研究者詳細 - 松崎　潤太郎

論文 - 松崎　潤太郎

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Serum microRNA profile enables preoperative diagnosis of uterine leiomyosarcoma

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

Cancer Science （Cancer Science） 110 （ 12 ） 3718 - 3726 2019年

研究論文（学術雑誌）, 筆頭著者, 査読有り

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 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.

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Peripheral neuropathy from paclitaxel: Risk prediction by serum microRNAs

Noda-Narita, S. and Shimomura, A. and Tanabe, Y. and Kawauchi, J. and Matsuzaki, J. and Takizawa, S. and Aoki, Y. and Shimizu, C. and Tamura, K. and Ochiya, T.

BMJ Supportive and Palliative Care （BMJ Supportive and Palliative Care） 2019年

研究論文（学術雑誌）, 査読有り

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objectives: MicroRNAs (miRNAs) have recently been reported as useful diagnostic markers in cancer; however, relationships of miRNAs with adverse events during chemotherapy have yet to be fully described. In this study, we examined the relationship between serum miRNA and the risk of peripheral neuropathy (PN), a common and persistent adverse event induced by paclitaxel, in patients with breast cancer. Methods: A total of 84 serum samples from patients with breast cancer, who received paclitaxel as neoadjuvant or adjuvant chemotherapy, were obtained between January 2011 and September 2013 at National Cancer Center Hospital. Samples were divided, 2:1, into a training cohort and a test cohort, respectively; both cohorts included specimens from patients with severe PN (≥grade 2, PN group) and non-severe PN controls (non-PN group). The training cohort was used to identify miRNAs, and combinations thereof, that could predict PN, which then were validated in the test cohort. Results: Eighty-four patients received paclitaxel: 38 and 46 patients in the PN and non-PN groups, respectively. We identified 15 discriminatory miRNAs with |fold change|>0.5, and 14 combinations of three miRNAs showed the ability to discriminate, with sensitivity, specificity and accuracy of >50%. The most discriminatory miRNA, with the highest |fold change|, was miR-451a, which regulates the expression of the drug-transporter protein P-glycoprotein, potentially promoting paclitaxel resistance. Conclusion: MiR-451a could be a predictive marker for PN caused by paclitaxel-containing chemotherapy; however, further investigation of the underlying mechanism is required to determine the role of miR-451a.

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Large-scale circulating microRNA profiling for the liquid biopsy of prostate cancer

Urabe, F. and Matsuzaki, J. and Yamamoto, Y. and Kimura, T. and Hara, T. and Ichikawa, M. and Takizawa, S. and Aoki, Y. and Niida, S. and Sakamoto, H. and Kato, K. and Egawa, S. and Fujimoto, H. and Ochiya, T.

Clinical Cancer Research （Clinical Cancer Research） 25 （ 10 ） 3016 - 3025 2019年

研究論文（学術雑誌）, 筆頭著者, 査読有り

© 2019 American Association for Cancer Research. Purpose: The high false-positive rate of prostate-specific antigen (PSA) may lead to unnecessary prostate biopsies. Therefore, the United States Preventive Services Task Force recommends that decisions regarding PSA-based screening of prostate cancer should be made with caution in men ages 55–69 years, and that men 70 years should not undergo PSA screening. Here, we investigated the potential of serum miRNAs as an accurate diagnostic method in patients with suspected prostate cancer. Experimental Design: Serum samples of 809 patients with prostate cancer, 241 negative prostate biopsies, and 500 patients with other cancer types were obtained from the National Cancer Center, Japan. Forty-one healthy control samples were obtained from two other hospitals in Japan. Comprehensive microarray analysis was performed for all samples. Samples were divided into three sets. Candidate miRNAs for prostate cancer detection were identified in the discovery set (n ¼ 123). A diagnostic model was constructed using combinations of candidate miRNAs in the training set (n ¼ 484). The performance of the diagnostic model was evaluated in the validation set (n ¼ 484). Results: In the discovery set, 18 candidate miRNAs were identified. A robust diagnostic model was constructed using the combination of two miRNAs (miR-17-3p and miR-1185-2-3p) in the training set. High diagnostic performance with a sensitivity of 90% and a specificity of 90% was achieved in the validation set regardless of the Gleason score and clinical tumor–node–metastasis stage. Conclusions: The model developed in this study may help improve the diagnosis of prostate cancer and reduce the number of unnecessary prostate biopsies.

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Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

Katsuda, T. and Matsuzaki, J. and Yamaguchi, T. and Yamada, Y. and Prieto-Vila, M. and Hosaka, K. and Takeuchi, A. and Saito, Y. and Ochiya, T.

eLife （eLife） 8 2019年

研究論文（学術雑誌）, 共著, 査読有り

© Katsuda et al. Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.

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Generation of functional human hepatocytes in vitro: Current status and future prospects

Yamaguchi, T. and Matsuzaki, J. and Katsuda, T. and Saito, Y. and Saito, H. and Ochiya, T.

Inflammation and Regeneration （Inflammation and Regeneration） 39 （ 1 ） 13 2019年

研究論文（学術雑誌）, 査読有り

© 2019 The Author(s). Liver and hepatocyte transplantation are the only effective therapies for late-stage liver diseases, in which the liver loses its regenerative capacity. However, there is a shortage of donors. As a potential alternative approach, functional hepatocytes were recently generated from various cell sources. Analysis of drug metabolism in the human liver is important for drug development. Consequently, cells that metabolize drugs similar to human primary hepatocytes are required. This review discusses the current challenges and future perspectives concerning hepatocytes and hepatic progenitor cells that have been reprogrammed from various cell types, focusing on their functions in transplantation models and their ability to metabolize drugs.

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Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori–Infected CAPZA1-Overexpressing Cells

Tsugawa, H. and Kato, C. and Mori, H. and Matsuzaki, J. and Kameyama, K. and Saya, H. and Hatakeyama, M. and Suematsu, M. and Suzuki, H.

Cellular and Molecular Gastroenterology and Hepatology （Cellular and Molecular Gastroenterology and Hepatology） 8 （ 3 ） 319 - 334 2019年

研究論文（学術雑誌）, 査読有り

© 2019 The Authors Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.

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Molecular characterization of the gastric commensal bacteria progressing gastric carcinogenesis in H. pylori-infected gastric mucosa

H TsugaWa, J Matsuzaki, H Mori, M Suematsu, H Suzuki

HELICOBACTER 24 2019年

研究論文（国際会議プロシーディングス）

P1. 11-10 Serum MicroRNA Biomarkers for Screening of Resectable Lung Cancer

K Asakura, T Kadota, J Matsuzaki, Y Yoshida, K Nakagawa, H Asamura, ...

Journal of Thoracic Oncology 14 (10), S519 2019年

研究論文（国際会議プロシーディングス）

MP13-09 NOVEL COMBINATION OF CIRCULATING MIRNAS FOR SPECIFIC DETECTION IN PROSTATE CANCER

F Urabe*, J Matsuzaki, Y Yamamoto, T Kimura, T Hara, S Egawa, ...

The Journal of Urology 201 (Supplement 4), e180-e180 2019年

研究論文（国際会議プロシーディングス）

ACTR-17. DIAGNOSTIC UTILITY OF SERUM microRNA CLASSIFICATION IN DIFFUSE GLIOMA

M Ohno, J Matsuzaki, J Kawauchi, Y Aoki, J Miura, S Takizawa, K Kato, ...

Neuro-Oncology 21 (Suppl 6), vi16 2019年

研究論文（国際会議プロシーディングス）

Integrated extracellular microRNA profiling for ovarian cancer screening

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 （Nature Communications） 9 （ 1 ） 4319 2018年12月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

© 2018, The Author(s). 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.

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Helicobacter pylori eradication failure may have confounded the recent large-scale health database study that showed proton pump inhibitors increase gastric cancer risk

Suzuki H., Matsuzaki J.

Gut （Gut） 67 （ 11 ） 2071 - 2072 2018年11月

研究論文（学術雑誌）, 最終著者, 査読有り

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Inhibiting xCT improves 5-fluorouracil resistance of gastric cancer induced by CD44 variant 9 expression

Miyoshi S., Tsugawa H., Matsuzaki J., Hirata K., Mori H., Saya H., Kanai T., Suzuki H.

Anticancer Research （Anticancer Research） 38 （ 11 ） 6163 - 6170 2018年11月

研究論文（学術雑誌）, 査読有り

© 2018 International Institute of Anticancer Research.All right reserved. Background/Aim: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance. Materials and Methods: The human gastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding human CD44 or CD44v9, which were used for in vitro and in vivo experiments. Results: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells. Conclusion: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer.

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Gastric cancer: evidence boosts Helicobacter pylori eradication

Suzuki H., Matsuzaki J.

Nature Reviews Gastroenterology and Hepatology （Nature Reviews Gastroenterology and Hepatology） 15 （ 8 ） 458 - 460 2018年08月

研究論文（学術雑誌）

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【がんはどこまでわかるようになったか】血液中miRNA検査

松崎潤太郎, 藏田隼也, 落谷孝広

医療と検査機器・試薬（ラボ・サービス） 41 （ 4 ） 334 - 336 2018年08月

共著, ISSN 1347-0434

Extracellular microRNAs and oxidative stress in liver injury: A systematic mini review

Matsuzaki J., Ochiya T.

Journal of Clinical Biochemistry and Nutrition （Journal of Clinical Biochemistry and Nutrition） 63 （ 1 ） 6 - 11 2018年07月

研究論文（学術雑誌）, 筆頭著者, 責任著者, 査読有り

© 2018 JCBN. Recent evidence has suggested that extracelluar microRNAs crucial roles in intercellular communications and are promising as minimally invasive biomarkers for various diseases including cancers. Oxidative stress also plays an essential role in homeostasis and disease development. This systematic review aims to clarify the current evidence on the interaction between oxidative stress and extracellular microRNAs. We identified 32 studies that provided information regarding the association between oxidative stress and extracellular microRNAs: 9 focused on the central nervous system, 11 focused on cardiovascular diseases, and 4 focused on liver injury. Endothelial cell-specific miR-126-3p was the most studied extracellular miRNA associated with oxidative stress. In addition, we highlight some reports that describe the mechanisms of how oxidative stress affects extracellular microRNA profiles in liver injury. In liver injury, the levels of miR-122-5p, miR-192-5p, miR-223-3p, and miR-1224-5p were reported to be elevated in the sera. The release of miR-122-5p, miR-192-5p, and miR-1224-5p from hepatocytes may be attributed to oxidative stress. miR-223-3p could be released from neutrophils and suppress oxidative stress in the liver. Elucidation of the mechanisms of the interaction between extracellular microRNAs and oxidative stress would improve our pathophysiological understanding as well as future medical practice.

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【上部消化管疾患の現況と今後の展望-病態・診断から治療を探る】バレット食道・食道腺癌

松崎潤太郎

カレントテラピー（(株)ライフメディコム） 36 （ 7 ） 639 - 644 2018年07月

共著, ISSN 0287-8445

Absence of high-risk stigmata predicts good prognosis even in severely anemic patients with suspected acute upper gastrointestinal bleeding

Horibe M., Ogura Y., Matsuzaki J., Kaneko T., Yokota T., Okawa O., Nakatani Y., Iwasaki E., Nishizawa T., Hosoe N., Masaoka T., Yahagi N., Namiki S., Kanai T.

United European Gastroenterology Journal （United European Gastroenterology Journal） 6 （ 5 ） 684 - 690 2018年06月

研究論文（学術雑誌）, 査読有り

© 2018, Author(s) 2018. Background: The need for a blood transfusion, defined as hemoglobin < 70 g/L, is the measure for assessing the risk levels in patients with upper gastrointestinal bleeding (UGIB). However, not all patients with a low hemoglobin level have a poor prognosis. Objective: We assessed the clinical predictive factors associated with poor short-term prognosis in patients with a low hemoglobin level. Methods: In this prospective cohort study, all consecutive patients with suspected acute UGIB at Tokyo Metropolitan Tama Medical Center were enrolled between 2008 and 2015. Then, we extracted those who needed a blood transfusion (hemoglobin < 70 g/L) and explored the variables associated with all-cause mortality within 28 days after presentation. Results: Among 1307 patients, 311 needed a blood transfusion and 13 (4.2%) died from all causes. The presence of high-risk stigmata requiring endoscopic treatment (peptic ulcers; Forrest scores Ia, Ib and IIa; varices with current bleeding or signs of recent bleeding; and spurting or gushing bleeding or visible vessel in other diseases), diagnosed by emergency endoscopy, was a unique factor affecting mortality (odds ratio: 8.47, 95% confidence interval: 1.45–160, P = 0.01). Patients without high-risk stigmata neither died from UGIB nor had rebleeding, irrespective of the hemoglobin levels. Conclusions: Patients without high-risk stigmata showed a good prognosis even if they needed a blood transfusion. This result could facilitate triage of patients with suspected acute UGIB who only need a blood transfusion.

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【Liquid biopsyへの期待と限界】miRNAによるliquid biopsy

松崎潤太郎

医学のあゆみ（医歯薬出版(株)） 265 （ 6 ） 499 - 503 2018年05月

共著, ISSN 0039-2359

血中マイクロRNA(miRNA)は、悪性腫瘍を含む体内のさまざまな異常を反映して固有のプロファイルを示すことがわかりつつあり、最適医療時代における次世代型のバイオマーカーとして注目されている。とくにがんの早期診断については、きわめて優れた診断性能が国内外から報告されている。加えて、がんの治療効果モニタリングや再発予測、予後予測によるハイリスク集団の層別化など、がん診断において広い応用範囲をもつと考えられている。またエクソソームなどの細胞外小胞に内包されて分泌されたmiRNAは、他の細胞に移行してその機能を発揮することができ、細胞間シグナル伝達ツールとしての役割を担っている。そのため血中miRNAプロファイルと疾患の関係を追究することにより、腫瘍の浸潤や転移に重要なあらたな治療標的の同定に寄与する可能性も期待できる。現在著者らの研究グループでは、バイオバンク保存血清を用いた大規模な血中miRNAデータベースを作成しており、がんの超早期診断の実用化をめざしている。(著者抄録)

Acquisition of double mutation in gyrA caused high resistance to sitafloxacin in Helicobacter pylori after unsuccessful eradication with sitafloxacin-containing regimens

Mori H., Suzuki H., Matsuzaki J., Masaoka T., Kanai T.

United European Gastroenterology Journal （United European Gastroenterology Journal） 6 （ 3 ） 391 - 397 2018年04月

研究論文（学術雑誌）, 査読有り

© 2017, © Author(s) 2017. Background and aim: Although sitafloxacin (STFX)-containing regimens are effective rescue treatments for Helicobacter pylori infection, prevalence of fluoroquinolone resistance in H. pylori has increased rapidly worldwide. The change in resistance levels and gyrA mutations, a major cause of fluoroquinolone resistance, after unsuccessful STFX-containing treatment has not been investigated. Methods: We conducted a retrospective, non-randomized study to compare the minimum inhibitory concentrations (MICs) of STFX and the location of gyrA mutations in H. pylori before and after unsuccessful eradication with STFX-containing regimens at Keio University Hospital between December 2011 and March 2015. Results: A total of 266 patients treated with STFX-containing regimens for third-line H. pylori eradication were evaluated. Double mutations in gyrA were acquired by 20.8% of strains that exhibited seven-fold increased STFX MICs, compared to pre-treatment MICs. The STFX MICs did not increase, however, when the location of the gyrA mutations did not change after treatment. Double mutations in gyrA developed in 60.0% of the strains in which eradication failed, which exhibited a baseline mutation at position D91, and in 11.1% of strains with baseline mutations at position N87. Conclusion: Acquisition of double mutations in gyrA evoked high-level resistance to STFX in H. pylori after unsuccessful eradication with STFX-containing regimens.

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松崎 潤太郎

論文 - 松崎 潤太郎

松崎　潤太郎

論文 - 松崎　潤太郎