|Kiyoko Kato||Last modified date：2022.06.16|
Professor / Reproductive and Developmental Medicine / Department of Clinical Medicine / Faculty of Medical Sciences
|Kiyoko Kato||Last modified date：2022.06.16|
|1.||Onoyama I, Kato M, Kawakami M, Kodama K, Yagi H, Asanoma K, Kato K, Downregulation of 5-hydroxymethylcytosine is associated with the progression of cervical intraepithelial neoplasia, 第80回日本癌学会学術総会, 2021.10.|
|2.||Asanoma K, Yagi H, Onoyama I, Yoshida S, Kodama K, Tomonobe H, Yasutake N, Yasunaga M, Ohgami T, Okugawa K, Yahata H, Kato K, BHLHE40 regulates glycolysis and oxidative phosphorylation in endometrial cancer cells, 第73回日本産科婦人科学会学術講演会, 2021.04, ［Objective］Cancer cells are known to depend on glycolysis for energy production. However, regulatory mechanism of metabolism in cancer cells remains largely unknown. In this study, we examined regulation of glycolysis and oxidative phosphorylation（OXPHOS）by a tumor suppressive transcription factor, BHLHE40 in endometrial cancer cells. ［Methods］We used HHUA and KLE cells to knockdown BHLHE40；and HEC-1 and Ishikawa cells to overexpress BHLHE40 to examine their cellular glycolysis and OXPHOS using a flux analyzer. The expression and activity of AMP-activated protein kinase, AMPK；lactate dehydrogenase A subunit, LDHA；and pyruvate dehydrogenase E1 subunit alpha 1, PDHA1 were examined by antibodies to detect total and phosphorylated forms of each protein.
［Results］Knockdown of BHLHE40 in the cancer cells resulted in upregulation of glycolysis accompanied with phosphorylation of LDHA Tyr10（activative phosphorylation）, and downregulation of OXPHOS accompanied with phosphorylation of PDHA1 Ser293（inactivative phosphorylation）. Remarkable suppression of phosphorylation of AMPKA Thr172（activative phosphorylation）, but no change in AMPKB Ser182（activative phosphorylation）was observed. On the contrary, forced expression of BHLHE40 in the cancer cells exert the reverse effects.
［Conclusion］BHLHE40 is suggested to regulate the expression and activity of AMPK to control metabolic balance between glycolysis and OXPHOS in endometrial cancer cells. Understanding mechanism of energy production in cancer cells might lead to a new strategy to control development of endometrial cancer..
|3.||Onoyama I, Kato M, Kawakami M, Yoshida S, Kawamura K, Yagi H, Asanoma K, Yahata H, Kato K, Downregulation of 5-hydroxymethylcytosine is associated with the progression of cervical intraepithelial neoplasia, 第73回日本産科婦人科学会学術講演会, 2021.04, ［Objective］Aberrant DNA methylation contributes to carcinogenesis in various cancers. Although 5-methylcytosine（5mC）has been analyzed intensively, the function of 5-hydroxymethylcytosine（5hmC）has not been clarified. We investigated the significance of 5hmC as a molecular biomarker for early diagnosis of cervical tumors.
［Methods］We performed immunohistochemistry（IHC）to characterize the level of 5hmC in 103 archived human cervical intraepithelial neoplasia（CIN）samples and cervical cancer specimens. Mouse embryonic fibroblasts（MEF）and the human cell line HHUA were also used to assess molecular basis of 5hmC level aberration.
［Results］The level of 5hmC was significantly decreased between CIN2 and CIN3. Next, we examined the effects of TP53 or RB1 knockdown in mouse embryonic fibroblasts（MEF）, a model of normal cells with HPV infection, and observed 5hmC levels were reduced in Tp53-knockdown cells. In HHUA cells with a wild-type TP53 gene, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B（A3B）was induced after TP53-knockdown, and A3B knockdown recovered 5hmC levels. Moreover, IHC showed that expression levels of A3B in CIN3 were significantly higher than those in both normal epithelium and in CIN2.
［Conclusion］5hmC levels are decreased between CIN2 and CIN3 through the TP53-A3B pathway. Since A3B could impair genome stability, 5hmC loss might increase the chances of accumulating mutations and of progressing from CIN3 to cervical cancer. Thus, these epigenetic changes could predict whether CINs are progressing to cancer or disappearing..
|4.||Gα₁₃-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer.|
|5.||Kaoru Okugawa, Shusaku Inoue, Keisuke Kodama, Shinichiro Yamaguchi, Hironori Kenjo, Hiroshi Yagi, Tatsuhiro Ohgami, Masafumi Yasunaga, Ichirou Onoyama, Eisuke Kaneki, Hideaki Yahata, Kiyoko Kato, Safety evaluation of abdominal trachelectomy in patients with cervical cancer with tumors ≥2 cm：A single-institution, retrospective analysis, 第71回日本産科婦人科学会学術講演会, 2019.04, Purpose：For oncologic safety, vaginal radical trachelectomy is generally limited to patients with cervical cancer ＜ 2 cm. However, inclusion criteria for abdominal trachelectomy are unclear. Our aim was to evaluate the safety of abdominal trachelectomy for cervical cancer 2 cm. Methods：Our institutional review board approved this clinical study, and informed consent was obtained from each patient. We began performing abdominal trachelectomy at our institution in 2005. The preoperative criteria consisted primarily of（1）stage IB1 or less advanced squamous cell cancer 3 cm（including stage IIA1 with slight vaginal involvement）；or（2）adenocarcinoma/adenosquamous carcinoma 2 cm. If a positive sentinel lymph node or cervical margin was diagnosed intraoperatively by frozen section, trachelectomy was converted to hysterectomy. The medical records of these patients were reviewed retrospectively. Results：We attempted trachelectomy in 217 patients. Among 142 patients with tumors ＜ 2 cm, trachelectomy was successful in 127, none of whom developed recurrence. Altogether, 29 pregnancies were achieved in 22 women with 15 infants delivered. For 75 patients with tumors 2 cm, trachelectomy was successful in 61. Among them, two developed recurrence, eight pregnancies were achieved in five women with five infants delivered. For 29 patients who could not undergo trachelectomy, 14 had tumors 2 cm, and 22 had vascular permeation.
Considerations ＆ Conclusions：Intraoperative frozen sections of sentinel lymph nodes and cervical margins allowed us to perform trachelectomy safely even in patients with tumors 2 cm..
|6.||Hiroshi Yagi、Ichirou Onoyama、Kazuo Asanoma、Masafumi Yasunaga、Keisuke Kodama、Shusaku Inoue、Shinichiro Yamaguchi、Tatsuhiro Ohgami、Eisuke Kaneki、Kaoru Okugawa、Hideaki Yahata、Kiyoko Kato, GEP oncogene induces epithelial-mesenchymal transition in ovarian cancer through LATS1 proteolysis, 第71回日本産科婦人科学会学術講演会, 2019.04, Purpose：Cancer cells can co-opt the activity of G protein-coupled receptors（GPCRs）for their progression. Recent studies have revealed that overexpression of, or activating mutations in, GPCR-linked heterotrimeric G proteins, including GNAS, GNAQ, GNA12 and GNA13, play critical roles in the progression of human cancers. Among them, G α 13, encoded by the GEP oncogene, GNA13, has been implicated in the progression of various human cancers. However, our understanding of the function of G α 13 in cancer progression remains limited because of the lack of experimental systems that enable the
exclusive examination of G α 13 signaling. Here, we evaluated downstream targets of GEP oncogene that are implicated in ovarian cancer progression. Methods：To examine the effect of G α 13 activation on ovarian cancer cells, we employed constitutively active mutant of G α 13（G α 13QL）or synthetic biology approach using a mutant GPCR and chimeric G protein. Morphological change, protein expression profiles and intracellular signaling pathways were analyzed.
Results：Regarding both in cell morphology and protein expression profile, sustained activation of G α 13 induced epithelial-mesenchymal transition in ovarian cancer cells through down regulation of LATS1, a critical component of the Hippo signaling pathway. A synthetic biology approach revealed that G α 13-regulated phosphorylation of LATS1 at Serine 909 within its activation loop induced recruitment of the E3 ubiquitin ligase, ITCH, to trigger LATS1 degradation.
Considerations ＆ Conclusions：Our findings uncover novel mechanisms through which G α 13 activation induces dysregulation of the Hippo signaling pathway, leading to aggressive cancer phenotypes, thereby identifying a potential target for preventing metastatic spread of ovarian cancer..
|7.||Onoyama I, Sonoda K, Mechael,R Green, Kato K, Poster Exhibition; Oncogenic BRAF promotes global DNA hypomethylation via upregulation of DNA demethylase TET3 level
, The 5th Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO), 2017.11, Although a hallmark of human cancer genomes is global DNA hypomethylation accompanied by focal DNA hypermethylation, the basis of DNA hypomethylation remains to be determined. We investigated the mechanisms and
the biological significance of DNA hypomethylation in the process of carcinogenesis.
With the use of embryonic fibroblasts from oncogenic BrafV600E knock-in mice, we found that the expression of BrafV600E is sufficient to promote global DNA hypomethylation. DNA demethylase Tet3 is maintained at low level resulting from ubiquitination and degradation by SCF-type ubiquitin ligase SCF Fbxw7 in wild type mice. BrafV600E increased Tet3 protein levels via inhibition of Gsk3β、an inhibitor of Tet3 phosphorylation that is required for SCF Fbxw7-mediated ubiquitination. Consistent with these results, we found that the levels of TET3 and 5-hydroxymethylcytosine, an intermediate product of 5-methylcytosine demethylation, increased in human colorectal adenomas containing BRAFV600E. Conversely, we showed that knockdown of Tet3 decreased BrafV600E-induced lung tumorigenesis in mice.
Our results elucidate a mechanism of global DNA hypomethylation promoted by oncogenic BRAF and establish an essential role for TET3 at an early stage of oncogenesis.
|8.||Kodama K, Sonoda K, Kijima M, Yamaguchi S, Yagi H, Yasunaga M, Ogami T, Onoyama I, Kaneki E, Okugawa K, Kato K, Retrospective analysis of 14 leiomyosarcoma cases treated in our institution, The 5th Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO), 2017.11, Background and Objectives: Uterine leiomyosarcoma is a highly aggresive and lethal disease. This malignancy remains the most common type of uterine sarcoma, affecting approximately 0.4/100,000 women per year. Our aim is to assess the treatment and prognosis of leiomysarcoma patients
Methods: We retrospectively analyzed the clinicopathological variables and prognosis in 14 patients who were treated at our institution.
Results: A total of 14 patients were trated at our institution between January 2008 and July 2017. The median patients age and observation period were 63 years(range, 35-83 years) and 17months(range, 5-75 months), respectively. The largest group of patients by tumor stage was IB(IB, n=8; IIB, n=1; IVB, n=3); the largest group by historogical subtype was conventional leiomyosarcoma(conventional, n=11; myxoid, n=2; epithelioid, n=1). We performed total abdominal hysterectomy and bilateral salpingo-oophorectomy for all patients with additional operative procedure(e.g. tumor resection, lymphadenectomy) if necessary. Twelve patients received adjuvant chemotherapy consisting of docetaxel and gemcitabine. Ten patients experienced recurrence and multidisciplinary therapy was performed including tumor resection, chemotherapy, radiation and molecular-targetted agents. In observation period so far, 11 patients are alive (without disease, n=5; with disease, n=6).
Conclusions: Although uterine leiomyosarcoma is a lethal tumor, multidisciplinary therapy might be useful to control disease after recurrence. .
|9.||Kato K, Study of endometrial cell aging, The 22nd Seoul International Symposium, 2017.09.|
|10.||Kitade S, Onoyama I, Yagi H, Yoshida S, Kato M, Tsunematsu R, Asanoma K, Sonoda K, Kobayashi H, Hata K, Kiyoko Kato, FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors.
, 第69回日本産科婦人科学会学術講演会, 2017.04, FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5'-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5'-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5'-upstream regions of FBXW7..
|11.||Yagi H, Kodama K, Yasunaga M, Ogami T, Onoyama I, Asanoma K, Sonoda K, Kato K, The pivotal role of LATS1 in ovarian cancer progression.
, 第69回日本産科婦人科学会学術講演会, 2017.04.
|12.||Kiyoko Kato, Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms., 第54回日本癌治療学会学術総会, 2016.10.|
|13.||Kiyoko Kato, Identification and characterization of human trophoblast stem-like cells., The 102nd Annual Congress of Korean Society of Obstetrics and Gynecology, 2016.09.|
|14.||加藤 聖子, The current state of female doctors in Japanese Obstetrics and Gynecology.
, Ludwig Boltzmann Forum／Woman’s development and ledership, 2016.05.
|15.||Kiyoko Kato, Identification and characterization of endometrial cancer stem-like cells.
, The 4th Biennial Meeting of Asian Society of Gynecologic Oncoligy, 2015.11.
|16.||Hiroshi Yagi, Kenzo Sonoda, Kiyoko Kato, The Gα12/13-YAP signaling axis driving proliferation of ovarian cancer cells., 第67回日本産科婦人科学会学術講演会, 2015.04.|
|17.||Kiyoko Kato, Identification of endometrial cancer stem-like cells as a target for cancer therapy., The 54th Annual Congress & The 4th International Symposium of Taiwan Association of Obstetrics and Gynecology, 2015.03, Stem-like cell subpopularions,side-population(SP)cells,have been identified in several tumor types based on their ability to remove intracellular Hoechst 33342,a fluorescent dye,We have demonstrated that endometrial cancer SP cells possess cancer stem-like cell features including self-renewal capacity, enhanced migration,and bi-potential development(tumor cells and stroma-like cells).We showed that sodium butyrate,a histone deacetylase(HDAC)inhibitor,inhibited the self-renewal capacity of endometrial cancer SP cells by inducing a DNA damage response and salinomycin suppressed migration and proliferation of endometrial cancer SP cells by inducing apoptosis.Recently,we have demonstrated that the level of SPARC(secreted protein acidic and rich in cysteine),which is a target molecule of nab-paclitaxel,was enhanced in endmetrial cancer SP cells.SPARC was overexpressed in poorly differentiated endometrioid,clear and serous adenocarcinoma,but not in normal endometrial tissue.These results suggest that HDAC inhibitors,salinomycin and nab-paclitaxel would be promising drugs for endometrial cancer stem-like cells..|
|18.||Hiroshi Yagi, Kenzo Sonoda, Hiroaki Kobayashi, Kiyoko Kato, IS Award Candiate：The role of GEP oncogenes, G12 and G13, in the progression of ovarian cancer．
, 第66回日本産科婦人科学会学術講演会, 2014.04.
|19.||KAZUO ASANOMA, Hiroaki Kobayashi, Norio Wake, Kiyoko Kato, Transcriptional factors, DEC1 and DEC2 cooperatively regulate epithelial-to-mesenchymal transition of uterine endometrial cancer cells.
, 第66回日本産科婦人科学会学術講演会, 2014.04.
|20.||加藤聖子, Development of new cancer therapy by targeting endometrial cancer stem cells, 第72回日本癌学会学術総会, 2013.10.|