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Summary of Hazard Ratios in ccRCC

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Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to antiangiogenic multikinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the HIF2α antagonists. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists. Cancer Res; 77(22); 6321–9. ©2017 AACR.

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d‐3‐Phosphoglycerate dehydrogenase (PHGDH) conducts an important step in the synthesis of serine. Importantly, the PHGDH gene is often amplified in certain cancers. Our previous studies revealed that PHGDH gene amplification was associated with poor overall survival in clear cell renal cell carcinoma (ccRCC) and that metabolic reprogramming of serine synthesis through PHGDH recruitment allowed ccRCC cells to survive in unfavorable environments. There have been no investigations of the role of PHGDH expression in bladder cancer (BC). In this investigation, we examined the clinical importance of PHDGH in BC. Furthermore, we asked whether PHGDH expression could be exploited for BC therapy. Finally, we investigated the regulatory mechanisms that modulated the expression of PHGDH. Using data from The Cancer Genome Atlas, we found that patients with high‐grade BC had significantly higher PHGDH expression levels than did those with low‐grade BC. In addition, patients with high PHGDH expression did not survive as long as those with low expression. PHGDH downregulation by si‐RNAs or an inhibitor in BC cell lines significantly inhibited proliferative ability and induced apoptosis. Furthermore, combined treatment using a PHGDH inhibitor and gemcitabine/cisplatin achieved synergistic tumor suppression compared to use of a single agent both in vitro as well as in vivo. Mechanistic analyses of PHGDH regulation showed that PHGDH expression might be associated with DNA copy number and hypomethylation in BC. These findings suggest novel therapeutic strategies could be used in BC. Finally, our data enhance our understanding of the role of PHGDH in BC., This research investigated PHGDH, a key enzyme in the serine biosynthesis, in bladder cancer. PHGDH downregulation significantly inhibited cell proliferation, and the combined treatment between PHGDH inhibitor and gemcitabine/cisplatin achieved synergistic tumor suppressive effect compared to each single agent group both in vitro and in vivo. We also indicated that PHGDH was regulated by DNA copy number and hypomethylation.

Morphological changes in neuromuscular junctions (NMJs), which are synapses formed between α-motor neurons and skeletal muscle fibers, are considered to be important in age-related motor dysfunction. We have previously shown that the intake of dietary milk fat globule membrane (MFGM) combined with exercise attenuates age-related NMJ alterations in the early phase of aging. However, it is unclear whether the effect of MFGM with exercise on age-related NMJ alterations persists into old age, and whether intervention from old age is still effective when age-related changes in NMJs have already occurred. In this study, 6- or 18-month-old mice were treated with a 1% MFGM diet and daily running wheel exercise until 23 or 24 months of age, respectively. MFGM treatment with exercise was effective in suppressing the progression of age-related NMJ alterations in old age, and even after age-related changes in NMJs had already occurred. Moreover, the effect of MFGM intake with exercise was not restricted to NMJs but extended to the structure and function of peripheral nerves. This study demonstrates that MFGM intake with exercise may be a novel approach for improving motor function in the elderly by suppressing age-related NMJ alterations.

The Calorimetric Electron Telescope (CALET), in operation on the International Space Station since 2015, collected a large sample of cosmic-ray iron over a wide energy interval. In this Letter a measurement of the iron spectrum is presented in the range of kinetic energy per nucleon from 10 GeV/n to 2.0 TeV/n allowing the inclusion of iron in the list of elements studied with unprecedented precision by space-borne instruments. The measurement is based on observations carried out from January 2016 to May 2020. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The energy is measured by a homogeneous calorimeter with a total equivalent thickness of 1.2 proton interaction lengths preceded by a thin (3 radiation lengths) imaging section providing tracking and energy sampling. The analysis of the data and the detailed assessment of systematic uncertainties are described and results are compared with the findings of previous experiments. The observed differential spectrum is consistent within the errors with previous experiments. In the region from 50 GeV/n to 2 TeV/n our present data are compatible with a single power law with spectral index -2.60±0.03.

The detections of gravitational waves (GW) by the LIGO/Virgo collaborations provide various possibilities for both physics and astronomy. We are quite sure that GW observations will develop a lot, both in precision and in number, thanks to the continuous work on the improvement of detectors, including the expected new detector, KAGRA, and the planned detector, LIGO-India. On this occasion, we review the fundamental outcomes and prospects of gravitational wave physics and astronomy. We survey the development, focusing on representative sources of gravitational waves: binary black holes, binary neutron stars, and supernovae. We also summarize the role of gravitational wave observations as a probe of new physics.

In this paper, we present the measurement of the energy spectra of carbon and oxygen in cosmic rays based on observations with the Calorimetric Electron Telescope (CALET) on the International Space Station from October 2015 to October 2019. Analysis, including the detailed assessment of systematic uncertainties, and results are reported. The energy spectra are measured in kinetic energy per nucleon from 10 GeV$/n$ to 2.2 TeV$/n$ with an all-calorimetric instrument with a total thickness corresponding to 1.3 nuclear interaction length. The observed carbon and oxygen fluxes show a spectral index change of $\sim$0.15 around 200 GeV$/n$ established with a significance $>3\sigma$. They have the same energy dependence with a constant C/O flux ratio $0.911\pm 0.006$ above 25 GeV$/n$. The spectral hardening is consistent with that measured by AMS-02, but the absolute normalization of the flux is about 27% lower, though in agreement with observations from previous experiments including the PAMELA spectrometer and the calorimetric balloon-borne experiment CREAM.

HiZ-GUNDAM is a future satellite mission which will lead the time-domain astronomy and the multi-messenger astronomy through observations of high-energy transient phenomena. A mission concept of HiZ-GUNDAM was approved by ISAS/JAXA, and it is one of the future satellite candidates of JAXA’s medium-class mission. We are in pre-phase A (before pre-project) and elaborating the mission concept, mission/system requirements for the launch in the late 2020s. The main themes of HiZ-GUNDAM mission are (1) exploration of the early universe with high-redshift gamma-ray bursts, and (2) contribution to the multi-messenger astronomy. HiZ-GUNDAM has two kinds of mission payload. The wide field X-ray monitors consist of Lobster Eye optics array and focal imaging sensor, and monitor ~1 steradian field of view in 0.5 – 4 keV energy range. The near infrared telescope has an aperture size 30 cm in diameter, and simultaneously observes four wavelength bands between 0.5 – 2.5 μm. In this paper, we introduce the mission overview of HiZ-GUNDAM.

CFRP is a composite material composed of carbon fiber and resin. CFRP is commonly applied to the aerospace industry which requires lightweight and intensity. Thanks to superior formability of CFRP, we can form shape of Wolter-1 optics, which consists of paraboloid and hyperboloid, to a monolithic substrate. Since the surface roughness of a CFRP substrate is a few µm, we have to make the smooth surface for reflecting X-rays on the CFRP substrate. We have developed a new method of shaping the reflective surface instead of the replica method used in lightweight X-ray mirrors such as Astro-H. In the new method, the reflective surface is formed by pasting thin sheet-glasses with 100 µm thick onto the CFRP substrate. The thin sheet-glass has a surface roughness about 0.4 nm as measured by Zygo. We fabricated a CFRP mirror pasting thin sheet-glasses, and then coated tungsten on the mirror in June 2020. The figure error (s) of the CFRP mirror was achieved to be about 1-2 μm by stacking the CFRP mirror on the housing module. X-ray imaging quality of the CFRP mirror was measured at Spring-8 in July 2020. The half-power diameter of the CFRP mirror was estimated to be about 150 arcsec, which was nearly equal to the prediction from a distribution of the slope error deduced from the surface profile. We describe a future plan to improve the image quality of the CFRP mirror.

Sunitinib is a standard molecular-targeted drug used as a first-line treatment for metastatic clear cell renal cell carcinoma (ccRCC); however, resistance to sunitinib has become a major problem in medical practice. Recently, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target, and its inhibitor JQ1 has been shown to have inhibitory effects in various human cancers. However, the anti-cancer effects of JQ1 in ccRCC, particularly sunitinib-resistant ccRCC, are still unclear. Here, we aimed to elucidate the anti-cancer effects of JQ1 and the mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCCs. Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high BRD4 expression had shorter overall survival than those with low expression. JQ1 treatment significantly inhibited tumor growth of sunitinib-sensitive and -resistant ccRCC cells in part through MYC regulation. Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of SCG5, SPOCD1, RGS19, and ARHGAP22 had poorer overall survival than those with low expression in TCGA ccRCC cohort. Chromatin immunoprecipitation assays revealed that these oncogenes may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.

著者人数: 18名, Accepted: 2017-09-01, 資料番号: SA1170188000

The alcohol-abuse drug disulfiram has antitumor effects against diverse cancer types via inhibition of the ubiquitin-proteasome protein nuclear protein localization protein 4 (NPL4). However, the antitumor effects of NPL4 and disulfiram in clear cell renal cell carcinoma (ccRCC) are unclear. Here, we evaluated the therapeutic potential of targeting the ubiquitin-proteasome pathway using disulfiram and RNA interference and investigated the mechanisms underlying disulfiram in ccRCC. According to data from The Cancer Genome Atlas, NPL4 mRNA expression was significantly upregulated in clinical ccRCC samples compared with that in normal kidney samples, and patients with high NPL4 expression had poor overall survival compared with patients with low NPL4 expression. Disulfiram and NPL4 siRNA inhibited ccRCC cell proliferation in vitro, and disulfiram inhibited ccRCC tumor growth in a xenograft model. Synergistic antiproliferative effects were observed for combination treatment with disulfiram and sunitinib in vitro and in vivo. In RCC cells from mice treated with disulfiram and/or sunitinib, several genes associated with serine biosynthesis and aldose reductase were downregulated in cells treated with disulfiram or sunitinib alone and further downregulated in cells treated with both disulfiram and sunitinib. These findings provided insights into the mechanisms of disulfiram and suggested novel therapeutic strategies for RCC treatment.

Exosomes are 40-100 nm nano-sized extracellular vesicles. They are released from many cell types and move into the extracellular space, thereby transferring their components to recipient cells. Exosomes are receiving increasing attention as novel structures participating in intracellular communication. RAB27B is one of the leading proteins involved in exosome secretion, and oncogenic effects have been reported in several cancers. In recent years, molecularly targeted agents typified by sunitinib are widely used for the treatment of metastatic or recurrent renal cell carcinoma (RCC). However, intrinsic or acquired resistance to sunitinib has become a major issue. The present study aimed to elucidate the role of RAB27B in RCC including sunitinib-resistant and its role in exosomes. Bioinformatic analyses revealed that high expression of RAB27B correlates with progression of RCC. The expression of RAB27B protein in RCC cell lines was significantly enhanced compared with that in normal kidney cell lines. Furthermore, RAB27B protein expression was enhanced in all of the tested sunitinib-resistant RCC cell lines compared to parental cells. Although no specific effect of RAB27B on exosomes was identified in RCC cells, loss-of-function studies demonstrated that knockdown of RAB27B suppressed cell proliferation, migration and invasive activities. Moreover, anti-tumor effects of RAB27B downregulation were also observed in sunitinib-resistant RCC cells. RNA sequence and pathway analysis suggested that the oncogenic effects of RAB27B might be associated with MAPK and VEGF signaling pathways. These results showed that RAB27B is a prognostic marker and a novel therapeutic target in sunitinib-sensitive and -resistant RCCs. Further analyses should improve our understanding of sunitinib resistance in RCC.

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor including vascular endothelial growth factor, has been widely used as a first‐line treatment against metastatic renal cell carcinoma (mRCC). However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink‐1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink‐1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink‐1 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib‐naïve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E‐binding protein 1 (4EBP1) and AKT. In addition, Rapalink‐1 had greater tumor suppressive effects than temsirolimus against the sunitinib‐resistant 786‐o cell line (SU‐R 786‐o), which we had previously established, as well as 3 additional SU‐R cell lines established here. RNA sequencing showed that Rapalink‐1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib‐sensitive or sunitinib‐resistant., A new mTOR inhibitor, Rapalink‐1, suppresses the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters.

Motor units are generally recruited from the smallest to the largest following the size principle, while cutaneous stimulation has the potential to affect spinal motor control. We aimed to examine the effects of stimulating transient receptor potential channel sub-family M8 (TRPM8) combined with exercise on the modulation of spinal motor neuron (MN) excitability. Mice were topically administrated 1.5% icilin on the hindlimbs, followed by treadmill stepping. Spinal cord sections were immunostained with antibodies against c-fos and choline acetyltransferase. Icilin stimulation did not change the number of c-fos+ MNs, but increased the average soma size of the c-fos+ MNs during low-speed treadmill stepping. Furthermore, icilin stimulation combined with stepping increased c-fos+ cholinergic interneurons near the central canal, which are thought to modulate MN excitability. These findings suggest that TRPM8-mediated cutaneous stimulation with low-load exercise promotes preferential recruitment of large MNs and is potentially useful as a new training method for rehabilitation.

5 wt.% yttria doped mullite ceramics were sintered using nanocomposite powders which consisted of a Y2O3–SiO2 core coated with pseudoboehmite. Firstly, the powders were heated up to 1300 °C; mullite began to form at 1050 °C which is ∼150 °C lower than in previous diphasic precursors. Then, the powders were sintered at 1550 °C for 0.5, 5 and 48 h, and characterized using XRD, SEM and TEM with EDS. The phases present were mullite and two intergranular glasses comprising silica-rich droplets embedded in a Y–Si–Al–O glassy matrix, providing direct evidence of liquid-liquid phase separation at the grain boundaries during sintering. This liquid-liquid separation is facilitated by the prior existence of yttrium disilicate which moves the overall sintering liquid compositions toward the two immiscible liquids region of the Y2O3–Al2O3–SiO2 phase diagram. The presence of the silica-rich phase in the grain boundaries will effectively increase their viscosity and thus the resistance of the Y2O3 densified mullite to creep.

The CALorimetric Electron Telescope (CALET) space experiment, which has been developed by Japan in collaboration with Italy and the United States, is a high-energy astroparticle physics mission on the International Space Station (ISS). The primary goals of the CALET mission include investigation of possible nearby sources of high-energy electrons, detailed study of galactic cosmic-ray acceleration and propagation, and search for dark matter signatures. With a long-term observation onboard the ISS, the CALET experiment measures the flux of cosmic-ray electrons (including positrons) up to 20 TeV, gamma-rays to 10 TeV, and nuclei up to 1,000 TeV based on its charge separation capability from Z = 1 to 40. Since the start of science operation in mid-October, 2015, a continuous observation has been maintained without any major interruptions. The number of triggered events over 10 GeV is nearly 20 million per month. By using the data obtained during the first two-years, here we present a summary of the CALET observations: 1) Electron+positron energy spectrum, 2) Nuclei analysis, 3) Gamma-ray observation with a characterization of the on-orbit performance. The search results for the electromagnetic counterparts of LIGO/Virgo gravitational wave events are also discussed.

The CALorimetric Electron Telescope (CALET) is a high-energy astroparticle physics space experiment installed on the International Space Station (ISS), developed and operated by Japan in collaboration with Italy and the United States. The CALET mission goals include the investigation of possible nearby sources of high-energy electrons, of the details of galactic particle acceleration and propagation, and of potential signatures of dark matter. CALET measures the cosmic-ray electron + positron flux up to 20 TeV, gamma-rays up to 10 TeV, and nuclei with Z=1 to 40 up to 1,000 TeV for the more abundant elements during a long-term observation aboard the ISS. Starting science operation in mid-October 2015, CALET performed continuous observation without major interruption with close to 20 million triggered events over 10 GeV per month. Based on the data taken during the first two-years, we present an overview of CALET observations: uses w/o major interruption 1) Electron + positron energy spectrum, 2) Nuclei analysis, 3) Gamma-ray observation including a characterization of on-orbit performance. Results of the electromagnetic counterpart search for LIGO/Virgo gravitational wave events are discussed as well., 10 pages, 10 figures, a contribution to the proceedings of 26th Extended European Cosmic Ray Symposium, 6-10 July 2018, Russia, which summarizes our recent publications such as arXiv:1712.01711, arXiv:1712.01757, arXiv:1803.05834, arXiv:1806.09728, and arXiv:1807.01435

著者人数: 193名(所属. 宇宙航空研究開発機構宇宙科学研究所 (JAXA)(ISAS): 堂谷, 忠靖; 海老沢, 研; 林, 克洋; 飯塚, 亮; 井上, 芳幸; 石田, 学; 石川, 久美; 岩井, 将親; 国分, 紀秀; 小山, 志勇; 前田, 良知; 満田, 和久; 中川, 貴雄; 尾崎, 正伸; 佐藤, 悟郎; 佐藤, 理江; Simionescu, Aurora; 菅原, 泰晴; 高橋, 忠幸; 竹井, 洋; 田村, 隆幸; 田中, 靖郎; 冨田, 洋; 辻本, 匡弘; 上田, 周太朗; 渡辺, 伸; 山崎, 典子; 内田, 悠介), Accepted: 2018-09-30, 資料番号: SA1180351000

Sunitinib is the most common primary molecular‑targeted agent for metastatic clear cell renal cell carcinoma (ccRCC); however, intrinsic or acquired sunitinib resistance has become a significant problem in medical practice. The present study focused on microRNA (miR)‑99a‑3p, which was significantly downregulated in clinical sunitinib‑resistant ccRCC tissues in previous screening analyses, and investigated the molecular network associated with it. The expression levels of miR‑99a‑3p and its candidate target genes were evaluated in RCC cells, including previously established sunitinib‑resistant 786‑o (SU‑R‑786‑o) cells, and clinical ccRCC tissues, using reverse transcription‑quantitative polymerase chain reaction. Gain‑of‑function studies demonstrated that miR‑99a‑3p significantly suppressed cell proliferation and colony formation in RCC cells, including the SU‑R‑786‑o cells, by inducing apoptosis. Based on in silico analyses and RNA sequencing data, followed by luciferase reporter assays, ribonucleotide reductase regulatory subunit‑M2 (RRM2) was identified as a direct target of miR‑99a‑3p in the SU‑R‑786‑o cells. Loss‑of‑function studies using small interfering RNA against RRM2 revealed that cell proliferation and colony growth were significantly inhibited via induction of apoptosis, particularly in the SU‑R‑786‑o cells. Furthermore, the RRM2 inhibitor Didox (3,4‑dihydroxybenzohydroxamic acid) exhibited anticancer effects in the SU‑R‑786‑o cells and other RCC cells. To the best of our knowledge, this is the first report demonstrating that miR‑99a‑3p directly regulates RRM2. Identifying novel genes targeted by tumor‑suppressive miR‑99a‑3p in sunitinib‑resistant RCC cells may improve our understanding of intrinsic or acquired resistance and facilitate the development of novel therapeutic strategies.

miRNA‑223 (miR‑223) has been reported to function not only as a tumor suppressor, but also as an oncogenic microRNA (miRNA or miR) in various cancer cells. Therefore, the functional role of miR‑223 has not been elucidated to date, at least to the best of our knowledge. We previously performed the deep sequencing analysis of clinical bladder cancer (BC) specimens. It was revealed that miR‑223 expression was significantly downregulated in BC, suggesting that miR‑223 functions as a tumor suppressor miRNA in BC. The aim of this study was to investigate the functional roles of miR‑223 and to identify its targets in BC. The expression levels of miR‑223 were significantly decreased in our clinical BC specimens. The Cancer Genome Atlas (TCGA) database indicated that miR‑223 expression was related to lymphovascular invasion and distant metastasis. The restoration of miR‑223 expression significantly inhibited tumor aggressiveness and induced apoptosis via caspase‑3/7 activation in BC cells. WD repeat domain 62 (WDR62), a candidate target of miR‑223 according to in silico analyses, has been previously proposed to play a role in neurodevelopment. Direct binding between WDR62 and miR‑223 was confirmed by luciferase assay. The TCGA database revealed positive associations between WDR62 mRNA expression and a higher tumor grade and stage in BC. The knockdown of WDR62 significantly inhibited tumor aggressiveness and induced the apoptosis of BC cells. On the whole, the findings of this study reveal a novel miR‑223 target, oncogenic WDR62, and provided insight into the oncogenesis of BC.

The active form of the small GTPase RAS binds to downstream effectors to promote cell growth and proliferation. RAS signal enhancement contributes to tumorigenesis, invasion, and metastasis in various different cancers. HRAS proto-oncogene GTPase (HRAS), one of the RAS isoforms, was the first human oncogene for which mutations were reported in T24 bladder cancer (BC) cells in 1982, and HRAS mutation or upregulation has been reported in several cancers. According to data from The Cancer Genome Atlas, HRAS expression was significantly upregulated in clinical BC samples compared to healthy samples (P=0.0024). HRAS expression was also significantly upregulated in BC with HRAS mutation compared to patients without HRAS mutation (P

著者人数: 270名（所属. 宇宙航空研究開発機構宇宙科学研究所(JAXA)(ISAS): 高橋, 忠幸; 国分, 紀秀; 満田, 和久; Baluta, Chris; 坂東, 信尚; 堂谷, 忠靖; 海老沢, 研; 林, 克洋; 廣瀬, 和之; 飯塚, 亮; 石田, 学; 石川, 久美; 石村, 康生; 岩井, 将親; 岩田, 直子; 河野, 太郎; 川崎, 繁男; 小山, 志勇; 前田, 良知; 峯杉, 賢治; 中川, 貴雄; 夏苅, 権; 小川, 博之; 小川, 美奈; 太田, 方之; 岡崎, 健; 尾崎, 正伸; 坂井, 真一郎; 鮫島, 寛明; 佐藤, 悟郎; 佐藤, 理江; 柴野, 靖子; 志田, 真樹; 嶋田, 貴信; Simionescu, Aurora; 菅原, 泰晴; 竹井, 洋; 田村, 隆幸; 田中, 靖郎; 田代, 信; 冨田, 洋; 辻本, 匡弘; 上田, 周太朗; 上野, 史郎; 和田, 篤始; 渡辺, 伸; 山田, 隆弘; 山崎, 典子）, Number of authors: 270 (Affiliation. Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency (JAXA)(ISAS): Takahashi, Tadayuki; Kokubun, Motohide; Mitsuda, Kazuhisa; Baluta, Chris; Bando, Nobutaka; Dotani, Tadayasu; Ebisawa, Ken; Hayashi, Katsuhiro; Hirose, Kazuyuki; Iizuka, Ryo; Ishida, Manabu; Ishikawa, Kumi; Ishimura, Kosei; Iwai, Masachika; Iwata, Naoko; Kawano, Taro; Kawasaki, Shigeo; Koyama, Shu; Maeda, Yoshitomo; Minesugi, Kenji; Nakagawa, Takao; Natsukari, Chikara; Ogawa, Hiroyuki; Ogawa, Mina; Ohta, Masayuki; Okazaki, Tsuyoshi; Ozaki, Masanobu; Sakai, Shinichiro; Sameshima, Hiroaki; Sato, Goro; Sato, Rie; Shibano, Yasuko; Shida, Maki; Shimada, Takanobu; Simionescu, Aurora; Sugawara, Yasuharu; Takei, Yoh; Tamura, Takayuki; Tanaka, Yasuo; Tashiro, Makoto; Tomida, Hiroshi; Tsujimoto, Masahiro; Ueda, Shutaro; Ueno, Shiro; Wada, Atsushi; Watanabe, Shin; Yamada, Takahiro; Yamasaki, Noriko Y.), Accepted: 2018-02-05, 資料番号: SA1170333000

著者人数: 19名, Accepted: 2018-01-22, 資料番号: SA1170310000

Background: Based on the microRNA (miRNA) signature of bladder cancer (BC) by deep sequencing, we recently found that several double-stranded mature miRNAs derived from the same pre-miRNAs were sufficiently expressed and acted as tumour suppressors by regulating common target genes in BC. Our deep-sequencing signature of BC showed that all miR-199 family members (miR-199a-3p/-5p and miR-199b-3p/-5p) were also downregulated. We hypothesised that these miRNAs may function as tumour suppressors by regulating common target genes. Methods: Functional assays of BC cells were performed using transfection of mature miRNA. In silico analyses and luciferase reporter analyses were applied to identify target genes of these miRNAs. The overall survival of patients with BC in The Cancer Genome Atlas (TCGA) database was evaluated by the Kaplan–Meier method. Results: Restoration of these miRNAs significantly inhibited cell migration and invasion in BC cells. Integrin α3 (ITGA3) was directly regulated by these miRNAs. The Cancer Genome Atlas database showed that patients with low pre-miR-199 family (miR-199a-1/-2 and miR-199b) expression exhibited significantly poorer overall survival compared with patients with high pre-miR-199 family expression. Conclusions: miR-199 family miRNAs functioned as tumour suppressors in BC cells by targeting ITGA3 and might be good prognostic markers for predicting survival in patients with BC.