研究者詳細 - 横井　暁

論文 - 横井　暁

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Spatial exosome analysis using cellulose nanofiber sheets reveals the location heterogeneity of extracellular vesicles 国際誌

Yokoi, A; Yoshida, K; Koga, H; Kitagawa, M; Nagao, Y; Iida, M; Kawaguchi, S; Zhang, M; Nakayama, J; Yamamoto, Y; Baba, Y; Kajiyama, H; Yasui, T

NATURE COMMUNICATIONS 14 巻 ( 1 ) 頁： 6915 - 6915 2023年11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：Nature Communications

Extracellular vesicles (EVs), including exosomes, are recognized as promising functional targets involved in disease mechanisms. However, the intravital heterogeneity of EVs remains unclear, and the general limitation for analyzing EVs is the need for a certain volume of biofluids. Here, we present cellulose nanofiber (CNF) sheets to resolve these issues. We show that CNF sheets capture and preserve EVs from ~10 μL of biofluid and enable the analysis of bioactive molecules inside EVs. By attaching CNF sheets to moistened organs, we collect EVs in trace amounts of ascites, which is sufficient to perform small RNA sequence analyses. In an ovarian cancer mouse model, we demonstrate that CNF sheets enable the detection of cancer-associated miRNAs from the very early phase when mice did not have apparent ascites, and that EVs from different locations have unique miRNA profiles. By performing CNF sheet analyses in patients, we identify further location-based differences in EV miRNA profiles, with profiles reflecting disease conditions. We conduct spatial exosome analyses using CNF sheets to reveal that ascites EVs from cancer patients exhibit location-dependent heterogeneity. This technique could provide insights into EV biology and suggests a clinical strategy contributing to cancer diagnosis, staging evaluation, and therapy planning.

DOI： 10.1038/s41467-023-42593-9

Identifying high-grade serous ovarian carcinoma-specific extracellular vesicles by polyketone-coated nanowires 国際誌

Yokoi, A; Ukai, M; Yasui, T; Inokuma, Y; Hyeon-Deuk, K; Matsuzaki, J; Yoshida, K; Kitagawa, M; Chattrairat, K; Iida, M; Shimada, T; Manabe, Y; Chang, IY; Asano-Inami, E; Koya, Y; Nawa, A; Nakamura, K; Kiyono, T; Kato, T; Hirakawa, A; Yoshioka, Y; Ochiya, T; Hasegawa, T; Baba, Y; Yamamoto, Y; Kajiyama, H

SCIENCE ADVANCES 9 巻 ( 27 ) 頁： eade6958 2023年7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：Science Advances

Cancer cell-derived extracellular vesicles (EVs) have unique protein profiles, making them promising targets as disease biomarkers. High-grade serous ovarian carcinoma (HGSOC) is the deadly subtype of epithelial ovarian cancer, and we aimed to identify HGSOC-specific membrane proteins. Small EVs (sEVs) and medium/large EVs (m/lEVs) from cell lines or patient serum and ascites were analyzed by LC-MS/MS, revealing that both EV subtypes had unique proteomic characteristics. Multivalidation steps identified FRα, Claudin-3, and TACSTD2 as HGSOC-specific sEV proteins, but m/lEV-associated candidates were not identified. In addition, for using a simple-to-use microfluidic device for EV isolation, polyketone-coated nanowires (pNWs) were developed, which efficiently purify sEVs from biofluids. Multiplexed array assays of sEVs isolated by pNW showed specific detectability in cancer patients and predicted clinical status. In summary, the HGSOC-specific marker detection by pNW are a promising platform as clinical biomarkers, and these insights provide detailed proteomic aspects of diverse EVs in HGSOC patients.

DOI： 10.1126/sciadv.ade6958

Exosomes and extracellular vesicles: Rethinking the essential values in cancer biology 査読有り国際誌

Yokoi, A; Ochiya, T

SEMINARS IN CANCER BIOLOGY 74 巻頁： 79 - 91 2021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：Seminars in Cancer Biology

Extracellular vesicles (EVs) such as exosomes are released by all living cells and contain diverse bioactive molecules, including nucleic acids, proteins, lipids, and metabolites. Accumulating evidence of EV-related functions has revealed that these tiny vesicles can mediate specific cell-to-cell communication. Within the tumor microenvironment, diverse cells are actively interacting with their surroundings via EVs facilitating tumor malignancy by regulating malignant cascades including angiogenesis, immune modulation, and metastasis. This review summarizes the recent studies of fundamental understandings of EVs from the aspect of EV heterogeneity and highlights the role of EVs in the various steps from oncogenic to metastatic processes. The recognition of EV subtypes is necessary to identify which pathways can be affected by EVs and which subtypes can be targeted in therapeutic approaches or liquid biopsies.

DOI： 10.1016/j.semcancer.2021.03.032

Mechanisms of nuclear content loading to exosomes. 査読有り国際誌

Yokoi A, Villar-Prados A, Oliphint PA, Zhang J, Song X, De Hoff P, Morey R, Liu J, Roszik J, Clise-Dwyer K, Burks JK, O'Halloran TJ, Laurent LC, Sood AK

Science advances 5 巻 ( 11 ) 頁： eaax8849 2019年11月

Integrated extracellular microRNA profiling for ovarian cancer screening 査読有り国際誌

Yokoi, A; Matsuzaki, J; Yamamoto, Y; Yoneoka, Y; Takahashi, K; Shimizu, H; Uehara, T; Ishikawa, M; Ikeda, S; Sonoda, T; Kawauchi, J; Takizawa, S; Aoki, Y; Niida, S; Sakamoto, H; Kato, K; Kato, T; Ochiya, T

NATURE COMMUNICATIONS 9 巻 ( 1 ) 頁： 4319 - 4319 2018年10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：Nature Communications

A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9–10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.

DOI： 10.1038/s41467-018-06434-4

Malignant extracellular vesicles carrying <i>MMP1</i> mRNA facilitate peritoneal dissemination in ovarian cancer 査読有り国際誌

Yokoi, A; Yoshioka, Y; Yamamoto, Y; Ishikawa, M; Ikeda, S; Kato, T; Kiyono, T; Takeshita, F; Kajiyama, H; Kikkawa, F; Ochiya, T

NATURE COMMUNICATIONS 8 巻頁： 14470 - 14470 2017年3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：Nature Communications

Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs.

DOI： 10.1038/ncomms14470

Serum miRNA as a predictive biomarker for ovarian reserve after endometrioma-cystectomy 国際誌

Yabuki, A; Muraoka, A; Osuka, S; Yokoi, A; Yoshida, K; Kitagawa, M; Bayasura; Sonehara, R; Miyake, N; Nakanishi, N; Nakamura, T; Iwase, A; Kajiyama, H

REPRODUCTIVE BIOLOGY 24 巻 ( 1 ) 頁： 100821 - 100821 2024年3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：Reproductive Biology

Ovarian endometrioma (OE) is a common gynecological disease that is often treated with surgery and hormonal treatment. However, ovarian cystectomy can impair the ovarian reserve (OR). Previously, we showed that perioperative administration of dienogest (DNG) is an effective option for OR preservation. However, there were differences in the extent of OR preservation among patients following perioperative DNG treatment. In the current study, we performed a global examination of serum microRNAs (miRNAs) to identify accurate biomarkers that predict post-operative restoration of OR following perioperative DNG treatment. We also sought to identify specific miRNAs related to the anti-Müllerian hormone (AMH). miRNA sequencing was performed on serum samples obtained from twenty-seven patients who received perioperative DNG treatment. Candidate miRNAs were selected by comparing patients whose ORs were restored postoperatively (responder group, n = 7) with those whose ORs were not (non-responder group, n = 7). miR-370–3p and miR-1307–3p were significantly upregulated in the responder group, whereas miR-27b-3p was upregulated in the non-responder group. The pretreatment value of each miRNA could predict DNG responsiveness for OR following ovarian cystectomy (area under the curve [AUC] > 0.8). The quantitative polymerase chain reaction (qPCR) revealed only miR-1307–3p was found to be significantly upregulated in the responder group (P < 0.05). In addition, we identified miR-139–3p, miR-140–3p, and miR-629–5p as AMH-associated miRNAs. The transition of AMH showed a correlation with miR-139–3p (P < 0.05, r = −0.76). The miRNAs identified herein represent potential serum biomarkers of clinical value in predicting OR prior to DNG treatment.

DOI： 10.1016/j.repbio.2023.100821

Small extracellular vesicles in follicular fluids for predicting reproductive outcomes in assisted reproductive technology 国際誌

Muraoka, A; Yokoi, A; Yoshida, K; Kitagawa, M; Asano-Inami, E; Murakami, M; Bayasula; Miyake, N; Nakanishi, N; Nakamura, T; Osuka, S; Iwase, A; Kajiyama, H

COMMUNICATIONS MEDICINE 4 巻 ( 1 ) 頁： 33 - 33 2024年2月

Uterine leiomyosarcoma cell-derived extracellular vesicles induce the formation of cancer-associated fibroblasts. 国際誌

Nagao Y, Yokoi A, Yoshida K, Kitagawa M, Asano-Inami E, Kato T, Ishikawa M, Yamamoto Y, Kajiyama H

Biochimica et biophysica acta. Molecular basis of disease 1870 巻 ( 4 ) 頁： 167103 - 167103 2024年2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：Biochimica et Biophysica Acta - Molecular Basis of Disease

Objective: Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs (miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function. Methods: Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients. Results: miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2. Conclusion: miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts.

DOI： 10.1016/j.bbadis.2024.167103

An update of oncologic and obstetric outcomes of radical trachelectomy for early-stage cervical cancer: The need for further minimally invasive treatment 国際誌

Tamauchi, S; Iyoshi, S; Yoshihara, M; Yoshida, K; Ikeda, Y; Shimizu, Y; Yokoi, A; Niimi, K; Yoshikawa, N; Kajiyama, H

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 50 巻 ( 2 ) 頁： 175 - 181 2024年2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：Journal of Obstetrics and Gynaecology Research

Aims: To investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early-stage cervical cancer and to evaluate the potential role of fertility-preserving treatments in improving pregnancy outcomes while oncologic status is stable. Methods: In this single-institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early-stage cervical cancer who underwent RT at Nagoya University Hospital. Results: The cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies. Conclusions: RT is a viable treatment option for selected patients with early-stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable.

DOI： 10.1111/jog.15824

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches 国際誌

Welsh J.A., Goberdhan D.C.I., O’Driscoll L., Buzas E.I., Blenkiron C., Bussolati B., Cai H., Di Vizio D., Driedonks T.A.P., Erdbrügger U., Falcon-Perez J.M., Fu Q.L., Hill A.F., Lenassi M., Lim S.K., Mahoney M.ỹ.G., Mohanty S., Möller A., Nieuwland R., Ochiya T., Sahoo S., Torrecilhas A.C., Zheng L., Zijlstra A., Abuelreich S., Bagabas R., Bergese P., Bridges E.M., Brucale M., Burger D., Carney R.P., Cocucci E., Crescitelli R., Hanser E., Harris A.L., Haughey N.J., Hendrix A., Ivanov A.R., Jovanovic-Talisman T., Kruh-Garcia N.A., Faustino V.K.L., Kyburz D., Lässer C., Lennon K.M., Lötvall J., Maddox A.L., Martens-Uzunova E.S., Mizenko R.R., Newman L.A., Ridolfi A., Rohde E., Rojalin T., Rowland A., Saftics A., Sandau U.S., Saugstad J.A., Shekari F., Swift S., Ter-Ovanesyan D., Tosar J.P., Useckaite Z., Valle F., Varga Z., van der Pol E., van Herwijnen M.J.C., Wauben M.H.M., Wehman A.M., Williams S., Zendrini A., Zimmerman A.J., Théry C., Witwer K.W., Ahmad S., Ahmed D.A.K., Ahmed S.H., Aikawa E., Akbar N., Akiyoshi K., Al-Adra D.P., Al-Masawa M.E., Albanese M., Alberro A., Alcaraz M.J., Alexander-Brett J., Alexander K.L., Ali N., Alibhai F.J., Allelein S., Allenby M.C., Almeida F., de Almeida L.P., Almousa S.W., Altan-Bonnet N., Altei W.F., Alvarez-Llamas G., Alvarez C.L., An H.J., Anand K., Andaloussi S.E.L., Anderson J.D.

Journal of Extracellular Vesicles 13 巻 ( 2 ) 頁： e12404 2024年2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：Journal of Extracellular Vesicles

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

DOI： 10.1002/jev2.12404

Effect of radical trachelectomy on ovarian reserve: A single-institute prospective study 国際誌

Nakagawa, A; Tamauchi, S; Sato, M; Yoshihara, M; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Niimi, K; Osuka, S; Kajiyama, H

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 50 巻 ( 2 ) 頁： 212 - 217 2024年2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：Journal of Obstetrics and Gynaecology Research

Aim: Reduced responses to controlled ovarian stimulation (COS) after radical trachelectomy (RT) have been previously reported. We aimed to assess the effect of RT on ovarian reserve by measuring anti-Müllerian hormone (AMH) levels before and after the procedure in this prospective study. Methods: We included 12 patients who underwent RT between September 2019 and December 2021 in this study. Serum AMH levels were measured preoperatively, 1 month postoperatively, and 6 months postoperatively. Differences in the AMH levels were assessed using a paired t-test. Results: The median age of the patients was 30.6 years, and the median follow-up time was 30.1 months. AMH levels at 1 and 6 months postoperatively did not show a consistent trend. At 1 month postoperatively, the average AMH level decreased insignificantly but returned to preoperative levels at 6 months. The differences in AMH levels before and after RT were insignificant. Conclusion: Our findings indicate that RT did not affect ovarian reserve as measured by AMH levels. However, the relationship between unchanged ovarian reserve and reduced response to COS remains unclear. Further research with larger sample sizes and additional measures of ovarian function is needed to corroborate these results and investigate the long-term effects of RT on ovarian reserve. Understanding these mechanisms will help guide surgical practices and provide patients with valuable information about their reproductive outcomes after RT.

DOI： 10.1111/jog.15828

Emerging bacterial factors for understanding pathogenesis of endometriosis 国際誌

Muraoka, A; Yokoi, A; Kajiyama, H

ISCIENCE 27 巻 ( 1 ) 頁： 108739 - 108739 2024年1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：iScience

The pathogenesis of endometriosis is a complex process, and recent research has introduced novel hypotheses in this field. This review summarizes recent studies on the pathogenesis of endometriosis. We focused on several classical hypotheses, as well as their interactions with the microenvironment of hormonal dependence and immunosuppression. Furthermore, we highlighted the emergence of bacterial factors associated with endometriosis. Recent advances in next-generation sequencing (NGS) have revealed the presence and detailed distribution of these bacteria as well as the involvement of specific bacteria in pathogenesis. These factors alter the microenvironment in the early stages of endometriosis development, leading to lesion formation. Understanding the mechanisms underlying the early development of endometriosis from a new perspective would be helpful for the development of novel therapeutic agents for endometriosis.

DOI： 10.1016/j.isci.2023.108739

Mean platelet volume as a potential biomarker for survival outcomes in ovarian clear cell carcinoma

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

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 28 巻 ( 12 ) 頁： 1680 - 1689 2023年12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：International Journal of Clinical Oncology

Objective: This study aimed to explore the prognostic value of mean platelet volume (MPV) in patients with ovarian clear cell carcinoma (OCCC) and evaluate the predictive performance of a random forest model incorporating MPV and other key clinicopathological factors. Methods: A total of 204 patients with OCCC treated between January 2004 and December 2019 were retrospectively analyzed. Clinicopathological characteristics and preoperative laboratory data were collected, and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional hazards models. An optimal MPV cutoff was determined by receiver operating characteristic (ROC) curve analysis. A random forest model was then constructed using the identified independent prognostic factors, and its predictive performance was evaluated. Results: The ROC analysis identified 9.3 fL as the MPV cutoff value for predicting 2-year survival. The MPV-low group had lower 5-year overall survival and progression-free survival rates than the MPV-high group (p = 0.003 and p = 0.034, respectively). High MPV emerged as an independent prognostic factor (p = 0.006). The random forest model, incorporating the FIGO stage, residual tumors, peritoneal cytology, and MPV, demonstrated robust predictive performance (area under the curve: 0.905). Conclusion: MPV is a promising prognostic indicator in OCCC. Lower MPV correlated with worse survival rates, advocating its potential utility in refining patient management strategies. The commendable predictive performance of the random forest model, integrating MPV and other significant prognostic factors, suggests a pathway toward enhanced survival prediction, thereby warranting further research.

DOI： 10.1007/s10147-023-02417-8

Establishment and characterization of a non-gestational choriocarcinoma patient-derived xenograft model 国際誌

Oda, Y; Niimi, K; Yoshida, K; Tamauchi, S; Yokoi, A; Yasui, Y; Nishiko, Y; Shibata, M; Shimizu, Y; Yoshihara, M; Ikeda, Y; Yoshikawa, N; Nishino, K; Yamamoto, E; Kajiyama, H

BMC CANCER 23 巻 ( 1 ) 頁： 1103 - 1103 2023年11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：BMC Cancer

Background: Non-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC. Methods: Fresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdc scid 1l2rg tm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate. Results: The PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour. Conclusions: We successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

DOI： 10.1186/s12885-023-11626-3

9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins 国際誌

Mogi, K; Koya, Y; Yoshihara, M; Sugiyama, M; Miki, R; Miyamoto, E; Fujimoto, H; Kitami, K; Iyoshi, S; Tano, S; Uno, K; Tamauchi, S; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Niimi, K; Yamakita, Y; Tomita, H; Shibata, K; Nawa, A; Tomoda, Y; Kajiyama, H

SCIENTIFIC REPORTS 13 巻 ( 1 ) 頁： 19208 - 19208 2023年11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：Scientific Reports

Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25–50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

DOI： 10.1038/s41598-023-44365-3

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer 国際誌

Suzuki, H; Yokoi, A; Uno, K; Yoshida, K; Kitagawa, M; Asano-Inami, E; Matsuo, S; Nagao, Y; Suzuki, K; Nakamura, K; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kajiyama, H; Yamamoto, Y

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 680 巻頁： 211 - 219 2023年11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：Biochemical and Biophysical Research Communications

Introduction: Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. Materials and methods: ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. Results: ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. Conclusion: ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

DOI： 10.1016/j.bbrc.2023.09.022

The sarcopenia index measured using the lumbar paraspinal muscle is associated with prognosis in endometrial cancer 国際誌

Uno, K; Yoshikawa, N; Kitami, K; Mori, S; Shibata, T; Iyoshi, S; Fujimoto, H; Mogi, K; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kato, K; Hoshiba, T; Oguchi, H; Kajiyama, H

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 53 巻 ( 10 ) 頁： 942 - 949 2023年10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：Japanese Journal of Clinical Oncology

Objective: The number of type-II endometrial cancer patients has been increasing and the prognosis is not favorable. We aim to investigate whether sarcopenia index in any of several different muscles could serve as a novel biomarker of prognosis in patients with type-II endometrial cancer. Methods: We retrospectively investigated a total of 194 patients at four hospitals. Ninety patients were treated as derivation set and the other 104 patients as validation set. Using preoperative computed tomography images, we measured the horizontal cross-sectional area at the third lumbar spine level: the (i) psoas major, (ii) iliac and (iii) paraspinal muscle. The clinical information including recurrence-free survival and overall survival were retrospectively collected. These results were validated with external data sets of three hospitals. Results: The median values of the sarcopenia index (cm2/m2) ± standard deviation with the first data of 90 patients using the psoas, iliac and paraspinal muscle were 3.4 ± 1.0, 1.7 ± 0.6 and 12.6 ± 3.2, respectively. In univariate analyses, the sarcopenia indexes measured using the psoas or paraspinal muscle were associated with recurrence-free survival and overall survival. On the other hand, in multivariate analyses, only the sarcopenia index using paraspinal muscle was significantly related to recurrence-free survival (hazard ratio = 3.78, 95% confidence intervals = 1.29-5.97, P = 0.009) and overall survival (hazard ratio = 3.13, 95% confidence interval = 1.18-8.26, P = 0.022). Paraspinal sarcopenia index was also related to overall survival (hazard ratio = 3.74, 95% confidence interval = 1.31-10.72, P = 0.014) even in patients with advanced stage. Serum albumin was significantly correlated with the sarcopenia index (P = 0.012). Within the analysis of the validation set, sarcopenia index using paraspinal muscle was related to recurrence-free survival (hazard ratio = 2.06, P = 0.045) in multivariate analysis and recurrence-free survival (P = 0.009) in patients with advanced stage. Conclusions: The sarcopenia index using the paraspinal muscle, not psoas, could be a suitable index to predict recurrence-free survival and overall survival in patients with type-II endometrial cancer even in advanced stage.

DOI： 10.1093/jjco/hyad086

Interleukin-17A stimulation induces alterations in Microglial microRNA expression profiles 国際誌

Iitani, Y; Miki, R; Imai, K; Fuma, K; Ushida, T; Tano, S; Yoshida, K; Yokoi, A; Kajiyama, H; Kotani, T

PEDIATRIC RESEARCH 95 巻 ( 1 ) 頁： 167 - 173 2023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：Pediatric Research

Background: Increased maternal interleukin (IL)-17A and activated microglia are pivotal factors contributing to the pathological phenotypes of maternal immune activation (MIA), developing neurodevelopmental disorders in offspring. This study aimed to determine whether IL-17A affects the microglial microRNA (miRNA) profiles. Methods: The miRNA expression profiles of primary cultured microglia stimulated with recombinant IL-17A were examined comprehensively using miRNA sequencing and validated through qRT-PCR. The expressions of miRNAs target genes identified using bioinformatics, were investigated in microglia transfected with mimic miRNA. The target gene’s expression was also examined in the fetal brains of the MIA mouse model induced by maternal lipopolysaccharide (LPS) administration. Results: Primary cultured microglia expressed the IL-17A receptor and increased proinflammatory cytokines and nitric oxide synthase 2 upon treatment with IL-17A. Among the three miRNAs with |log2FC | >1, only mmu-miR-206-3p expression was significantly up-regulated by IL-17A. Transfection with the mmu-miR-206-3p mimic resulted in a significant decrease in the expression of Hdac4 and Igf1, target genes of mmu-miR-206-3p. Hdac4 expression also significantly decreased in the LPS-induced MIA model. Conclusions: IL-17A affected microglial miRNA profiles with upregulated mmu-miR-206-3p. These findings suggest that targeting the IL-17A/mmu-miR-206-3p pathway may be a new strategy for predicting MIA-related neurodevelopmental deficits and providing preventive interventions. Impact: Despite the growing evidence of interleukin (IL)-17A and microglia in the pathology of maternal immune activation (MIA), the downstream of IL-17A in microglia is not fully known.IL-17A altered microRNA profiles and upregulated the mmu-miR-206-3p expression in microglia. The mmu-miR-206-3p reduced autism spectrum disorder (ASD) related gene expressions, Hdac4 and Igf1.The Hdac4 expression was also reduced in the brain of MIA offspring.The hsa-miR-206 sequence is consistent with that of mmu-miR-206-3p.This study may provide clues to pathological mechanisms leading to predictions and interventions for ASD children born to mothers with IL-17A-related disorders.

DOI： 10.1038/s41390-023-02825-6

DDIT4 Facilitates Lymph Node Metastasis via the Activation of NF-kB Pathway and Epithelial-Mesenchymal Transition 国際誌

Lin, XX; Yoshikawa, N; Liu, WT; Matsukawa, T; Nakamura, K; Yoshihara, M; Koya, Y; Sugiyama, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Shimizu, Y; Kajiyama, H

REPRODUCTIVE SCIENCES 30 巻 ( 9 ) 頁： 2829 - 2841 2023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：Reproductive Sciences

This study was aimed to identify a novel metastasis-promoting molecule and elucidate its functional and prognostic roles in cervical cancer. DDIT4 (DNA-damage-inducible transcript 4), a hypoxia-inducible gene, was identified by analyzing multiple microarray databases. The correlation between DDIT4 expression in immunohistochemistry and clinicopathological characteristics in the public database and our cohort was evaluated by statistical analysis. Transwell® assay and wound-healing assay to determine cell migration and invasion were performed. DDIT4 was knocked down using siRNA or lentiviral vectors. The potential downstream pathways of DDIT4 were explored and verified by a gene set enrichment analysis and western blotting. The in vivo metastatic capability was determined with the use of an intraperitoneal injection mouse model. In the analysis of the public database and our cohort, DDIT4 high expression was significantly related to short overall survival and lymph node metastasis in patients with early-stage cervical cancer. The knockdown of DDIT4 attenuated the migration and invasion activity of tumor cells in vitro and reduced the expression of epithelial–mesenchymal transition (EMT)-related proteins and the NF-κB pathway in cervical cancer cells. DDIT4 also promoted tumor progression in the mouse model. Our results indicate that DDIT4 can be a prognostic indicator in cervical cancer and promote lymph node metastasis, augmenting malignancy via the EMT and NF-kB pathways.

DOI： 10.1007/s43032-023-01230-y

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