohata Hirokazu, Nakagama Hitoshi, Taya Yoichi, Saya Hideyuki

Journal of Biological Chemistry (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC) 287 ( 11 ) 7896 - 7906 2012.03

ISSN 0021-9258

Wepreviously showed that depletion of the retinoblastoma protein (RB) induces down-regulation of the adhesion molecule E-cadherin and thereby triggers the epithelial-mesenchymal transition. To further characterize the effect of RB inactivation on the phenotype of cancer cells, we have now examined RB expression in human breast cancer cell lines and clinical specimens. We found that RB-inactive cells exhibit a mesenchymal-like morphology and are highly invasive. We also found that ZEB proteins, transcriptional repressors of the E-cadherin gene, are markedly up-regulated in these cells in a manner sensitive to the miR-200 family of microRNAs. Moreover, depletion of ZEB in RB-inactive cells suppressed cell invasiveness and proliferation and induced epithelial marker expression. These results implicate ZEB in induction of the epithelial-mesenchymal transition, as well as in maintenance of the mesenchymal phenotype in RB-inactive cells. We also developed a screening program for inhibitors of ZEB1 expression and thereby identified several cyclin-dependent kinase inhibitors that blocked both ZEB1 expression and RB phosphorylation. Together, our findings suggest that RB inactivation contributes to tumor progression not only through loss of cell cycle control but also through up-regulation of ZEB expression and induction of an invasive phenotype.

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EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy

Kataoka Fumio, Tsuda Hiroshi, Arao Tokuzo, Nishimura Sadako, Tanaka Hideo, Nomura Hiroyuki, Chiyoda Tatsuyuki, Hirasawa Akira, Akahane Tomoko, Nishio Hiroshi, Nishio Kazuto, Aoki Daisuke

Genes Chromosomes and Cancer (WILEY-BLACKWELL) 51 ( 3 ) 300 - 312 2012.03

ISSN 1045-2257

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and α-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC.

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Expression profiles of carcinosarcoma of the uterine corpus-are these similar to carcinoma or sarcoma?

Chiyoda Tatsuyuki, Tsuda Hiroshi, Tanaka Hideo, Kataoka Fumio, Nomura Hiroyuki, Nishimura Sadako, Takano Masashi, Susumu Nobuyuki, Saya Hideyuki, Aoki Daisuke

Genes Chromosomes and Cancer (WILEY-BLACKWELL) 51 ( 3 ) 229 - 239 2012.03

ISSN 1045-2257

Uterine carcinosarcoma (CS) is usually classified as uterine endometrial carcinoma (EC). However, CS is more aggressive even compared with high grade EC. CS is also reported to undergo epithelial to mesenchymal transition (EMT). In this study, we compared the gene expression profiles of CS, EC, and uterine sarcoma (US) and evaluated the role of EMT and chromosomal aberrations in CS tumor formation. Frozen tissues of 46 patients (14 CS, 24 EC, and 8 US) were included. The similarity was examined by Gene Set Enrichment Analysis (GSEA), Fisher's exact test, and clustering using "intrinsic gene set". We examined the expression of 39 EMT-related genes and evaluated TGF-beta signaling by phospho-SMAD2/3 (p-SMAD2/3) staining. Chromosomal regions differing between CS and EC were identified by chromosomal GSEA and comparative genomic hybridization (CGH) microarrays. Three statistical methods confirmed that CS resembled US rather than EC. Acquired markers of EMT were upregulated and attenuated markers of EMT were downregulated in CS. Immunohistochemistry showed that carcinomatous region of CS have higher expression of p-SMAD2/3 than EC (P = 0.008). Chromosomal GSEA showed that genes located at 19q13 had higher expression in CS. Furthermore, CGH microarray indicated that the TGFB1 locus at 19q13.1 was amplified in 4 of 7 samples. Based on the expression profile, CS resembles US rather than EC. TGF-beta signaling is activated in CS and chromosomal gains at 19q13, which includes the TGFB1 locus, suggest that this may contribute to high expression of TGF-beta and thereby EMT phenotype of CS.

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Role of circulating free Alu DNA in endometrial cancer

Tanaka Hideo, Tsuda Hiroshi, Nishimura Sadako, Nomura Hiroyuki, Kataoka Fumio, Chiyoda Tatsuyuki, Tanaka Kyoko, Iguchi Yoko, Susumu Nobuyuki, Aoki Daisuke

International Journal of Gynecological Cancer (LIPPINCOTT WILLIAMS & WILKINS) 22 ( 1 ) 82 - 86 2012.01

ISSN 1048-891X

Background: Endometrial cancer (EC) is the most common cancer of the female genital tract. However, no screening method for EC has been established yet. In this study, we evaluated the cell-free DNA in EC. Methods: Fifteen healthy individuals, 9 with benign gynecologic diseases, and 53 with ECs were included in this study. Alu sequences in free DNA fragments were used as surrogate markers, and cell-free DNA density was measured by quantitative real-time polymerase chain reaction. Results: The cell-free DNA levels in ECs tended to be higher than in benign condition (healthy individuals + benign gynecologic diseases, n = 24; P = 0.095). There was no significant difference in cell-free DNA among stage or histological grade of EC, and no significant change in cell-free DNA before and after operation (P = 0.25): Moreover, in 19 ECs, cell-free DNA decreased after operation, however, in 6 ECs, cell-free DNA did not decrease. Three ECs recurred, and cell-free DNA did not decrease in these cases. Conclusions: Measurement of cell-free DNA is not useful for EC screening; however, the change of cell-free DNA in a patient may be a prognostic biomarker of EC.

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Retrospective study comparing irinotecan and pegylated liposomal doxorubicin in treatment of recurrent platinum-refractory/resistant epithelial ovarian cancer

Nomura H., Tsuda H., Kataoka F., Chiyoda T., Yamagami W., Tominaga E., Susumu N., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 33 ( 1 ) 86 - 89 2012

ISSN 0392-2936

Purpose: The standard regimen for platinum-resistant/refractory recurrent epithelial ovarian cancer (EOC) remains to be determined. In this study, we retrospectively compared the effect of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in the treatment of platinum-resistant recurrent EOC. Methods: Thirty patients who received salvage chemotherapy with CPT-11 or PLD were included in the study. CPT-11 (100 mg/m ²) was administered intravenously on days 1, 8 and 15 every four weeks. PLD (50 mg/m ²) was administered on day 1 every four weeks. Treatment was repeated, provided that no disease progression or intolerable toxicity occurred. Results: Response rate in the CPT-11 group and PLD group showed no difference at 26.7% (p = 0.66) in both, while non-PD rate was 73.3% vs 33.3% (p < 0.05), respectively. Progression-free survival after CPT-11 treatment and PLD treatment was 28.4 weeks and 16.8 weeks (p = 0.07), respectively. Hand-foot syndrome and mucositis were more common in the PLD group than in the CPT-11 group (p < 0.05). Conclusions: The results indicate that CPT-11 is a promising drug for the treatment of platinum-resistant recurrent EOC.

Successfully treated case of epithelioid sarcoma of the vulva.

Chiyoda Tatsuyuki, Ishikawa Mitsuya, Nakamura Masaru, Ogawa Mariko, Takamatsu Kiyoshi

The journal of obstetrics and gynaecology research (WILEY-BLACKWELL) 37 ( 12 ) 1856 - 1859 2011.12

ISSN 1341-8076

Epithelioid sarcoma of the vulva is an extremely rare and aggressive tumor. This tumor most commonly occurs on the labia majora in women of reproductive age. The molecular pathogenesis remains largely unknown. Only 20 cases of vulvar epithelioid sarcoma have been reported to date and more than half have had poor outcomes. We report a successfully treated case of vulvar epithelioid sarcoma in a 33-year-old woman. We performed a radical vulvectomy with flap reconstruction. Three years after surgery, the patient remains well, showing no evidence of recurrence. Early tissue diagnosis of vulvar epithelioid sarcoma is essential because this tumor can be clinically misdiagnosed as a benign lesion. Gynecologists should be aware of this rare tumor variant and carefully plan the treatment.

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Establishment of a choriocarcinoma model from immortalized normal extravillous trophoblast cells transduced with HRASV12

Kobayashi Yusuke, Shimizu Takatsune, Naoe Hideaki, Ueki Arisa, Ishizawa Joe, Chiyoda Tatsuyuki, Onishi Nobuyuki, Sugihara Eiji, Nagano Osamu, Banno Kouji, Kuninaka Shinji, Aoki Daisuke, Saya Hideyuki

American Journal of Pathology 179 ( 3 ) 1471 - 1482 2011.09

ISSN 0002-9440

Gestational choriocarcinoma is a malignant trophoblastic tumor. The development of novel molecular-targeted therapies is needed to reduce the toxicity of current multiagent chemotherapy and to treat successfully the chemoresistant cases. The molecular mechanisms underlying choriocarcinoma tumorigenesis remain uncharacterized, however, and appropriate choriocarcinoma animal models have not yet been developed. In this study, we established a choriocarcinoma model by inoculating mice with induced-choriocarcinoma cell1 (iC ³-1) cells, generated from HTR8/SVneo human trophoblastic cells retrovirally transduced with activated H-RAS (HRASV12). The iC ³-1 cells exhibited constitutive activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and developed into lethal tumors in all inoculated mice. Histopathological analysis revealed that the tumors consisted of two distinct types of cells, reminiscent of syncytiotrophoblasts and cytotrophoblasts, as seen in the human choriocarcinoma. The tumors expressed HLA-G and cytokeratin (trophoblast markers) and hCG (a choriocarcinoma marker). Comparative analysis of gene expression profiles between iC ³-1 cells and parental HTR8/SVneo cells revealed that iC ³-1 cells expressed matrix metalloproteinases, epithelialmesenchymal transition-related genes, and SOX3 at higher levels than parental trophoblastic cells. Administration of SOX3-specific short-hairpin RNA decreased SOX3 expression and attenuated the tumorigenic activity of iC ³-1 cells, suggesting that SOX3 overexpression might be critically involved in the pathogenesis of choriocarcinoma. Our murine model represents a potent new tool for studying the pathogenesis and treatment of choriocarcinoma.

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The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress

Ishizawa Jo, Kuninaka Shinji, Sugihara Eiji, Naoe Hideaki, Kobayashi Yusuke, Chiyoda Tatsuyuki, Ueki Arisa, Araki Kimi, Yamamura Ken Ichi, Matsuzaki Yumi, Nakajima Hideaki, Ikeda Yasuo, Okamoto Shinichiro, Saya Hideyuki

Cancer Science (WILEY-BLACKWELL) 102 ( 5 ) 967 - 974 2011.05

ISSN 1347-9032

Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co-activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in adult hematopoiesis and showing a role of Cdh1 in a G2/M checkpoint regulation in vivo.

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Overexpression of cofilin 1 can predict progression-free survival in patients with epithelial ovarian cancer receiving standard therapy

Nishimura Sadako, Tsuda Hiroshi, Kataoka Fumio, Arao Tokuzo, Nomura Hiroyuki, Chiyoda Tatsuyuki, Susumu Nobuyuki, Nishio Kazuto, Aoki Daisuke

Human Pathology (W B SAUNDERS CO-ELSEVIER INC) 42 ( 4 ) 516 - 521 2011.04

ISSN 0046-8177

The aim of this study was to examine the relation between cofilin 1 expression and progression-free survival in advanced epithelial ovarian cancer. We performed quantitative reverse transcriptase polymerase chain reaction and immunohistochemical analysis in 78 patients with advanced epithelial ovarian cancer (excluding those with mucinous and clear-cell types). All patients received the standard therapy, including staging laparotomy and adjuvant chemotherapy consisting of carboplatin and paclitaxel. Of 78 samples, RNA from 62 samples was available for reverse transcriptase polymerase chain reaction analysis. We defined cofilin 1 high expression as relative gene expression equal to or higher than the median and low expression as gene expression lower than median. The progression-free survival was longer in cofilin 1 low-expression cases than in high-expression cases (P = .039). Multivariate analysis demonstrated that stage and cofilin 1 expression were significant predictors of progression-free survival. Of the 78 samples, 54 were appropriate for immunohistochemical study. In 35 of those 54 cases, cofilin 1 protein expression was detected. The progression-free survival was longer in cofilin 1 protein-negative cases than in protein-positive cases (P = .042). Expression of cofilin 1 may predict the progression-free survival of patients with advanced epithelial ovarian cancer receiving standard therapy.

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Expression of hypoxia-inducible 2 (HIG2) protein in uterine cancer

Nishimura S., Tsuda H., Nomura H., Kataoka F., Chiyoda T., Tanaka H., Tanaka K., Susumu N., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 32 ( 2 ) 146 - 149 2011

ISSN 0392-2936

For both cervical cancer (UCC) and endometrial cancer (EMC) there are no effective prognostic markers. In this study, we evaluated HIG2 protein expression in 332 uterine cancers (186 UCCs and 146 EMCs) and examined the relationship between HIG2 protein expression and clinical factors, including prognosis. Totally, HIG2 expression was detected in 58% of UCC and 66% of EMC. However, there was no significant relationship between HIG2 expression and age, clinical stage and histology in either UCC or EMC. In addition, HIG2 protein expression was not related to prognosis of UCC or EMC. The positivity rate of HIG2 protein was 56% and 61% in early-stage UCC and EMC, respectively and 67% in non-squamous cell carcinoma of UCC. The positivity rate of HIG2 protein was high even in early-stage UCC and EMC.

The chemosensitivity of nodal metastases in recurrent epithelial ovarian cancer

Kataoka F., Tsuda H., Nomura H., Chiyoda T., Tominaga E., Suzuki A., Susumu N., Aoki D.

European Journal of Gynaecological Oncology (I R O G CANADA, INC) 32 ( 2 ) 160 - 163 2011

ISSN 0392-2936

Purpose: In this study, we compared second-line chemotherapy effects of nodal metastases with other metastases sites. Methods: The medical records of 44 women with recurrent ovarian cancer who received second-line chemotherapy were retrospectively reviewed. Results: Median age at the time of second-line chemotherapy was 55 years (range: 31-74). Recurrent sites were as follows: 29 patients had a solitary site (abdominal cavity: 8; lymph node: 3; pelvic cavity: 10; liver: 4; lung: 4) and 15 patients had multiple sites In total, the response rate was 30% (CR: 8, PR: 5). The response rate in sensitive cases was higher than in refractory/resistant cases (50% vs 5% p = 0.002). However, age, chemotherapy regimen, histologic type and number of diseases were not related with chemotherapy effect. In all diseases, response rate tended to be higher in lymph node disease than in the others (44% vs 27%). In both sensitive and refractory/resistant cases, response rate tended to be higher in lymph node disease. Conclusion: The response rate for lymph node diseases tended to be relatively high. Further study analyzing survival will be required to conclude the chemotherapy effect.

The anaphase-promoting complex/cyclosome activator Cdh1 modulates Rho GTPase by targeting p190 RhoGAP for degradation

Naoe Hideaki, Araki Kimi, Nagano Osamu, Kobayashi Yusuke, Ishizawa Jo, Chiyoda Tatsuyuki, Shimizu Takatsune, Yamamura Ken Ichi, Sasaki Yutaka, Saya Hideyuki, Kuninaka Shinji

Molecular and Cellular Biology (AMER SOC MICROBIOLOGY) 30 ( 16 ) 3994 - 4005 2010.08

ISSN 0270-7306

Cdh1 is an activator of the anaphase-promoting complex/cyclosome and contributes to mitotic exit and G₁ maintenance by targeting cell cycle proteins for degradation. However, Cdh1 is expressed and active in postmitotic or quiescent cells, suggesting that it has functions other than cell cycle control. Here, we found that homozygous Cdh1 gene-trapped (Cdh1 ^GT/GT) mouse embryonic fibroblasts (MEFs) and Cdh1-depleted HeLa cells reduced stress fiber formation significantly. The GTP-bound active Rho protein was apparently decreased in the Cdh1-depleted cells. The p190 protein, a major GTPase-activating protein for Rho, accumulated both in Cdh1 ^GT/GT MEFs and in Cdh1-knockdown HeLa cells. Cdh1 formed a physical complex with p190 and stimulated the efficient ubiquitination of p190, both in in vitro and in vivo. The motility of Cdh1-depleted HeLa cells was impaired; however, codepletion of p190 rescued the migration activity of these cells. Moreover, Cdh1^GT/GT embryos exhibited phenotypes similar to those observed for Rho-associated kinase I and II knockout mice: eyelid closure delay and disruptive architecture with frequent thrombus formation in the placental labyrinth layer, respectively. Furthermore, the p190 protein accumulated in the Cdh1^GT/GT embryonic tissues. Our data revealed a novel function for Cdh1 as a regulator of Rho and provided insights into the role of Cdh1 in cell cytoskeleton organization and cell motility.

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