Tanri Shiozawa

Shinshu University, Shonai, Nagano, Japan

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Publications (129)419.51 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (P<0.05), and its overexpression was associated with a shorter survival (P<0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.
    Laboratory Investigation 09/2015; DOI:10.1038/labinvest.2015.119 · 3.68 Impact Factor
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    ABSTRACT: Objectives: Molecular markers associated with tumor progression in uterine carcinoma are poorly defined. In this study, we determine whether upregulation of LAMC1, a gene encoding extracellular matrix protein laminin γ1, is associated with various uterine carcinoma subtypes and stages of tumor progression. Methods: An analysis of the immunostaining patterns of laminin γ1 in normal endometrium, atypical hyperplasia, and a total of 150 uterine carcinomas, including low-grade and high-grade endometrioid carcinomas, uterine serous and clear cell carcinoma, was performed. Clinicopathological correlation was performed to determine biological significance. The Cancer Genome Atlas (TCGA) dataset was used to validate our results. Results: As compared to normal proliferative and secretory endometrium, for which laminin γ1 immunoreactivity was almost undetectable, increasing laminin C1 staining intensity was observed in epithelial cells from atypical hyperplasia to low-grade endometrioid to high-grade endometrioid carcinoma, respectively. Laminin γ1 expression was significantly associated with FIGO stage, myometrial invasion, cervical/adnexal involvement, angiolymphatic invasion and lymph node metastasis. Similarly, analysis of the endometrial carcinoma data set from TCGA revealed that LAMC1 transcript levels were higher in high-grade than in low-grade endometrioid carcinoma. Silencing LAMC1 expression by siRNAs in a high-grade endometrioid carcinoma cell line did not affect its proliferative activity but significantly suppressed cell motility and invasion in vitro. Conclusions: These data suggest that tumoral laminin γ1 may contribute to the development and progression of uterine carcinoma, likely through enhancing tumor cell motility and invasion. Laminin γ1 warrants further investigation regarding its role as a biomarker and therapeutic target in uterine carcinoma.
    Gynecologic Oncology 09/2015; DOI:10.1016/j.ygyno.2015.08.025 · 3.77 Impact Factor
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    ABSTRACT: Although most smooth muscle neoplasms detected in the human uterus are benign, uterine leiomyosarcoma (Ut-LMS) is extremely malignant with high rates of recurrence and metastasis. CAVEOLIN 1 (CAV1) levels in the epithelial cells of some carcinomas have been reported to increase during tumor progression. We herein evaluated the relationship between CAV1 expression and the pathological features of patients diagnosed with uterine mesenchymal tumors at several clinical facilities. No clinical link was observed between CAV1 expression and the malignancy of human uterine mesenchymal tumors. CAV1 expression was decreased in the normal myometrium, whereas it was strongly expressed in uterine mesenchymal tumors. However, the expression of CAV1 was not a potential biomarker to distinguish Ut-LMS from other types of uterine mesenchymal tumors. The perivascular expression of CAV1 was clearly observed in all types of uterine mesenchymal tumors and myometria. Therefore, the results of the present study suggest that CAV1 may not act as a potential biomarker of uterine malignant mesenchymal tumors. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 06/2015; 463(4). DOI:10.1016/j.bbrc.2015.06.046 · 2.30 Impact Factor
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    ABSTRACT: In order to determine indications for less radical surgery such as modified radical hysterectomy, the risk of pathological parametrial involvement and prognosis of FIGO stage IB1 cervical cancer patients undergoing standard radical hysterectomy with pre-operatively assessed tumor diameter ≤2cm were investigated. We conducted a retrospective multi-institutional chart review of patients with FIGO stage IB1 cervical cancer who underwent primary surgical treatment between 1998 and 2002. The eligibility criteria for the analyses were (i) histologically-proven squamous cell carcinoma, adenocarcinoma or, adenosquamous cell carcinoma, (ii) radical hysterectomy performed, (iii) clinical tumor diameter data available by MR imaging or specimens by cone biopsy, and (iv) age between 20 and 70. Based on the clinical tumor diameter, patients were stratified into those with the following tumors: i) 2cm or less (cT≤2cm) and ii) greater than 2cm (cT>2cm). We expected 5-year OS of ≥95% and parametrial involvement <2-3% for patients with cT≤2cm who underwent radical hysterectomy. Of the 1269 patients enrolled, 604 were eligible for the planned analyses. Among these, 571 underwent radical hysterectomy (323 with cT≤2cm and 248 with cT>2cm). Parametrial involvement was present in 1.9% (6/323) with cT≤2cm and 12.9% (32/248) with cT>2cm. Five-year overall survivals were 95.8% (95% CI 92.9-97.6%) in cT≤2cm and 91.9% (95% CI 87.6-94.8%) in cT>2cm patients. Patients with cT≤2cm had lower risk of parametrial involvement and more favorable 5-year overall survival. They could therefore be good candidates for receiving less radical surgery. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 02/2015; 137(1). DOI:10.1016/j.ygyno.2015.01.548 · 3.77 Impact Factor
  • He Ke · Akihisa Suzuki · Tsutomu Miyamoto · Hiroyasu Kashima · Tanri Shiozawa ·
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    ABSTRACT: Catechol estrogens, such as 4-hydroxyestradiol (4-OHE2), are estrogen metabolites that form DNA adducts and may induce mutations and subsequent cell transformation in mammary cells; however, little is known about their roles in endometrial carcinogenesis. Furthermore, it remains unclear whether 4-OHE2 is able to induce DNA damage on specific genes involved in carcinogenesis or a ‘pro’-mutation status such as microsatellite instability (MSI). Therefore, we modified terminal transferase-dependent PCR by the application of a capillary sequencer to detect DNA damage at the single base level. Using this method, we demonstrated that 4-OHE2 directly induced DNA damage on codon 130/131 in exon 5 of PTEN, which is a mutation hot spot for PTEN in endometrial carcinoma. Whereas, both estradiol and 4-OHE2 treatment did not affect MSI status in immortalized endometrial glandular cells. 4-OHE2 might contribute to endometrial carcinogenesis by inducing PTEN mutation on codon 130/131.
    Molecular and Cellular Endocrinology 11/2014; 400(C). DOI:10.1016/j.mce.2014.10.027 · 4.41 Impact Factor
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    Journal of Clinical Medicine Research 10/2014; 6(5):392-4. DOI:10.14740/jocmr1867e

  • Placenta 10/2014; 35(10):A8–A9. DOI:10.1016/j.placenta.2014.08.030 · 2.71 Impact Factor
  • Satoshi Ohira · Tanri Shiozawa ·

    Placenta 10/2014; 35(10):A5. DOI:10.1016/j.placenta.2014.08.018 · 2.71 Impact Factor
  • Satoshi Ohira · Tanri Shiozawa ·

    22nd Meeting of the Japan-Placenta-Association; 10/2014

  • Placenta 10/2014; 35(10):A11. DOI:10.1016/j.placenta.2014.08.041 · 2.71 Impact Factor
  • H Utsuno · T Miyamoto · K Oka · T Shiozawa ·
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    ABSTRACT: How are protamine deficiencies associated with sperm head morphology in subfertile men?
    Human Reproduction 09/2014; 29(11):2374-2381. DOI:10.1093/humrep/deu225 · 4.57 Impact Factor
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    ABSTRACT: Polypoid endometriosis is a rare type of endometriosis. We report a case of polypoid endometriosis of the ovary mimicking ovarian carcinoma with peritoneal dissemination. Computed tomography and magnetic resonance imaging showed a left ovarian endometriotic cyst containing several nodules in the cystic wall that displayed enhancement, and pelvic nodules on the right ovary. A preoperative or intraoperative diagnosis to avoid the unnecessary extended operation is important for such disease. Retrospective magnetic resonance imaging analysis identified a peculiar finding for polypoid endometriosis: all solid nodules had a round and smooth shape and displayed a low-signal-intense marginal edge on T2-weighted images, suggesting that this is an important finding for differentiating polypoid endometriosis from ovarian carcinoma arising from endometriosis.
    Journal of Obstetrics and Gynaecology Research 05/2014; 40(5). DOI:10.1111/jog.12358 · 0.93 Impact Factor
  • H Kobara · T Miyamoto · A Suzuki · R Asaka · Y Yamada · K Ishikawa · N Kikuchi · S Ohira · T Shiozawa ·
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    ABSTRACT: The invasion of extravillous trophoblasts (EVTs) to the decidua and spiral arteries in early pregnancy is a crucial step for a successful pregnancy; however, its mechanisms are not fully understood. Lipocalin2 (LCN2), a multifunctional secretory protein known as neutrophil gelatinase-associated lipocalin (NGAL), reportedly enhanced invasiveness via the activation of matrix metalloproteinase-9 (MMP-9) in several cancer cells. In this study, the expression and function of LCN2 in early placenta were analyzed. Early placental tissues between 7 and 10 weeks of gestation were obtained from normal pregnant women who underwent elective termination. The expression of LCN2 was examined using immunostaining and RT-PCR. EVTs isolated from these placental tissues and a choriocarcinoma cell line (JAR) were used to investigate the effects of LCN2 on proliferation, invasion potential, and MMP-9 activity under hypoxia using a WST-1 assay, Matrigel invasion assay, and gelatin gel zymography, respectively. The immunohistochemical expression of LCN2 was observed in the cytoplasm of EVTs, cytotrophoblasts and the decidua, but not in syncytiotrophoblasts. The addition of recombinant LCN2 did not affect proliferation, but enhanced the invasiveness (500 ng/mL, p < 0.01) and MMP-9 activity of primary cultured EVTs and JAR in a dose-dependent manner. Silencing LCN2 using shRNA reduced the invasiveness (p < 0.01) and MMP-9 activity of JAR. In addition, the hypoxic condition (2% O2) increased LCN2 expression (p < 0.01), MMP-9 activity, and invasive ability (p < 0.01). LCN2 was involved in the invasiveness of EVTs, especially under hypoxia, via increased MMP-9 activity.
    Placenta 08/2013; 34(11). DOI:10.1016/j.placenta.2013.08.004 · 2.71 Impact Factor

  • Cancer Research 08/2013; 73(8 Supplement):845-845. DOI:10.1158/1538-7445.AM2013-845 · 9.33 Impact Factor
  • Tanri Shiozawa · Tsutomu Miyamoto · Akihisa Suzuki · R.-i. Asaka ·

    Cancer Research 08/2013; 73(8 Supplement):3002-3002. DOI:10.1158/1538-7445.AM2013-3002 · 9.33 Impact Factor

  • Cancer Research 08/2013; 73(8 Supplement):3046-3046. DOI:10.1158/1538-7445.AM2013-3046 · 9.33 Impact Factor
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    ABSTRACT: Lobular endocervical glandular hyperplasia (LEGH) is a benign proliferative disease of cervical glands. Although histological resemblance of minimal deviation adenocarcinoma (MDA) to LEGH and frequent association of LEGH with MDA have been reported, it still remains unclear whether LEGH is a precancerous lesion of MDA. The present study was undertaken to examine the pathogenetic relationship between LEGH and MDA using a clonality analysis and mutational analyses of the STK11 gene, of which mutations have been reported in MDA. Of nine cases of LEGH only, four were polyclonal and five were monoclonal in composition. Of six LEGH lesions associated with MDA or adenocarcinoma, two were polyclonal and four were monoclonal. In cases of MDA or adenocarcinoma coexisting with LEGH, the patterns of X chromosome inactivation in malignant lesions were identical to those in coexisting LEGH lesions. A mutation of STK11 was only identified in one MDA, but not in LEGH. These results indicate that a subset of LEGH may be a precursor to malignant tumors including MDA and that a mutation of STK11 may be involved in progression of LEGH to MDA.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 05/2013; 462(6). DOI:10.1007/s00428-013-1417-1 · 2.65 Impact Factor
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    ABSTRACT: Placental mesenchymal dysplasia (PMD) is characterized by multiple hypoechoic vesicles which are similar to molar changes in the placenta; however, the process of such morphological changes of PMD during pregnancy has not been fully understood. We performed a review of all PMD cases published in English and identified 49 articles including 110 cases. With regard to the gestational age at which the multicystic pattern was seen, approximately 70% of cases were diagnosed at 13-20 weeks of gestation. Another characteristic feature of PMD is varicose dilation of fetal chorionic vessels. As many as 90% of cases were diagnosed as placenta with dilated fetal chorionic vessels in the third trimester. We also report a case of PMD which was found at 10 weeks of gestation according to ultrasonic molar patterns. Serial observations of the placenta using ultrasound and magnetic resonance imaging revealed that multicystic lesions became smaller after 23 weeks. In contrast, dilated placental vessels on the fetal side became apparent at 38 weeks. The present review highlights that placental vesicular lesions of PMD may precede dilation of fetal chorionic vessels during pregnancy. It also indicates the potential of a gradual reduction in size of PMD's placental vesicular lesions by serial study of placental images.
    Gynecologic and Obstetric Investigation 04/2013; 75(4). DOI:10.1159/000350661 · 1.70 Impact Factor
  • Hiroki Utsuno · Kenji Oka · Ayako Yamamoto · Tanri Shiozawa ·
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    ABSTRACT: OBJECTIVE: To test for an association between DNA fragmentation and head shape at high magnification in fresh motile spermatozoa. DESIGN: Observational study. SETTING: Academic tertiary care center. PATIENT(S): A total of 60 men in our assisted reproductive program. INTERVENTION(S): Quantifying sperm head shape using elliptic Fourier analysis, and detecting DNA fragmentation by use of a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. MAIN OUTCOME MEASURE(S): Correlation between percentage of spermatozoa with abnormal head shape and percentage of DNA fragmentation. RESULT(S): Elliptic Fourier analysis decomposed sperm head shapes into four quantitative parameters: ellipticity, anteroposterior (AP) symmetry, lateral symmetry, and angularity. The DNA fragmentation was statistically significantly correlated with abnormal angularity, and moderately with abnormal ellipticity but not with abnormal AP symmetry or lateral symmetry. Forward stepwise multiple logistic regression analysis revealed a statistically significantly higher percentage of DNA fragmentation in spermatozoa with abnormal ellipticity and abnormal angularity than in spermatozoa with normal-shaped head (6.1% and 5.4% vs. 2.8%). Spermatozoa with large nuclear vacuoles also correlated with sperm DNA fragmentation, and had a statistically significantly higher percentage of DNA fragmentation (4.7%). CONCLUSION(S): Among the morphologic features of the sperm head, abnormal ellipticity, angularity, and large nuclear vacuoles are associated with DNA fragmentation.
    Fertility and sterility 03/2013; 99(6). DOI:10.1016/j.fertnstert.2013.01.100 · 4.59 Impact Factor
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    ABSTRACT: Aims: It has been reported that the expression of core 2 β1,6-N-acetylglucosaminyl transferase 1 (C2GnT1), which synthesizes the core 2 branching structure on O-glycans, may be associated with the biological aggressiveness of tumour cells. Therefore, the aim of this study was to examine the relationship between the expression of C2GnT1 and clinicopathological parameters of patients with endometrial carcinoma. Methods and results: The immunohistochemical expression of C2GnT1 was examined in 84 cases of endometrioid-type endometrial carcinoma, 15 cases of endometrial hyperplasia, and 30 normal endometria. The staining intensity was reported according to a positivity index (PI, full score 100), calculated from the percentage of positive cells. The expression of C2GnT1 was significantly higher in endometrial carcinoma (PI = 8.31 ± 15.29) than in normal endometrium (PI = 0.52 ± 1.24) (P < 0.0005). In carcinomas, the PI was higher in high-grade or advanced-stage tumours, but not significantly. Topologically, C2GnT1 was strongly expressed at sites of deep myometrial invasion. In addition, patients with C2GnT1 overexpression (PI ≥ 10) had significantly shorter survival (P < 0.0005). Multivariable analysis also indicated that C2GnT1 overexpression was an independent prognostic factor (P = 0.017). Conclusions: C2GnT1 appears to be involved in the biological aggressiveness of endometrial carcinoma. C2GnT1 might become a novel prognostic factor for endometrial carcinoma.
    Histopathology 02/2013; 62(7). DOI:10.1111/his.12107 · 3.45 Impact Factor

Publication Stats

2k Citations
419.51 Total Impact Points


  • 1991-2015
    • Shinshu University
      • • Department of Obstetrics and Gynecology
      • • Department of Medicine
      • • Department of Laboratory Medicine
      Shonai, Nagano, Japan
  • 2012
    • Aizawa Hospital
      Honjō, Saitama, Japan
  • 2006
    • Hospital Universitario La Paz
      Madrid, Madrid, Spain