研究者詳細 - 河合　穂高

論文 - 河合　穂高

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A Rare Case of Multiple Myeloma Identified Following the Diagnosis of Amyloidosis of the Tongue. 国際誌

Hideka Kanemoto, Kyoichi Obata, Koichi Kadoya, Kisho Ono, Hotaka Kawai, Yuki Kunisada, Mayumi Yao, Soichiro Ibaragi

Case reports in dentistry 2024 8836103 - 8836103 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyloidosis is a disease in which amyloid protein is deposited in organs and tissues, resulting in functional impairment. Amyloidosis occurs in 12%-30% of patients with multiple myeloma, but in rare cases, amyloidosis may precede the diagnosis of multiple myeloma. Our patient was a 76-year-old Japanese male on dialysis. Multiple nodules accompanied by ulcers were observed on his tongue. He had no subjective symptoms or clinical findings associated with multiple myeloma. The histopathological findings suggested amyloidosis. We suspected both systemic and localized amyloidosis and performed a comprehensive systemic examination. Since the patient had been on dialysis for only a short period of time (~3 months), dialysis-related amyloidosis was ruled out. After blood and urine tests, a diagnosis of multiple myeloma was made. Chemotherapy treatment was started, but the patient's multiple myeloma could not be suppressed and the tongue amyloidosis worsened, leading to his death 2 years and 2 months after the initial diagnosis.

DOI： 10.1155/2024/8836103

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Transcutaneous carbon dioxide suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma. 国際誌

Aki Sasaki, Daisuke Takeda, Hotaka Kawai, Yoshiaki Tadokoro, Aki Murakami, Nanae Yatagai, Satomi Arimoto, Hitoshi Nagatsuka, Masaya Akashi, Takumi Hasegawa

PloS one 19 ( 4 ) e0302194 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Cancer cachexia causes skeletal muscle atrophy, impacting the treatment and prognosis of patients with advanced cancer, but no treatment has yet been established to control cancer cachexia. We demonstrated that transcutaneous application of carbon dioxide (CO2) could improve local blood flow and reduce skeletal muscle atrophy in a fracture model. However, the effects of transcutaneous application of CO2 in cancer-bearing conditions are not yet known. In this study, we calculated fat-free body mass (FFM), defined as the skeletal muscle mass, and evaluated the expression of muscle atrophy markers and uncoupling protein markers as well as the cross-sectional area (CSA) to investigate whether transcutaneous application of CO2 to skeletal muscle could suppress skeletal muscle atrophy in cancer-bearing mice. Human oral squamous cell carcinoma was transplanted subcutaneously into the upper dorsal region of nude mice, and 1 week later, CO2 gas was applied to the legs twice a week for 4 weeks and FFM was calculated by bioimpedance spectroscopy. After the experiment concluded, the quadriceps were extracted, and muscle atrophy markers (muscle atrophy F-box protein (MAFbx), muscle RING-finger protein 1 (MuRF-1)) and uncoupling protein markers (uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3)) were evaluated by real-time polymerase chain reaction and immunohistochemical staining, and CSA by hematoxylin and eosin staining. The CO2-treated group exhibited significant mRNA and protein expression inhibition of the four markers. Furthermore, immunohistochemical staining showed decreased MAFbx, MuRF-1, UCP2, and UCP3 in the CO2-treated group. In fact, the CSA in hematoxylin and eosin staining and the FFM revealed significant suppression of skeletal muscle atrophy in the CO2-treated group. We suggest that transcutaneous application of CO2 to skeletal muscle suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma.

DOI： 10.1371/journal.pone.0302194

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Rab11 suppresses head and neck carcinoma by regulating EGFR and EpCAM exosome secretion. 国際誌

Kunihiro Yoshida, Kaung Htike, Takanori Eguchi, Hotaka Kawai, Htoo Shwe Eain, Manh Tien Tran, Chiharu Sogawa, Koki Umemori, Tatsuo Ogawa, Hideka Kanemoto, Kisho Ono, Hitoshi Nagatsuka, Akira Sasaki, Soichiro Ibaragi, Kuniaki Okamoto

Journal of oral biosciences 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Rab11(Rab11a and Rab11b) localizes primarily along recycling endosomes in cells and is involved in various intracellular trafficking processes, including membrane receptor recycling and secretion of exosomes or small extracellular vesicles (EVs). Although Rab11 is closely associated with the progression and metastasis of various cancer types, little is known about Rab11' role in head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the roles of Rab11a and Rab11b in HNSCC. METHODS: The clinical significance of Rab11 expression in HNSCC was investigated using a public database and tissue microarray analysis. Stable cell lines with loss and gain of Rab11a or Rab11b were originally established to investigate their roles in the proliferative, migratory, and invasive capabilities of HNSCC cells. RESULTS: Database analysis revealed a significant association between Rab11b mRNA expression and a favorable patient survival rate in HNSCC. Tissue microarray analysis revealed that Rab11b expression was the highest in normal tissues and gradually decreased across the stages of HNSCC progression. Overexpression of Rab11a or Rab11b resulted in a decrease in epidermal growth factor receptor (EGFR), Epithelial cell adhesion molecule (EpCAM) exosome secretion, and the migratory and invasive potential of HNSCC cells. The knockdown of Rab11a or Rab11b increased EpCAM/CD9 exosome secretion in addition to the migratory and invasive potential of HNSCC cells. CONCLUSIONS: Rab11 suppresses HNSCC by regulating EGFR recycling and EpCAM exosome secretion in HNSCC cells. Our results indicate that Rab11b is a superior prognostic indicator of HNSCC and holds promise for developing novel therapeutic strategies.

DOI： 10.1016/j.job.2023.11.007

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口腔扁平上皮癌腫瘍間質が腫瘍関連マクロファージの集簇・分化に与える影響について

Piao Tianyan, 高畠清文, Chan Anqi, 河合穂高, 中野敬介, 長塚仁

岡山歯学会雑誌 42 ( 2 ) 70 - 71 2023年12月

口腔癌におけるCX3CL1とリンパ節転移の関係(Relationship between CX3CL1 and lymph node metastasis in oral cancer)

河合穂高, トゥ・シュエイン, 中山真彰, 大原利章, 長塚仁

日本癌学会総会記事 82回 1421 - 1421 2023年9月

口腔癌におけるCX3CL1とリンパ節転移の関係(Relationship between CX3CL1 and lymph node metastasis in oral cancer)

河合穂高, トゥ・シュエイン, 中山真彰, 大原利章, 長塚仁

日本癌学会総会記事 82回 1421 - 1421 2023年9月

Effectiveness of deep learning classifiers in histopathological diagnosis of oral squamous cell carcinoma by pathologists. 国際誌

Shintaro Sukegawa, Sawako Ono, Futa Tanaka, Yuta Inoue, Takeshi Hara, Kazumasa Yoshii, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Shimada Katsumitsu, Fumi Nakai, Yasuhiro Nakai, Ryo Miyazaki, Satoshi Murakami, Hitoshi Nagatsuka, Minoru Miyake

Scientific reports 13 ( 1 ) 11676 - 11676 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The study aims to identify histological classifiers from histopathological images of oral squamous cell carcinoma using convolutional neural network (CNN) deep learning models and shows how the results can improve diagnosis. Histopathological samples of oral squamous cell carcinoma were prepared by oral pathologists. Images were divided into tiles on a virtual slide, and labels (squamous cell carcinoma, normal, and others) were applied. VGG16 and ResNet50 with the optimizers stochastic gradient descent with momentum and spectral angle mapper (SAM) were used, with and without a learning rate scheduler. The conditions for achieving good CNN performances were identified by examining performance metrics. We used ROCAUC to statistically evaluate diagnostic performance improvement of six oral pathologists using the results from the selected CNN model for assisted diagnosis. VGG16 with SAM showed the best performance, with accuracy = 0.8622 and AUC = 0.9602. The diagnostic performances of the oral pathologists statistically significantly improved when the diagnostic results of the deep learning model were used as supplementary diagnoses (p-value = 0.031). By considering the learning results of deep learning model classifiers, the diagnostic accuracy of pathologists can be improved. This study contributes to the application of highly reliable deep learning models for oral pathological diagnosis.

DOI： 10.1038/s41598-023-38343-y

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口腔扁平上皮癌の病理組織学的診断におけるAI深層学習補助診断の効果検討

助川信太郎, 中野敬介, 小野佐和子, 嶋田勝光, 高畠清文, 河合穂高, 村上聡, 長塚仁, 三宅実

日本口腔科学会雑誌 72 ( 2 ) 131 - 132 2023年7月

骨髄由来間葉系幹細胞の新規採取技術および骨髄由来間葉系幹細胞移植法の確立

河合穂高, メイワトゥ, 高畠清文, 佐能彰, 中野敬介, 宝田剛, 長塚仁

日本口腔科学会雑誌 72 ( 2 ) 134 - 134 2023年7月

口腔癌の細胞外小胞と銅輸送経路に着目したシスプラチン耐性機構の解明と克服のための挑戦的研究

小野喜章, 竜門省二, 小畑協一, 河合穂高, 奥井達雄, 伊原木聰一郎

日本口腔科学会雑誌 72 ( 2 ) 131 - 131 2023年7月

EpEX, the soluble extracellular domain of EpCAM, resists cetuximab treatment of EGFR-high head and neck squamous cell carcinoma. 国際誌

Koki Umemori, Kisho Ono, Takanori Eguchi, Hotaka Kawai, Tomoya Nakamura, Tatsuo Ogawa, Kunihiro Yoshida, Hideka Kanemoto, Kohei Sato, Kyoichi Obata, Shoji Ryumon, Hirokazu Yutori, Naoki Katase, Tatsuo Okui, Hitoshi Nagatsuka, Soichiro Ibaragi

Oral oncology 142 106433 - 106433 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Cetuximab (Cmab) is a molecularly targeted monoclonal antibody drug for head and neck squamous cell carcinoma (HNSC), although cetuximab resistance is a serious challenge. Epithelial cell adhesion molecule (EpCAM) is an established marker for many epithelial tumors, while the soluble EpCAM extracellular domain (EpEX) functions as a ligand for epidermal growth factor receptor (EGFR). We investigated the expression of EpCAM in HNSC, its involvement in Cmab action, and the mechanism by which soluble EpEX activated EGFR and played key roles in Cmab resistance. MATERIALS AND METHODS: We first examined EPCAM expression in HNSCs and its clinical significance by searching gene expression array databases. We then examined the effects of soluble EpEX and Cmab on intracellular signaling and Cmab efficacy in HNSC cell lines (HSC-3 and SAS). RESULTS: EPCAM expression was found to be enhanced in HNSC tumor tissues compared to normal tissues, and the enhancement was correlated with stage progression and prognosis. Soluble EpEX activated the EGFR-ERK signaling pathway and nuclear translocation of EpCAM intracellular domains (EpICDs) in HNSC cells. EpEX resisted the antitumor effect of Cmab in an EGFR expression-dependent manner. CONCLUSION: Soluble EpEX activates EGFR to increase Cmab resistance in HNSC cells. The EpEX-activated Cmab resistance in HNSC is potentially mediated by the EGFR-ERK signaling pathway and the EpCAM cleavage-induced nuclear translocation of EpICD. High expression and cleavage of EpCAM are potential biomarkers for predicting the clinical efficacy and resistance to Cmab.

DOI： 10.1016/j.oraloncology.2023.106433

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分化度が異なるOSCCにおけるCXCR4阻害剤の有用性

吉田沙織, 河合穂高, 竹下洋平, 岡田俊輔, 藤倉満美子, 久富美紀, 河津俊幸, 長塚仁, 浅海淳一, 柳文修

日本病理学会会誌 112 ( 1 ) 290 - 290 2023年3月

CX3CL1の口腔癌リンパ節転移における役割の検討

河合穂高, トゥシュ・エイン, 高畠清文, 中野敬介, 長塚仁

日本病理学会会誌 112 ( 1 ) 263 - 263 2023年3月

Novel Artificial Scaffold for Bone Marrow Regeneration: Honeycomb Tricalcium Phosphate. 国際誌

Yasunori Inada, Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Keisuke Nakano, Qiusheng Shan, Tianyan Piao, Anqi Chang, Hotaka Kawai, Hitoshi Nagatsuka

Materials (Basel, Switzerland) 16 ( 4 ) 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Bone marrow is complex structure containing heterogenetic cells, making it difficult to regenerate using artificial scaffolds. In a previous study, we succeeded in developing honeycomb tricalcium phosphate (TCP), which is a cylindrical scaffold with a honeycomb arrangement of straight pores, and we demonstrated that TCP with 300 and 500 μm pore diameters (300TCP and 500TCP) induced bone marrow structure within the pores. In this study, we examined the optimal scaffold structure for bone marrow with homeostatic bone metabolism using honeycomb TCP. 300TCP and 500TCP were transplanted into rat muscle, and bone marrow formation was histologically assessed. Immunohistochemistry for CD45, CD34, Runt-related transcription factor 2 (Runx2), c-kit single staining, Runx2/N-cadherin, and c-kit/Tie-2 double staining was performed. The area of bone marrow structure, which includes CD45(+) round-shaped hematopoietic cells and CD34(+) sinusoidal vessels, was larger in 300TCP than in 500TCP. Additionally, Runx2(+) osteoblasts and c-kit(+) hematopoietic stem cells were observed on the surface of bone tissue formed within TCP. Among Runx2(+) osteoblasts, spindle-shaped N-cadherin(+) cells existed in association with c-kit(+)Tie-2(+) hematopoietic stem cells on the bone tissue formed within TCP, which formed a hematopoietic stem cell niche similar to as in vivo. Therefore, honeycomb TCP with 300 μm pore diameters may be an artificial scaffold with an optimal geometric structure as a scaffold for bone marrow formation.

DOI： 10.3390/ma16041393

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腫瘍微小環境における間質細胞は口腔扁平上皮癌の進行を促進する(Stromal cells in the tumor microenvironment promote the progression of oral squamous cell carcinoma)

Shan Qiusheng, 高畠清文, 河合穂高, Oo May Wathone, 稲田靖則, 中野敬介, 長塚仁

日本口腔診断学会雑誌 36 ( 1 ) 79 - 79 2023年2月

分化度の異なる口腔扁平上皮癌におけるシスプラチンとCXCR4阻害剤併用の効果

吉田沙織, 河合穂高, 竹下洋平, 岡田俊輔, 藤倉満美子, 久富美紀, 河津俊幸, 長塚仁, 浅海淳一, 柳文修

日本口腔診断学会雑誌 36 ( 1 ) 82 - 82 2023年2月

腫瘍微小環境における間質細胞は口腔扁平上皮癌の進行を促進する(Stromal cells in the tumor microenvironment promote the progression of oral squamous cell carcinoma)

Shan Qiusheng, 高畠清文, 河合穂高, Oo May Wathone, 稲田靖則, 中野敬介, 長塚仁

日本口腔診断学会雑誌 36 ( 1 ) 79 - 79 2023年2月

EGFR活性化経路としてのEpCAMに着目した口腔扁平上皮癌のセツキシマブ耐性機構の解明

梅森洸樹, 小野喜章, 小畑協一, 竜門省二, 中村友哉, 金本栄華, 吉田国弘, 河合穂高, 伊原木聰一郎

口腔組織培養学会誌 32 ( 1 ) 11 - 12 2023年2月

Multiplex Immunostaining Method to Distinguish HSP Isoforms in Cancer Tissue Specimens. 国際誌

Hotaka Kawai, Kisho Ono, Takanori Eguchi

Methods in molecular biology (Clifton, N.J.) 2693 281 - 291 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）

Heat shock proteins (HSPs) are often expressed in all nucleated cells, but their expression profiles differ. In particular, HSP90α and HSP90β have high sequence identity and have not been fully examined for their individual and compensatory functions as molecular chaperones, differences in client proteins, and extracellular distributions with exosomes. Immunohistochemical staining is a technique to visualize the presence and localization of target antigens using specific antibodies, of which the multiplex immunostaining method can reveal differences in protein expression in the same tumor tissue and the localization of proteins of interest within tumor tissue or single cells. The common multiplex immunostaining method uses multiple secondary antibodies of different reacting animal species to identify and detect different antigens, thus requiring different animals to be immunized with each primary antibody. Furthermore, the fluorescent-antibody method is the predominant multiplex staining method but has the critical disadvantage that permanent specimens cannot be prepared. Here, we outline a multiplex staining method for HSP90α and HSP90β based on the enzyme-antibody method that allows permanent specimens to be prepared without the restriction of immunized animal species.

DOI： 10.1007/978-1-0716-3342-7_21

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SCAND1 Reverses Epithelial-to-Mesenchymal Transition (EMT) and Suppresses Prostate Cancer Growth and Migration. 査読国際誌

Takanori Eguchi, Eva Csizmadia, Hotaka Kawai, Mona Sheta, Kunihiro Yoshida, Thomas L Prince, Barbara Wegiel, Stuart K Calderwood

Cells 11 ( 24 ) 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epithelial-mesenchymal transition (EMT) is a reversible cellular program that transiently places epithelial (E) cells into pseudo-mesenchymal (M) cell states. The malignant progression and resistance of many carcinomas depend on EMT activation, partial EMT, or hybrid E/M status in neoplastic cells. EMT is activated by tumor microenvironmental TGFβ signal and EMT-inducing transcription factors, such as ZEB1/2, in tumor cells. However, reverse EMT factors are less studied. We demonstrate that prostate epithelial transcription factor SCAND1 can reverse the cancer cell mesenchymal and hybrid E/M phenotypes to a more epithelial, less invasive status and inhibit their proliferation and migration in DU-145 prostate cancer cells. SCAND1 is a SCAN domain-containing protein and hetero-oligomerizes with SCAN-zinc finger transcription factors, such as MZF1, for accessing DNA and the transcriptional co-repression of target genes. We found that SCAND1 expression correlated with maintaining epithelial features, whereas the loss of SCAND1 was associated with mesenchymal phenotypes of tumor cells. SCAND1 and MZF1 were mutually inducible and coordinately included in chromatin with hetero-chromatin protein HP1γ. The overexpression of SCAND1 reversed hybrid E/M status into an epithelial phenotype with E-cadherin and β-catenin relocation. Consistently, the co-expression analysis in TCGA PanCancer Atlas revealed that SCAND1 and MZF1 expression was negatively correlated with EMT driver genes, including CTNNB1, ZEB1, ZEB2 and TGFBRs, in prostate adenocarcinoma specimens. In addition, SCAND1 overexpression suppressed tumor cell proliferation by reducing the MAP3K-MEK-ERK signaling pathway. Of note, in a mouse tumor xenograft model, SCAND1 overexpression significantly reduced Ki-67(+) and Vimentin(+) tumor cells and inhibited migration and lymph node metastasis of prostate cancer. Kaplan-Meier analysis showed high expression of SCAND1 and MZF1 to correlate with better prognoses in pancreatic cancer and head and neck cancers, although with poorer prognosis in kidney cancer. Overall, these data suggest that SCAND1 induces expression and coordinated heterochromatin-binding of MZF1 to reverse the hybrid E/M status into an epithelial phenotype and, inhibits tumor cell proliferation, migration, and metastasis, potentially by repressing the gene expression of EMT drivers and the MAP3K-MEK-ERK signaling pathway.

DOI： 10.3390/cells11243993

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