論文 - 小山内　誠

膵癌におけるJAM-Aの機能

及能 大輔, 高澤 啓, 高澤 久美, 小野 佑輔, 真柄 和史, 仲盛 優菜, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 239 - 239  2022年03月

タイト結合蛋白質Claudin-1は細胞接着、微絨毛形成を制御する

高澤 啓, 高澤 久美, 青山 智志, 村上 太朗, 真柄 和史, 小野 佑輔, 及能 大輔, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 249 - 249  2022年03月

ビタミンD代謝酵素CYP24A1の発現様式は口腔扁平上皮がんにおける予後規定因子である

仲盛 優菜, 紙谷 咲良, 真柄 和史, 小野 佑輔, 及能 大輔, 高澤 久美, 高澤 啓, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 278 - 279  2022年03月

乳がんにおいてJAM-Aの異常高発現が悪性化に関与する

真柄 和史, 高澤 啓, 高澤 久美, 小野 佑輔, 及能 大輔, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 284 - 284  2022年03月

レチノイン酸代謝酵素CYP26A1の異常発現は、膵癌細胞の悪性形質の促進に関与する

井上 彩乃, 小野 佑輔, 高澤 啓, 及能 大輔, 真柄 和史, 青山 智志, 高澤 久美, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 351 - 352  2022年03月

ビタミンD代謝酵素CYP24A1は乳癌に対する新規治療標的である

紙谷 咲良, 仲盛 優菜, 真柄 和史, 小野 佑輔, 及能 大輔, 高澤 久美, 高澤 啓, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 354 - 354  2022年03月

舌扁平上皮癌におけるPVR発現とその意義

永井 佐和, 高澤 啓, 永井 美佐, 仲盛 優菜, 小野 佑輔, 真柄 和史, 及能 大輔, 高澤 久美, 村田 雅樹, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 354 - 354  2022年03月

両側肺の壊死組織周囲への黒色色素、シュウ酸カルシウム結晶の沈着をともなった深在性真菌症の一剖検例

久保田 雄策, 小野 佑輔, 高澤 啓, 多田 聡法, 真柄 和史, 青山 智志, 及能 大輔, 高澤 久美, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 357 - 357  2022年03月

Aberrant expression of claudin-6 contributes to malignant potentials and drug resistance of cervical adenocarcinoma.

Yui Ito, Akira Takasawa, Kumi Takasawa, Taro Murakami, Taishi Akimoto, Daisuke Kyuno, Yuka Kawata, Kodai Shano, Kurara Kirisawa, Misaki Ota, Tomoyuki Aoyama, Masaki Murata, Kotaro Sugimoto, Hideki Chiba, Tsuyoshi Saito, Makoto Osanai

Cancer science   113 ( 4 ) 1519 - 1530  2022年01月  [査読有り]  [国際誌]

　概要を見る

Recent studies have revealed that aberrant expression of tight junction (TJ) proteins is a hallmark of various solid tumors and it is recognized as a useful therapeutic target. Claudin-6 (CLDN6), a member of the family of TJ transmembrane proteins, is an ideal therapeutic target because it is not expressed in human adult normal tissues. In this study, we found that CLDN6 is highly expressed in uterine cervical adenocarcinoma and that high CLDN6 expression was correlated with lymph node metastasis and lymphovascular infiltration and was an independent prognostic factor. Shotgun proteome analysis revealed that cell-cell adhesion-related proteins and drug metabolism-associated proteins (aldo-keto reductase (AKR) family proteins) were significantly increased in CLDN6-overexpressing cells. Furthermore, overexpression of CLDN6 enhanced cell-cell adhesion properties and attenuated sensitivity to anticancer drugs including doxorubicin, daunorubicin and cisplatin. Taken together, the results indicate that aberrant expression of CLDN6 enhances malignant potentials and drug resistance of cervical adenocarcinoma, possibly due to increased cell-cell adhesion properties and drug metabolism. Our findings provide an insight into a new therapeutic strategy, a CLDN6-targeting therapy, against cervical adenocarcinoma.

DOI PubMed

Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials.

Daisuke Kyuno, Akira Takasawa, Kumi Takasawa, Yusuke Ono, Tomoyuki Aoyama, Kazufumi Magara, Yuna Nakamori, Ichiro Takemasa, Makoto Osanai

Tissue barriers   10 ( 1 ) 1967080 - 1967080  2022年01月  [国際誌]

　概要を見る

Claudins are major components of tight junctions that maintain cell polarity and intercellular adhesion. The dynamics of claudins in cancer cells have attracted attention as a therapeutic target. During carcinogenesis, claudin expression is generally downregulated; however, overexpression of claudin-18.2 has been observed in several types of cancers. Upregulated and mislocalized claudin-18.2 expression in cancer cells has been suggested as a therapeutic target. Research on claudin-18.2 has revealed its involvement in carcinogenesis. Clinical trials using zolbetuximab, a monoclonal antibody targeting claudin-18.2, for patients with advanced cancer yielded positive results with few high-grade adverse events; thus, it is expected to be a novel and effective therapeutic. Here, we review current insights into the role that claudin-18.2 plays in basic cancer research and clinical applications. A better understanding of these roles will facilitate the development of new treatment strategies for cancer patients with poor prognoses.

DOI PubMed

Claudin 6 is associated with a short survival and a short recurrent free interval in non-small cell lung carcinoma.

Ylermi Soini, Risto Pirinen, Kumi Takasawa, Makoto Osanai, Akira Takasawa

Polish journal of pathology : official journal of the Polish Society of Pathologists   73 ( 1 ) 1 - 5  2022年  [国際誌]

　概要を見る

We investigated the expression of claudin 6 in non-small-cell lung carcinomas (NSCLC) by immunohistochemistry. Samples of 164 patients with NSCLC were studied by immunohistochemistry. Claudin 6 was expressed in 42 % of cases. Its expression was significantly more frequent in adeno- than in squamous cell carcinoma (p = 0.002). There was no association between the TNM status and claudin 6 expression. Claudin 6 associated with a poor prognosis of the patients and with a short recurrence-free interval (p = 0.002, p < 0.001). The association with survival had independent prognostic value (p = 0.011). The results show that claudin 6 can be regarded as a marker of poor prognosis in lung cancer. This is different to some other cancers, such as breast and cervical carcinoma suggesting that claudin 6 probably induces other cellular pathways in neoplastic lung cells than in those tumors. In lung cancer, adenocarcinomas were most abundantly positive indicating a higher linkage of claudin 6 to glandular differentiation.

DOI PubMed

悪性末梢神経鞘腫のFFPE組織標本を用いた新規バイオマーカー探索の試み

車野 晃大, 高澤 啓, 伊藤 祐衣, 桐澤 くらら, 青山 智志, 小野 祐輔, 高澤 久美, 及能 大輔, 小山内 誠

日本病理学会会誌 ( (一社)日本病理学会 )  110 ( 2 ) 71 - 71  2021年10月

蛍光標識単球を用いた肝区域の可視化技術の開発

及能 大輔, 高澤 啓, 高澤 久美, 小野 佑輔, 真柄 和史, 仲盛 優菜, 竹政 伊知朗, 小山内 誠

日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [P14 - 3]  2021年09月

活性化マクロファージはIL-1β-SAA1 axisを介して早期大腸がんの浸潤を促進する

須藤 豪太, 山本 英一郎, 青木 敬則, 高澤 啓, 新沼 猛, 久保 俊之, 萬 顕, 吉戸 文乃, 北嶋 洋志, 甲斐 正広, 小山内 誠, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [P14 - 3]  2021年09月

頭頸部扁平上皮がんの腫瘍微小環境におけるAEBP1の解析

関口 翔平, 萬 顕, 山本 英一郎, 新沼 猛, 高澤 啓, 須藤 豪太, 小池 和茂, 畠中 柚衣, 吉戸 文乃, 北嶋 洋志, 甲斐 正広, 小山内 誠, 高野 賢一, 宮崎 晃亘, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [J14 - 5]  2021年09月

Regulatory roles of claudin-1 in cell adhesion and microvilli formation.

Kumi Takasawa, Akira Takasawa, Taishi Akimoto, Kazufumi Magara, Tomoyuki Aoyama, Hiroshi Kitajima, Taro Murakami, Yusuke Ono, Daisuke Kyuno, Hiromu Suzuki, Makoto Osanai

Biochemical and biophysical research communications   565   36 - 42  2021年08月  [国際誌]

　概要を見る

Aberrant expression of tight junction proteins has recently been focused on in the cancer research field. We previously showed that claudin-1 is aberrantly expressed from an early stage of uterine cervical adenocarcinoma and contributes to malignant potentials. To elucidate the molecular mechanisms underlying tumor-promoting roles of claudin-1, we established and analyzed claudin-1 knockout cells. Knockout of claudin-1 suppressed conventional tight junctional functions, barrier and fence functions, and expression of cell adhesion-associated proteins including E-cadherin. Comparative proteome analysis revealed that expression of claudin-1 affected expression of a wide range of proteins, especially proteins that are associated with cell adhesion and actin cytoskeleton remodeling. Interactome analysis of the identified proteins revealed that E-cadherin and focal adhesion kinase play central roles in the claudin-1-dependently affected protein network. Moreover, knockout of claudin-1 significantly suppressed microvilli formation and activity of Ezrin/Radixin/Moesin. Taken together, the results indicate that expression of claudin-1 affects not only conventional tight junction function but also expression and activity of a wide range of proteins, especially proteins that are associated with cell adhesion and actin cytoskeleton remodeling, to contribute to malignant potentials and microvilli formation in cervical adenocarcinoma cells.

DOI PubMed

Activated macrophages promote invasion by early colorectal cancer via an IL-1β-SAA1 axis.

Gota Sudo, Hironori Aoki, Eiichiro Yamamoto, Akira Takasawa, Takeshi Niinuma, Ayano Yoshido, Hiroshi Kitajima, Akira Yorozu, Toshiyuki Kubo, Taku Harada, Kazuya Ishiguro, Masahiro Kai, Akio Katanuma, Hiro-O Yamano, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

Cancer science   112 ( 10 ) 4151 - 4165  2021年07月  [国際誌]

　概要を見る

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues, and detected significant upregulation of SAA1 in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Co-culture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of MMP-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1, and that SAA1 may be a predictive biomarker and a useful therapeutic target.

DOI PubMed

A systemic apolipoprotein A-IV-associated amyloidosis confirmed by proteome analysis

Taro Murakami, Akira Takasawa, Asako Moriki, Yusuke Igaki, Hiroshi Ikeda, Kazuyuki Murase, Kohichi Takada, Kazufumi Magara, Tomoyuki Aoyama, Yusuke Ono, Daisuke Kyuno, Kumi Takasawa, Masaki Murata, Makoto Osanai

Virchows Archiv ( Springer Science and Business Media LLC )  479 ( 5 ) 1041 - 1046  2021年03月  [査読有り]  [国際誌]

　概要を見る

Amyloidosis is induced by extracellular deposition of certain proteins. Thirty-six proteins have so far been identified as amyloidogenic proteins in humans. Although it is very important to determine the specific amyloid protein type for the choice of therapy for amyloidosis patient, it might be difficult to identify specific proteins from amyloid-deposited tissue. Apolipoprotein A-IV is known as an amyloid-associated protein, but there have been few reports of apolipoprotein A-IV amyloidosis. Here we report a case of systemic apolipoprotein A-IV-associated amyloidosis that was confirmed by proteome analysis using formalin-fixed paraffin-embedded tissue and an immunohistochemical technique.

DOI PubMed

Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells.

Daisuke Kyuno, Akira Takasawa, Shin Kikuchi, Ichiro Takemasa, Makoto Osanai, Takashi Kojima

Biochimica et biophysica acta. Biomembranes   1863 ( 3 ) 183503 - 183503  2021年03月  [国際誌]

　概要を見る

The epithelial-mesenchymal transition (EMT) is an essential step in cancer progression. Epithelial cells possess several types of cell-cell junctions, and tight junctions are known to play important roles in maintaining the epithelial program. EMT is characterized by a loss of epithelial markers, including E-cadherin and tight junction proteins. Somewhat surprisingly, the evidence is accumulating that upregulated expression of tight junction proteins plays an important role in the EMT of cancer cells. Tight junctions have distinct tissue-specific and cancer-specific regulatory mechanisms, enabling them to play different roles in EMT. Tight junctions and related signaling pathways are attractive targets for cancer treatments; signal transduction inhibitors and monoclonal antibodies for tight junction proteins may be used to suppress EMT, invasion, and metastasis. Here we review the role of bicellular and tricellular tight junction proteins during EMT. Further investigation of regulatory mechanisms of tight junctions during EMT in cancer cells will inform the development of biomarkers for predicting prognosis as well as novel therapies.

DOI PubMed

Aberrant expression of junctional adhesion molecule-A contributes to the malignancy of cervical adenocarcinoma by interaction with poliovirus receptor/CD155.

Taro Murakami, Akira Takasawa, Kumi Takasawa, Taishi Akimoto, Tomoyuki Aoyama, Kazufumi Magara, Yuki Saito, Misaki Ota, Daisuke Kyuno, Soh Yamamoto, Tadashi Hasegawa, Tsuyoshi Saito, Makoto Osanai

Cancer science   112 ( 2 ) 906 - 917  2021年02月  [国際誌]

　概要を見る

Recent studies have shown that aberrant expression of tight junction proteins (TJP) contributes to malignant potential of various cancers. In the present study, we investigated the expression of junctional adhesion molecule-A (JAM-A), one of the transmembrane TJP, in uterine cervical adenocarcinoma and the significance of its expression for malignancy. Immunohistochemistry on human surgical specimens showed that JAM-A was aberrantly expressed in neoplastic regions including adenocarcinoma in situ (AIS). Knockout of JAM-A significantly suppressed cell proliferation and colony-forming and migration abilities. We also showed that an antibody specific to an extracellular region of JAM-A reduced cell proliferation ability and that loss of JAM-A increased drug sensitivity of cervical adenocarcinoma cells. Based on a comprehensive proteome analysis, we found that poliovirus receptor (PVR/CD155) was regulated by JAM-A and formed a physical interaction with JAM-A. In human surgical specimens, PVR/CD155 expression was significantly correlated with some clinicopathological features and prognosis of cervical adenocarcinoma. Interestingly, most of the PVR/CD155-positive cases expressed a high level of JAM-A, and patients with the expression pattern of PVR/CD155 positive/JAM-A high had significantly shorter periods of relapse-free survival (P = .00964) and overall survival (P = .0204) than those for the other patients. Our observations suggest that aberrant expression of JAM-A promotes malignancy of uterine cervical adenocarcinoma by regulation of PVR/CD155, and JAM-A is therefore a potential therapeutic target for this malignancy.

DOI PubMed