研究者詳細 - 横井　暁

ChrXq27.3 miRNA cluster functions in cancer development 査読有り国際誌

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

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 40 巻 ( 1 ) 頁： 112 - 112 2021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：Journal of Experimental and Clinical Cancer Research

MicroRNAs (miRNAs) regulate the expression of their target genes post-transcriptionally; thus, they are deeply involved in fundamental biological processes. miRNA clusters contain two or more miRNA-encoding genes, and these miRNAs are usually coexpressed due to common expression mechanisms. Therefore, miRNA clusters are effective modulators of biological pathways by the members coordinately regulating their multiple target genes, and an miRNA cluster located on the X chromosome q27.3 region has received much attention in cancer research recently. In this review, we discuss the novel findings of the chrXq27.3 miRNA cluster in various types of cancer. The chrXq27.3 miRNA cluster contains 30 mature miRNAs synthesized from 22 miRNA-encoding genes in an ~ 1.3-Mb region. The expressions of these miRNAs are usually negligible in many normal tissues, with the male reproductive system being an exception. In cancer tissues, each miRNA is dysregulated, compared with in adjacent normal tissues. The miRNA-encoding genes are not uniformly distributed in the region, and they are further divided into two groups (the miR-506-514 and miR-888-892 groups) according to their location on the genome. Most of the miRNAs in the former group are tumor-suppressive miRNAs that are further downregulated in various cancers compared with normal tissues. miR-506-3p in particular is the most well-known miRNA in this cluster, and it has various tumor-suppressive functions associated with the epithelial–mesenchymal transition, proliferation, and drug resistance. Moreover, other miRNAs, such as miR-508-3p and miR-509-3p, have similar tumor-suppressive effects. Hence, the expression of these miRNAs is clinically favorable as prognostic factors in various cancers. However, the functions of the latter group are less understood. In the latter group, miR-888-5p displays oncogenic functions, whereas miR-892b is tumor suppressive. Therefore, the functions of the miR-888–892 group are considered to be cell type- or tissue-specific. In conclusion, the chrXq27.3 miRNA cluster is a critical regulator of cancer progression, and the miRNAs themselves, their regulatory mechanisms, and their target genes might be promising therapeutic targets.

DOI： 10.1186/s13046-021-01910-0

Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance 査読有り国際誌

Yoshida, K; Yokoi, A; Sugiyama, M; Oda, S; Kitami, K; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kikkawa, F; Yokoi, T; Kajiyama, H

ONCOGENE 40 巻 ( 7 ) 頁： 1255 - 1268 2021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：Oncogene

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.

DOI： 10.1038/s41388-020-01595-3

Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype. 査読有り国際誌

Ma S, McGuire MH, Mangala LS, Lee S, Stur E, Hu W, Bayraktar E, Villar-Prados A, Ivan C, Wu SY, Yokoi A, Dasari SK, Jennings NB, Liu J, Lopez-Berestein G, Ram P, Sood AK

Cell reports 34 巻 ( 6 ) 頁： 108726 - 108726 2021年2月

A novel approach for liquid biopsy by using nuclear derived exosomes in ovarian cancer 査読有り国際誌

Yokoi, A

CANCER SCIENCE 112 巻頁： 986 - 986 2021年2月

The role of chrXq27.3 miRNA cluster in advanced ovarian clear cell carcinoma 査読有り国際誌

Yoshida, K; Yokoi, A; Yoshihara, M; Tamauchi, S; Yoshikawa, N; Nishino, K; Niimi, K; Kikkawa, F; Kajiyama, H

CANCER SCIENCE 112 巻頁： 291 - 291 2021年2月

Luteolin suppresses Ovarian Cancer progression via decrease the expression of VRK1 査読有り国際誌

Chang, XY; Kajiyama, H; Yoshikawa, N; Yokoi, A; Tamauchi, S; Yoshihara, M

CANCER SCIENCE 112 巻頁： 770 - 770 2021年2月

Intra-tumoral polarity induced by Notch signaling can be a novel therapeutic target for advanced ovarian cancer 査読有り国際誌

Yoshihara, M; Sugiyama, M; Koya, Y; Iyoshi, S; Kitami, K; Uno, K; Mogi, K; Tano, S; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

CANCER SCIENCE 112 巻頁： 363 - 363 2021年2月

How do peritoneal mesothelial cells on adipose tissue attract ovarian cancer cells? 査読有り国際誌

Mogi, K; Yoshihara, M; Kitami, K; Iyoshi, S; Uno, K; Tano, S; Sugiyama, M; Koya, Y; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

CANCER SCIENCE 112 巻頁： 341 - 341 2021年2月

Extracellular miRNAs as Predictive Biomarkers for Glypican-3-Derived Peptide Vaccine Therapy Response in Ovarian Clear Cell Carcinoma 査読有り国際誌

Ukai, M; Yokoi, A; Yoshida, K; Suzuki, S; Shibata, K; Kikkawa, F; Nakatsura, T; Kajiyama, H

CANCERS 13 巻 ( 3 ) 頁： 550 - 550 2021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：Cancers

Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy; however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine.

DOI： 10.3390/cancers13030550

Exploring the biological roles of extracellular vesicles carrying nucleic acids in ovarian cancer 査読有り国際誌

Yokoi, A

CANCER SCIENCE 112 巻頁： 204 - 204 2021年2月

Comprehensive analyses of small extracellular vesicles carrying nucleic acids in ovarian cancer 査読有り国際誌

Yokoi, A; Ochiya, T

CANCER SCIENCE 112 巻頁： 973 - 973 2021年2月

Active vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer 査読有り国際誌

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

CANCER SCIENCE 112 巻頁： 351 - 351 2021年2月

血液マイクロRNAによる子宮肉腫と変性筋腫の術前鑑別診断

加藤友康, 横井暁, 松崎潤太郎, 山本雄介, 舘慶生, 米岡完, 清水華子, 植原貴史, 石川光也, 滝澤聡子, 青木良晃, 加藤健, 落谷孝広, 東レ株式会社新事業開発部門DNAチップG

日本婦人科腫瘍学会雑誌 39 巻 ( 1 ) 頁： 297 - 297 2021年1月

Establishment and characterization of cell lines from human endometrial epithelial and mesenchymal cells from patients with endometriosis. 査読有り国際誌

Muraoka A, Osuka S, Kiyono T, Suzuki M, Yokoi A, Murase T, Nishino K, Niimi K, Nakamura T, Goto M, Kajiyama H, Kondo Y, Kikkawa F

F&S science 1 巻 ( 2 ) 頁： 195 - 205 2020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：F and S Science

Objective: To establish and characterize cell lines derived from human endometrial epithelial cells (ECs) and mesenchymal cells (MCs) from patients with and without endometriosis. Design: In vitro experimental study. Setting: University and national cancer center research institute. Patient(s): Two women with endometriosis and two women without endometriosis. Intervention(s): Sampling of endometrial ECs and MCs. Main Outcome Measure(s): Establishing immortalized endometrial ECs and MCs with quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunocytochemical analysis, and RNA sequence profiling performed to characterize the immortalized cells and a cell proliferation assay, three-dimensional culture, and assays for hormone responses performed to characterize the features of ECs. Result(s): The qRT-PCR, immunocytochemical analysis, and Western blot analysis revealed that the ECs and MCs maintained their original features. Moreover, the immortalized cells were found to retain responsiveness to sex steroid hormones. The ECs formed a gland-like structure in three-dimensional culture, indicating the maintenance of normal EC phenotypes. The RNA sequence profiling, principal component analysis, and clustering analysis showed that the gene expression patterns of the immortalized cells were different from those of cancer cells. Several signaling pathways that were statistically significantly enriched in ECs and MCs with endometriosis were revealed. Conclusion(s): We successfully obtained four paired immortalized endometrial ECs and MCs from patients with and without endometriosis. Using these cells could help identify diagnostic and therapeutic targets for endometriosis. The cell lines established in this study will thus serve as powerful experimental tools in the study of endometriosis.

DOI： 10.1016/j.xfss.2020.09.001

The clinical impact of intra- and extracellular miRNAs in ovarian cancer 査読有り国際誌

Yoshida, K; Yokoi, A; Kato, T; Ochiya, T; Yamamoto, Y

CANCER SCIENCE 111 巻 ( 10 ) 頁： 3435 - 3444 2020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：Cancer Science

Ovarian cancer is the most lethal gynecological cancer due to lack of early screening methods and acquired drug resistance. MicroRNAs (miRNAs) are effective post-transcriptional regulators that are transferred by extracellular vesicles, such as exosomes. Numerous studies have revealed that miRNAs are differentially expressed in epithelial ovarian cancer and act either as oncogenes or tumor suppressor genes. Cancer cells secrete exosomes containing miRNAs, which exert various effects on the components of the tumor microenvironment, including cancer-associated fibroblasts, macrophages, and adipocytes. Conversely, cancer cells also receive exosomes from these cells. As a result of cell-to-cell communication, epithelial ovarian cancer acquires a more aggressive phenotype and resistance to multiple drugs. In addition, some circulating miRNAs are protected from RNase degradation in the peripheral blood and can be potential non-invasive biomarkers. In particular, the combination of several circulating miRNAs enhances the accuracy of cancer screening. Likewise, comprehensive analyses revealed specific miRNA signatures in non-epithelial ovarian tumors and several miRNAs contributing to alterations of carcinogenic pathways. Overall, miRNAs play a crucial role in ovarian cancer progression. In this review, we discuss the emerging roles of intra- and extracellular miRNAs in ovarian cancers. In the near future, miRNAs will be practical biomarkers and computational deep learning will help in the clinical application of miRNAs. Moreover, miRNAs are potential therapeutic targets and agents, and there are ongoing clinical trials of miRNA replacement therapy. Therefore, accelerating research on miRNA might improve the prognosis of patients with ovarian cancer.

DOI： 10.1111/cas.14599

Ovarian cancer-associated mesothelial cells induce acquired platinum-resistance in peritoneal metastasis <i>via</i> the FN1/Akt signaling pathway 査読有り国際誌

Yoshihara, M; Kajiyama, H; Yokoi, A; Sugiyama, M; Koya, Y; Yamakita, Y; Liu, WT; Nakamura, K; Moriyama, Y; Yasui, H; Suzuki, S; Yamamoto, Y; Ricciardelli, C; Nawa, A; Shibata, K; Kikkawa, F

INTERNATIONAL JOURNAL OF CANCER 146 巻 ( 8 ) 頁： 2268 - 2280 2020年4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 Cancer

Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

DOI： 10.1002/ijc.32854

Prognostic impact of pelvic and para-aortic lymphadenectomy on clinically-apparent stage I primary mucinous epithelial ovarian carcinoma: a multi-institutional study with propensity score-weighted analysis 査読有り国際誌

Yoshihara, M; Kajiyama, H; Tamauchi, S; Iyoshi, S; Yokoi, A; Suzuki, S; Kawai, M; Nagasaka, T; Takahashi, K; Matsui, S; Kikkawa, F

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 50 巻 ( 2 ) 頁： 145 - 151 2020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：Japanese Journal of Clinical Oncology

Background: The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. Methods: We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Results: Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P = 0.696) and recurrence-free survival (P = 0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. Conclusions: The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

DOI： 10.1093/jjco/hyz163

Serum microRNA profile enables preoperative diagnosis of uterine leiomyosarcoma 査読有り国際誌

Yokoi, A; Matsuzaki, J; Yamamoto, Y; Tate, K; Yoneoka, Y; Shimizu, H; Uehara, T; Ishikawa, M; Takizawa, S; Aoki, Y; Kato, K; Kato, T; Ochiya, T

CANCER SCIENCE 110 巻 ( 12 ) 頁： 3718 - 3726 2019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：Cancer Science

Uterine leiomyosarcoma (ULMS) is the major subtype of uterine sarcoma (US) and contributes to uterine cancer deaths. Although preoperative diagnosis of US remains challenging, frequent application of laparoscopic surgery for benign uterine leiomyomas (ULM) requires precise exclusion of US. MicroRNAs are stably present in the bloodstream, and the application of circulating miRNAs as disease biomarkers has been recognized. In the present study, we aimed to identify diagnostic biomarkers for distinguishing US from ULM by focusing on circulating miRNAs. All serum samples were collected preoperatively between 2009 and 2017, and all cases were histopathologically diagnosed. Whole miRNA profiles were obtained using a miRNA microarray. By analyzing expression levels of the miRNAs, candidate miRNAs were selected based on diagnostic performance in discriminating US from ULM, and a diagnostic model was then constructed. A total of 90 serum samples were analyzed, and clustering analyses revealed that the profiles of ULMS were distinct from those of controls. Based on leave-one-out cross-validation, seven miRNAs were selected as biomarker candidates. Based on model construction, the optimal model consisted of two miRNAs (miR-1246 and miR-191-5p), with an area under the receiver operating characteristic curve (AUC) for identifying ULMS of 0.97 (95% confidence interval [CI], 0.91-1.00). In contrast, serum lactate dehydrogenase had an AUC of only 0.64 (95% CI, 0.34-0.94). Seven serum miRNAs with high diagnostic performance for preoperative US screening were detected, and a promising diagnostic model for ULMS was generated.

DOI： 10.1111/cas.14215