研究者詳細 - 松川　昭博

論文 - 松川　昭博

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Decreased miR-200b-3p in cancer cells leads to angiogenesis in HCC by enhancing endothelial ERG expression. 査読国際誌

Aye Moh-Moh-Aung, Masayoshi Fujisawa, Sachio Ito, Hiroshi Katayama, Toshiaki Ohara, Yoko Ota, Teizo Yoshimura, Akihiro Matsukawa

Scientific reports 10 ( 1 ) 10418 2020年6月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Transcription factor ERG (erythroblast transformation-specific (ETS)-related gene) is essential in endothelial differentiation and angiogenesis, in which microRNA (miR)-200b-3p targeting site is expected by miRNA target prediction database. miR-200b is known decreased in hepatocellular carcinoma (HCC), however, the functional relation between ERG and miR-200b-3p, originating from pre-miR-200b, in HCC angiogenesis remains unclear. We investigated whether hepatocyte-derived miR-200b-3p governs angiogenesis in HCC by targeting endothelial ERG. Levels of miR-200b-3p in HCC tissues were significantly lower than those in adjacent non-HCC tissues. Poorly differentiated HCC cell line expressed lower level of miR-200b-3p compared to well-differentiated HCC cell lines. The numbers of ERG-positive endothelial cells were higher in HCC tissues than in adjacent non-HCC tissues. There was a negative correlation between the number of ERG-positive cells and miR-200b-3p expression in HCC tissues. Culture supernatants of HCC cell lines with miR-200b-3p-overexpression reduced cell migration, proliferation and tube forming capacity in endothelial cells relative to the control, while those with miR-200b-3p-inhibition augmented the responses. Exosomes isolated from HCC culture supernatants with miR-200b-3p overexpression suppressed endothelial ERG expression. These results suggest that exosomal miR-200b-3p from hepatocytes suppresses endothelial ERG expression, and decreased miR-200b-3p in cancer cells promotes angiogenesis in HCC tissues by enhancing endothelial ERG expression.

DOI： 10.1038/s41598-020-67425-4

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Development of self-adhesive pulp-capping agents containing a novel hydrophilic and highly polymerizable acrylamide monomer. 査読国際誌

Kumiko Yoshihara, Noriyuki Nagaoka, Takumi Okihara, Masao Irie, Akihiro Matsukawa, Mariano Simón Pedano, Yukinori Maruo, Yasuhiro Yoshida, Bart Van Meerbeek

Journal of materials chemistry. B 8 ( 24 ) 5320 - 5329 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Several studies have shown the clinical success of hydraulic calcium-silicate cements (hCSCs) for direct and indirect pulp capping and root repair. However, hCSCs have various drawbacks, including long setting time, poor mechanical properties, low bond strength to dentin, and relatively poor handling characteristics. To overcome these limitations, a light-curable, resin-based hCSC (Theracal LC, Bisco) was commercially introduced; however, it did not exhibit much improvement in bond strength. We developed a light-curable self-adhesive pulp-capping material that contains the novel acrylamide monomer N,N'-{[(2-acrylamido-2-[(3-acrylamidopropoxy)methyl]propane-1,3-diyl)bis(oxy)]bis(propane-1,3-diyl)}diacrylamide (FAM-401) and the functional monomer 4-methacryloxyethyl trimellitate anhydride (4-MET). Two experimental resin-based hCSCs containing different calcium sources (portlandite: Exp_Pl; tricalcium silicate cement: Exp_TCS) were prepared, and the commercial hCSCs Theracal LC and resin-free hCSC Biodentine served as controls. The performance of each cement was evaluated based on parameters relevant for vital pulp therapy, such as curing degree on a wet surface, mechanical strength, as determined using a three-point bending test, shear bond strength to dentin, cytotoxicity, as determined using an MTT assay, and the amount of calcium released, as determined using inductively coupled plasma atomic emission spectrometry. Both experimental cements cured on wet surfaces and showed relatively low cytotoxicity. Furthermore, their flexural and shear bond strength to dentin were significantly higher than those of the commercial references. High calcium release was observed for both Exp_Pl and Biodentine. Thus, Exp_Pl as a new self-adhesive pulp-capping agent performed better than the commercial resin-based pulp-capping agent in terms of mechanical strength, bond strength, and calcium release.

DOI： 10.1039/d0tb00079e

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【パンデミック下の医学教育-現在進行形の実践報告-】オンライン授業 COVID-19によるパンデミック下での医学科5年生に対するオンラインを用いたプロフェッショナリズム・行動科学教育

三好智子, 山根正修, 小崎吉訓, 片岡仁美, 横田雄也, 光田栄子, 越智可奈子, 小比賀美香子, 伊野英男, 松川昭博, 大塚愛二

医学教育 51 ( 3 ) 279 - 281 2020年6月

Juvenile Granulosa Cell Tumor with an Unusual Clinical Course: A Late-onset and Late Recurrent Case. 査読

Thar Htet San, Yoko Ota, Soichiro Fushimi, Masayoshi Fujisawa, Hiroyuki Yanai, Hiroko Toda, Tadayoshi Kunitomo, Keisuke Kodama, Akihiro Matsukawa

Acta medica Okayama 74 ( 2 ) 159 - 163 2020年4月

担当区分：最終著者,　責任著者記述言語：英語

Juvenile granulosa cell tumors (JGCTs) are rare ovarian tumors with overall good prognoses. They differ from adult granulosa cell tumors (AGCTs), which are well known for late recurrence. Most JGCTs (～97%) occur in individuals <30 years old. We report a recurrent JGCT in a 40-year-old woman 5 years after initial presentation. The histological appearance and lack of 402C>G missense point mutation of FOXL2 gene (characteristic of AGCT but absent in JGCT) allowed differentiation from AGCT. This is the first comprehensive report of JGCT with late recurrence. Although rare, late recurrence of JGCT can occur; long-term surveillance is suggested.

DOI： 10.18926/AMO/58275

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A Promising New Anti-Cancer Strategy: Iron Chelators Targeting CSCs. 査読

Yuehua Chen, Toshiaki Ohara, Boyi Xing, Jiping Qi, Kazuhiro Noma, Akihiro Matsukawa

Acta medica Okayama 74 ( 1 ) 1 - 6 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Iron is a trace but vital element in the human body and is necessary for a multitude of crucial processes in life. However, iron overload is known to induce carcinogenesis via oxidative stress. Cancer cells require large amounts of iron for their rapid division and cell growth. Iron was recently found to play a role in cancer stem cells (CSCs); it maintains stemness during development. Iron also plays an important role in stemness by moderating reactive oxygen species. Thus, iron metabolism in CSCs is a promising therapeutic target. In this review, we summarize the roles of iron in cancer cells and CSCs. We also summarize anti-cancer therapeutic studies with iron chelators and describe our expectation of a new therapeutic strategy for CSCs on the basis of our findings.

DOI： 10.18926/AMO/57946

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A Surgical Instructor Training Course for the Next Generation. 査読

Masaomi Yamane, Yasuhiro Mandai, Hideo Ino, Akihiro Matsukawa, Shinichi Toyooka

Acta medica Okayama 74 ( 1 ) 73 - 76 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

In 2016, Gunma University Hospital's Medical Accident Investigation Committee released a report reiterating the necessity of medical education and the need for surgeons to master non-technical skills. We designed a 17-h training course for surgical instructors, designed to teach participants how to sufficiently educate surgeon trainees and encourage their professional identity formation. A post-training survey showed that participants improved their awareness, and their behavioral changes led to favorable team performances. We then began offering a 3-h workshop focusing on the participants' experiences. We propose that the training course using participant narratives is required and effective to establish surgeons' self-reflection and professional identity as surgeons.

DOI： 10.18926/AMO/57956

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Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer. 査読国際誌

Teizo Yoshimura, Kaoru Nakamura, Chunning Li, Masayoshi Fujisawa, Tsuyoshi Shiina, Mayu Imamura, Tiantian Li, Naofumi Mukaida, Akihiro Matsukawa

International journal of molecular sciences 20 ( 24 ) 2019年12月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.

DOI： 10.3390/ijms20246342

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Multipotent Neurotrophic Effects of Hepatocyte Growth Factor in Spinal Cord Injury. 査読国際誌

Kentaro Yamane, Haruo Misawa, Tomoyuki Takigawa, Yoshihiro Ito, Toshifumi Ozaki, Akihiro Matsukawa

International journal of molecular sciences 20 ( 23 ) 2019年12月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies have been conducted in the field of SCI; however, no satisfactory treatment has been established to date. Hepatocyte growth factor (HGF) is one of the neurotrophic growth factors and has been listed as a candidate medicine for SCI treatment. The highlighted effects of HGF on neural regeneration are associated with its anti-inflammatory and anti-fibrotic activities. Moreover, HGF exerts positive effects on transplanted stem cell differentiation into neurons. This paper reviews the mechanisms underlying the therapeutic effects of HGF in SCI recovery, and introduces recent advances in the clinical applications of HGF therapy.

DOI： 10.3390/ijms20236078

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Negative impact of recipient SPRED2 deficiency on transplanted lung in a mouse model. 査読国際誌

Hashimoto K, Yamane M, Sugimoto S, Hirano Y, Kurosaki T, Otani S, Miyoshi K, Ohara T, Okazaki M, Yoshimura T, Oto T, Matsukawa A, Toyooka S

Transplant immunology 57 101242 - 101242 2019年12月

Rechargeable anti-microbial adhesive formulation containing cetylpyridinium chloride montmorillonite. 査読国際誌

Kenya Matsuo, Kumiko Yoshihara, Noriyuki Nagaoka, Yoji Makita, Hideki Obika, Takumi Okihara, Akihiro Matsukawa, Yasuhiro Yoshida, Bart Van Meerbeek

Acta biomaterialia 100 388 - 397 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Long-term anti-bacterial effect is a desired ability of any dental material in combating tooth caries as one of the most common and widespread persistent diseases today. Among several cationic quaternary ammonium compounds with antiseptic properties, cetylpyridinium chloride (CPC) is often used in mouthrinses and toothpastes. In this study, we incorporated CPC in a soft phyllosilicate mineral (clay), referred to as montmorillonite (Mont), to enable gradual CPC release with rechargeability. Besides measuring CPC release and recharge, we examined the anti-bacterial effect, cytotoxicity and bonding effectiveness of five experimental adhesive formulations, prepared by adding 1 and 3 wt% CPC_Mont, 3 wt% Mont (without CPC), and 1 and 3 wt% CPC (without Mont) to the commercial adhesive Clearfil S3 Bond ND Quick ('C-S3B'; Kuraray Noritake). Strong inhibition of Streptococcus mutans biofilm formation by CPC_Mont adhesives was confirmed by optical density and SEM. CPC release from CPC_Mont adhesives was higher and lasted longer than from CPC adhesives, while CPC_Mont adhesives could also be recharged with CPC upon immersion in 2 wt% CPC. In conclusion, CPC_Mont technology rendered adhesives anti-bacterial properties with recharge ability, this without reducing its bonding potential, neither increasing its cytotoxicity. STATEMENT OF SIGNIFICANCE: Dental caries is one of the most prevalent chronic diseases in the population worldwide and is the major cause of tooth loss. In this study, we developed cetylpyridinium chloride (CPC) loaded montmorillonite (CPC-Mont) with a long-term antibacterial efficacy to prevent caries. CPC is an antibacterial agent approved by FDA, used as an OTC drug and contained in oral hygiene aids. CPC-Mont was incorporated in a dental adhesive to gradually release CPC. CPC_Mont technology rendered adhesives anti-bacterial properties with rechargeability, this without reducing its bonding potential, neither increasing its cytotoxicity.

DOI： 10.1016/j.actbio.2019.09.045

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The relationship between the PD-L1 expression of surgically resected and fine-needle aspiration specimens for patients with pancreatic cancer. 査読

Matsumoto K, Ohara T, Fujisawa M, Takaki A, Takahara M, Tanaka N, Kato H, Horiguchi S, Yoshida R, Umeda Y, Fushimi S, Yagi T, Matsukawa A, Okada H

Journal of gastroenterology 54 ( 11 ) 1019 - 1028 2019年11月

Prolonged warm ischemia exacerbated acute rejection after lung transplantation from donation after cardiac death in a mouse. 査読

Hirano Y, Sugimoto S, Yamamoto S, Okada M, Otani S, Ohara T, Yamane M, Matsukawa A, Oto T, Toyooka S

General thoracic and cardiovascular surgery 68 ( 1 ) 57 - 62 2019年7月

SOCS3 overexpression in T cells ameliorates chronic airway obstruction in a murine heterotopic tracheal transplantation model. 査読

Mesaki K, Yamane M, Sugimoto S, Fujisawa M, Yoshimura T, Kurosaki T, Otani S, Miyoshi S, Oto T, Matsukawa A, Toyooka S

Surgery today 49 ( 5 ) 443 - 450 2019年5月

THE RELATIONSHIP BETWEEN THE PD-L1 EXPRESSION OF SURGICAL RESECTED AND FINE-NEEDLE ASPIRATION SPECIMENS FOR PATIENTS WITH PANCREATIC CANCER 査読

Matsumoto Kazuyuki, Ohara Toshiaki, Fujisawa Masayoshi, Takaki Akinobu, Takahara Masahiro, Kato Hironari, Horiguchi Shigeru, Matsukawa Akihiro, Okada Hiroyuki

GASTROENTEROLOGY 156 ( 6 ) S758 2019年5月

Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice. 査読国際誌

Kazuki Hatayama, Nobuyuki Nosaka, Mutsuko Yamada, Masato Yashiro, Yosuke Fujii, Hirokazu Tsukahara, Keyue Liu, Masahiro Nishibori, Akihiro Matsukawa, Tsuneo Morishima

Journal of medical virology 91 ( 3 ) 361 - 369 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti-HMGB1 mAb significantly improved survival rate whereas the anti-HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti-HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti-HMGB1 with conventional anti-influenza therapy might be useful against severe influenza virus infection.

DOI： 10.1002/jmv.25330

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A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. 査読国際誌

Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

Cancers 11 ( 2 ) 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

DOI： 10.3390/cancers11020177

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Abrogated Caveolin-1 expression via histone modification enzyme Setdb2 regulates brain edema in a mouse model of influenza-associated encephalopathy. 査読国際誌

Imakita N, Kitabatake M, Ouji-Sageshima N, Hara A, Morita-Takemura S, Kasahara K, Matsukawa A, Wanaka A, Mikasa K, Ito T

Scientific reports 9 ( 1 ) 284 2019年1月

Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice. 査読国際誌

Takahiro Ohkura, Teizo Yoshimura, Masayoshi Fujisawa, Toshiaki Ohara, Rie Marutani, Kaya Usami, Akihiro Matsukawa

Frontiers in immunology 10 17 - 17 2019年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome.

DOI： 10.3389/fimmu.2019.00017

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SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation. 査読

Okada M, Yamane M, Yamamoto S, Otani S, Miyoshi K, Sugimoto S, Matsukawa A, Toyooka S, Oto T, Miyoshi S

Surgery today 48 ( 12 ) 1089 - 1095 2018年12月

A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines. 査読国際誌

Toshiaki Ohara, Yasuko Tomono, Xing Boyi, Sun Yingfu, Kazuhiro Omori, Akihiro Matsukawa

Oncotarget 9 ( 67 ) 32751 - 32760 2018年8月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

Iron chelation therapy is the main treatment for iron overload disease. Iron chelators were recently reported to be useful for cancer therapy; however, they cause side effects that make them difficult to use in some cancer patients. Thus, a novel oral iron chelator, super-polyphenol (SP), was developed for cancer therapy to decrease the side effects. SP is either water soluble or insoluble, and has different isoforms according to the number of side chains. Of these isoforms, water-soluble SP6 and SP10 appear to be the best candidates, as they have the strongest chelating abilities. In this study, we focused on the usefulness and safety of SP6 and SP10 as anti-cancer drugs, and examined their anti-cancer effects and toxicity. The results showed that SP6 and SP10 inhibited cancer cell proliferation by inducing apoptosis in HCT116, HSC-2, A549, and MCF-7 cancer cells. SP10 also inhibited tumor growth in an HCT116 xenograft model. SP6 and SP10 had no acute toxicities. An intravenous injection test revealed that SP6 and SP10 had better safety profiles than the iron chelator deferoxamine. In conclusion, SP is a novel oral iron chelator with anti-cancer effects and few adverse side effects. This is the first report of SP in the literature.

DOI： 10.18632/oncotarget.25973

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