研究者詳細 - 横井　暁

Downregulation of miR-10b-5p facilitates the proliferation of uterine leiomyosarcoma cells: A microRNA sequencing-based approach 査読有り

Yoshida, K; Yokoi, A; Kitagawa, M; Sugiyama, M; Yamamoto, T; Nakayama, J; Yoshida, H; Kato, T; Kajiyama, H; Yamamoto, Y

ONCOLOGY REPORTS 49 巻 ( 5 ) 2023年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncology Reports

Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In addition, the molecular background of ULMS has not been fully elucidated due to its low incidence. Therefore, no effective treatment strategies have been established based on its molecular back- ground. The present study aimed to investigate the roles of microRNAs (miRNAs/miRs) in the development of ULMS. Comprehensive miRNA sequencing was performed using six ULMS and three myoma samples, and revealed 53 and 11 significantly upregulated and downregulated miRNAs, respectively. One of the most abundant miRNAs in myoma samples was miR-10b-5p. The mean normalized read count of miR-10b-5p was 93,650 reads in myoma, but only 27,903 reads in ULMS. Subsequently, to investigate the roles of miR-10b-5p, gain-of-function analysis was performed using SK-UT-1 and SK-LMS-1 cell lines. The overexpression of miR-10b-5p suppressed cell proliferation and reduced the number of colonies. Moreover, miR-10b-5p increased the number of cells in the G1 phase. In conclusion, tumor-suppressive miR-10b-5p was significantly downregulated in ULMS compared with in myoma; thus, miR-10b-5p may serve a specific role in sarcoma progression.

DOI： 10.3892/or.2023.8523

Preoperative serum microRNAs as potential prognostic biomarkers in ovarian clear cell carcinoma 査読有り国際誌

Suzuki, K; Yokoi, A; Yoshida, K; Kato, T; Ochiya, T; Yamamoto, Y; Kajiyama, H

JOURNAL OF GYNECOLOGIC ONCOLOGY 34 巻 ( 3 ) 頁： e34 - 3310 2023年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gynecologic Oncology

Objective: Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian carcinoma with poor prognosis. However, no effective biomarkers have been established for predicting unfavorable events, including recurrence and poor prognoses. Serum microRNAs (miRNAs) have been increasingly reported to be useful in predicting a patient’s condition and have been recognized as a potentially less-invasive source for liquid biopsy in cancer. Therefore, this study aimed to evaluate serum miRNA profiles from patients with OCCC and to establish biomarker for predicting the prognoses. Methods: The GSE106817, which included preoperative serum miRNA profiles of patients with ovarian tumors, was used, and clinical information was investigated. In all, 66 patients with OCCC were included, excluding those with other histological subtypes or insufficient prognostic information. Moreover, miRNA profiles of OCCC tissues were also examined. Results: The median follow-up period was 64.3 (8.0–153.3) months. Based on multivariable Cox regression analyses and the expression of miRNAs in OCCC tissues, miR-150-3p, miR-3195, and miR-7704 were selected as miRNA candidates associated with both progression-free survival (PFS) and overall survival (OS). Then, the prognostic index was calculated based on expression values of 3 serum miRNAs. Kaplan-Meier survival analysis indicated that the prognostic index was significantly predictive of PFS and OS (p=0.004 and p=0.012, respectively). Conclusion: Preoperative serum miRNA profiles of miR-150-3p, miR-3195, and miR-7704 can be used to potentially predict the prognosis of patients with OCCC.

DOI： 10.3802/jgo.2023.34.e34

The association of UBAP2L and G3BP1 mediated by small nucleolar RNA is essential for stress granule formation 査読有り国際誌

Asano-Inami, E; Yokoi, A; Sugiyama, M; Hyodo, T; Hamaguchi, T; Kajiyama, H

COMMUNICATIONS BIOLOGY 6 巻 ( 1 ) 頁： 415 - 415 2023年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Communications Biology

Stress granules (SGs) are dynamic, non-membranous structures composed of non-translating mRNAs and various proteins and play critical roles in cell survival under stressed conditions. Extensive proteomics analyses have been performed to identify proteins in SGs; however, the molecular functions of these components in SG formation remain unclear. In this report, we show that ubiquitin-associated protein 2-like (UBAP2L) is a crucial component of SGs. UBAP2L localized to SGs in response to various stresses, and its depletion significantly suppressed SG organization. Proteomics and RNA sequencing analyses found that UBAP2L formed a protein-RNA complex with Ras-GTP-activating protein SH3 domain binding protein 1 (G3BP1) and small nucleolar RNAs (snoRNAs). In vitro binding analysis demonstrated that snoRNAs were required for UBAP2L association with G3BP1. In addition, decreased expression of snoRNAs reduced the interaction between UBAP2L and G3BP1 and suppressed SG formation. Our results reveal a critical role of SG component, the UBAP2L/snoRNA/G3BP1 protein-RNA complex, and provide new insights into the regulation of SG assembly.

DOI： 10.1038/s42003-023-04754-w

Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma 査読有り国際誌

Nagao, Y; Yokoi, A; Yoshida, K; Sugiyama, M; Watanabe, E; Nakamura, K; Kitagawa, M; Asano-Inami, E; Koya, Y; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kato, T; Yamamoto, Y; Kajiyama, H

PHARMACOLOGICAL RESEARCH 189 巻頁： 106693 - 106693 2023年3月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pharmacological Research

Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.

DOI： 10.1016/j.phrs.2023.106693

Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma 査読有り国際誌

Watanabe, E; Yokoi, A; Yoshida, K; Sugiyama, M; Kitagawa, M; Nishino, K; Yamamoto, E; Niimi, K; Yamamoto, Y; Kajiyama, H

CANCER MEDICINE 12 巻 ( 4 ) 頁： 4543 - 4556 2023年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Medicine

Background: Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy. Methods: Three choriocarcinoma cell lines (JAR, JEG-3, and BeWo) and a human extravillous trophoblast cell line (HTR-8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA-approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor-bearing mice. Functional analyses of drug effects were performed based on RNA sequencing. Results: Muti-step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti-cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis-related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell-bearing mice model. Conclusion: Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T-cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis-related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma.

DOI： 10.1002/cam4.5243

Tumor suppressive miRNAs in small extracellular vesicles derived from ADSCs shows anti-tumor capacity in ovarian cancer

Suzuki, H; Yokoi, A; Uekusa, R; Kitagawa, M; Yoshida, K; Uno, K; Kajiyama, H

CANCER SCIENCE 114 巻頁： 1374 - 1374 2023年2月

Preoperative serum microRNAs as potential prognostic biomarkers in ovarian clear cell carcinoma

Suzuki, K; Yokoi, A; Yoshida, K; Kato, T; Ochiya, T; Yamamoto, Y; Kajiyama, H

CANCER SCIENCE 114 巻頁： 1986 - 1986 2023年2月

Novel exosome analyses for micro volume ascites in ovarian cancer dissemination

Yokoi, A; Yasui, T; Yoshida, K; Kitagawa, M; Kajiyama, H

CANCER SCIENCE 114 巻頁： 20 - 20 2023年2月

Notch signaling can be a new therapeutic target for advanced ovarian cancer

Sugiyama, M; Yoshihara, M; Koya, Y; Kitami, K; Uno, K; Iyoshi, S; Mogi, K; Yokoi, A; Nakamura, K; Nawa, A; Kajiyama, H

CANCER SCIENCE 114 巻頁： 2065 - 2065 2023年2月

Identifying Copy Number Variations in Extracellular Vesicles as a Novel Biomarker of High Grade Serous Ovarian Carcinoma

Uekusa, R; Yokoi, A; Kitagawa, M; Yoshida, K; Yoshihara, M; Tamauchi, S; Niimi, K; Matsuzaki, J; Yamamoto, Y; Kajiyama, H

CANCER SCIENCE 114 巻頁： 1063 - 1063 2023年2月

Aberrant activation of cell cycle-related kinases as novel therapeutic targets for uterine leiomyosarcoma

Yoshida, K; Yokoi, A; Kato, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 114 巻頁： 1457 - 1457 2023年2月

Aberrant activation of cell cycle-related kinases as novel therapeutic targets for uterine leiomyosarcoma

Yoshida, K; Yokoi, A; Kato, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 114 巻頁： 913 - 913 2023年2月

Development of mortality prediction models for infants with isolated, left-sided congenital diaphragmatic hernia before and after birth

Yoneda Kota, Amari Shoichiro, Mikami Masashi, Uchida Keiichi, Yokoi Akiko, Okawada Manabu, Furukawa Taizo, Toyoshima Katsuaki, Inamura Noboru, Okazaki Tadaharu, Yamoto Masaya, Masumoto Kouji, Terui Keita, Okuyama Hiroomi, Hayakawa Masahiro, Taguchi Tomoaki, Usui Noriaki, Isayama Tetsuya

PEDIATRIC PULMONOLOGY 58 巻 ( 1 ) 頁： 152 - 160 2023年1月

記述言語：英語出版者・発行元：Pediatric Pulmonology

Background: Mortality prediction of congenital diaphragmatic hernia (CDH) is essential for developing treatment strategies, including fetal therapy. Several researchers have reported prognostic factors for this rare but life-threatening condition; however, the optimal combination of prognostic factors remains to be elucidated. Objectives: This study aimed to develop the most discriminative prenatal and postnatal models to predict the mortality of infants with an isolated left-sided CDH. Methods: This multi-institutional retrospective cohort study included infants with CDH born at 15 tertiary hospitals of the Japanese CDH Study Group between 2011 and 2016. We developed multivariable logistic models with every possible combination of predictors and identified models with the highest cross-validated area under the receiver operating characteristic curve (AUC) for prenatal and postnatal predictions. Results: Among 302 eligible infants, 44 died before discharge. The prenatal mortality prediction model was based on the observed/expected lung area to head circumference ratio (O/E LHR), liver herniation, and stomach herniation (AUC, 0.830). The postnatal mortality prediction model was based on O/E LHR, liver herniation, and the lowest oxygenation index (AUC, 0.944). Conclusion: Our models can facilitate the prenatal and postnatal mortality prediction of infants with isolated left-sided CDH.

DOI： 10.1002/ppul.26172

The prognostic significance of DDIT4 in endometrial cancer 国際誌

Yoshikawa, N; Yoshida, K; Liu, WT; Matsukawa, T; Hattori, S; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Shimizu, Y; Niimi, K; Kajiyama, H

CANCER BIOMARKERS 37 巻 ( 4 ) 頁： 217 - 225 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Biomarkers

BACKGROUND: Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE: This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS: Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. RESULTS: The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS: The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.

DOI： 10.3233/CBM-220368

Prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia: a systematic review and meta-analysis

Masahata Kazunori, Yamoto Masaya, Umeda Satoshi, Nagata Kouji, Terui Keita, Fujii Makoto, Shiraishi Masayuki, Hayakawa Masahiro, Amari Shoichiro, Masumoto Kouji, Okazaki Tadaharu, Inamura Noboru, Toyoshima Katsuaki, Koike Yuki, Furukawa Taizo, Yazaki Yuta, Yokoi Akiko, Endo Masayuki, Tazuke Yuko, Okuyama Hiroomi, Usui Noriaki

PEDIATRIC SURGERY INTERNATIONAL 38 巻 ( 12 ) 頁： 1745 - 1757 2022年12月

記述言語：英語出版者・発行元：Pediatric Surgery International

Purpose: This study aimed to evaluate prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia (CDH). Methods: A systematic literature search was performed to identify relevant observational studies that evaluated the ability of lung-to-head ratio (LHR), observed-to-expected LHR (o/e-LHR), observed-to-expected total fetal lung volume (o/e-TFLV), lung-to-thorax transverse area ratio (L/T ratio), intrathoracic herniation of the liver and the stomach, and side of diaphragmatic hernia, using a threshold for the prediction of mortality in fetuses with CDH. Study quality was assessed using the QUADAS-2 tool. Hierarchical summary receiver operating characteristic curves were constructed. Results: A total of 50 articles were included in this meta-analysis. The QUADAS-2 tool identified a high risk of bias in more than one domain scored in all parameters. Among those parameters, the diagnostic odds ratio of mortality with o/e-LHR < 25%, o/e-TFLV < 25%, and L/T ratio < 0.08 were 11.98 [95% confidence interval (CI) 4.65–30.89], 11.14 (95% CI 5.19–23.89), and 10.28 (95% CI 3.38–31.31), respectively. The predictive values for mortality were similar between the presence of liver herniation and retrocardiac fetal stomach position. Conclusions: This systematic review suggests that o/e-LHR, o/e-TFLV, and L/T ratio are equally good predictors of neonatal mortality in fetuses with isolated CDH.

DOI： 10.1007/s00383-022-05232-w

Hypoalbuminemia for the prediction of survival in patients with stage IVB cervical cancer 国際誌

Yoshikawa, N; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kajiyama, H

PLOS ONE 17 巻 ( 9 ) 頁： e0273876 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

We evaluated the prognostic significance of malnutrition in patients with metastatic cervical cancer. In this study, we retrospectively analyzed the cases of 43 patients with stage IVB (FIGO2018) cervical cancer treated at our institute from December 2004 to December 2017. We determined the correlation between clinicopathological characteristics and survival by performing univariate and multivariate analyses. The serum albumin value at diagnosis was used as an index of malnutrition. The median follow-up period was 16.4 months (range, 0.9–91.4 months). On Kaplan-Meier analysis, the 1- and 2-year overall survival (OS) rates for all patients were 61.6% and 48.6%, respectively. The optimal serum albumin for predicting 1-year survival was 3.3 g/dL, as determined by the receiver operating characteristic curve to maximize the area under the curve. The OS of the patients with albumin >3.3 g/ dL (n = 28) was significantly better than that of the patients with albumin ≤3.3 g/dL (n = 15) (p = 0.004). The univariate and multivariate analyses revealed that pretreatment serum albumin and mode of primary treatment were significantly associated with survival in patients with stage IVB cervical cancer. Hypoalbuminemia was an unfavorable prognostic factor for patients with metastatic cervical cancer.

DOI： 10.1371/journal.pone.0273876