研究者詳細 - 小山内　誠

論文 - 小山内　誠

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Establishment and characterization of the novel myxofibrosarcoma cell line, SMU-MFS

Naoya Nakahashi, Makoto Emori, Kohichi Takada, Yasutaka Murahashi, Junya Shimizu, Kazuyuki Murase, Tomohide Tsukahara, Shintaro Sugita, Akira Takasawa, Kousuke Iba, Atsushi Teramoto, Makoto Osanai

Human Cell ( Springer Science and Business Media LLC ) 38 ( 1 ) 2024年12月

Multilayered proteomics reveals that JAM-A promotes breast cancer progression via regulation of amino acid transporter LAT1.

Kazufumi Magara, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Misaki Ota, Daisuke Kyuno, Yusuke Ono, Taro Murakami, Soh Yamamoto, Yuna Nakamori, Naoya Nakahashi, Goro Kutomi, Ichiro Takemasa, Tadashi Hasegawa, Makoto Osanai

Cancer science 2024年06月 [国際誌]

Recent studies have shown that transmembrane-type tight junction proteins are upregulated in various cancers compared with their levels in normal tissues and are involved in cancer progression, suggesting that they are potential therapeutic targets. Here, we demonstrated the expression profile and a novel role of junctional adhesion molecule-A (JAM-A) in breast cancer. Immunohistochemistry of surgical specimens showed that JAM-A was highly expressed from carcinoma in situ lesions, as in other adenocarcinomas, with higher expression in invasive carcinomas. High expression of JAM-A contributed to malignant aspects such as lymph node metastasis and lymphatic involvement positivity. In breast cancer cells, JAM-A expression status affects malignant potentials including proliferation and migration. Multilayered proteomics revealed that JAM-A interacts with the amino acid transporter LAT1 in breast cancer cells. JAM-A regulates the expression of LAT1 and interacts with it on the whole cell membrane, leading to enhanced amino acid uptake to promote tumor growth. Double high expression of JAM-A and LAT1 predicts poor prognosis in patients with breast cancer. Of note, an antibody against an extracellular domain of JAM-A suppressed the proliferation of breast cancer cells. Our findings indicate the possibility of JAM-A-targeted therapy ideally combined with LAT1-targeted therapy as a new therapeutic strategy against breast cancer.

Vitamin D-metabolizing enzyme CYP24A1 affects oncogenic behaviors of oral squamous cell carcinoma and its prognostic implication.

Yuna Nakamori, Akira Takasawa, Kumi Takasawa, Daisuke Kyuno, Yusuke Ono, Kazufumi Magara, Naoya Nakahashi, Shohei Sekiguchi, Kei Tsuchihashi, Akihiro Miyazaki, Makoto Osanai

Medical molecular morphology 2024年05月 [国内誌]

Vitamin D is an essential molecule for cellular homeostasis, playing a critical role in cell fate decisions including cell proliferation, differentiation, and viability. Accumulating evidence has revealed that expression of the vitamin D-metabolizing enzyme CYP24A1 is dysregulated in different types of human malignancy. CYP24A1 has been shown to be involved in the oncogenic property of a variety of carcinoma cells. However, the pathological relevance of CYP24A1 expression level in human oral malignancy remains to be clarified. In the present study, suppression of CYP24A1 expression in oral squamous cell carcinoma (OSCC) cells increased cell proliferation, invasive activity, colony formation efficacy, and tumor growth in vivo. In addition, knockout of CYP24A1 expression inhibited cell death induced by two different types of anticancer drugs, i.e., fluorouracil and cisplatin. Gene clustering by RNA-sequence analysis revealed that several signaling molecules associated with MYC are involved in CYP24A1-mediated oncogenic behaviors. Furthermore, decreased expression level of CYP24A1 was observed in 124/204 cases (61%) of OSCC and was shown to be associated with short relapse-free and overall survival periods. The results showed that a low expression level of CYP24A1 promotes the oncogenic activity of OSCC and is significantly associated with poor prognosis in patients with this malignancy.

MPNSTで異常発現するPVRはがん悪性化に寄与し,治療標的となりうる

中橋尚也, 江森誠人, 高澤久美, 太田未咲, 真柄和史, 小野祐輔, 及能大輔, 杉田真太朗, 長谷川匡, 小山内誠, 高澤啓

日本整形外科学会雑誌 ( (公社)日本整形外科学会 ) 98 ( 2 ) S194 - S194 2024年03月

膵癌の進展におけるClaudin-1の機能(The role of Claudin-1 in Pancreatic Cancer)

浅野日南英, 及能大輔, 奥村礼央菜, 真柄和史, 小野佑輔, 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 ) 113 ( 1 ) 474 - 474 2024年02月

乳癌患者における癌幹細胞マーカーに対する血中自己抗体価と術後予後の相関(Autoantibodies against breast cancer stem cells are associated with a poor prognosis in patients)

奥村礼央菜, 及能大輔, 水江由佳, 廣橋良彦, 浅野日南英, 真柄和史, 小野佑輔, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 113 ( 1 ) 475 - 475 2024年02月

胎盤FFPE組織を用いた比較プロテオーム解析による妊娠高血圧症候群のバイオマーカー探索(Biomarker analysis of hypertensive disorders of pregnancy by proteomics from placental FFPE tissues)

太田未咲, 高澤啓, 高澤久美, 真柄和史, 小野佑輔, 及能大輔, 杉田真太朗, 長谷川匡, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 113 ( 1 ) 328 - 328 2024年02月

Common pathological findings in the heart in COVID-19-related sudden death cases: An autopsy case series.

Daisuke Kyuno, Masatoshi Tateno, Yusuke Ono, Kazufumi Magara, Kumi Takasawa, Akira Takasawa, Makoto Osanai

Heliyon 9 ( 10 ) e20564 2023年10月 [国際誌]

BACKGROUND: Cardiomyopathy is a leading cause of sudden out-of-hospital death after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination. Such unexpected COVID-19-related cardiomyopathies are challenging to diagnose as specific pathological findings are not always identified. CASE SUMMARY: We reported the autopsy findings of two cases of sudden death due to COVID-19-related cardiomyopathies. In one case, death occurred after SARS-CoV-2 infection, while in the other, after COVID-19 vaccination. We found common pathological findings in both hearts: decreased staining intensity with special stains, loss of rhabdomeres, and multivacuolation in cardiomyocytes without inflammatory cell infiltration. The remaining organs showed no findings that could have contributed to the deaths. CONCLUSION: In cases of sudden death after SARS-CoV-2 infection or COVID-19 vaccination, the decreased staining intensity with special stains may aid the diagnosis of sudden death due to COVID-19-related cardiomyopathy, even when H&E staining shows few findings.

癌幹細胞マーカーに対する自己抗体を利用した乳癌患者の予後予測(Prediction of Prognosis in Breast Cancer Patients Using Autoantibodies to Cancer Stem Cell Markers)

及能大輔, 廣橋良彦, 和田朝香, 島宏彰, 九冨五郎, 真柄和史, 高澤久美, 高澤啓, 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 ) 82回 2116 - 2116 2023年09月

癌幹細胞マーカーに対する自己抗体を利用した乳癌患者の予後予測(Prediction of Prognosis in Breast Cancer Patients Using Autoantibodies to Cancer Stem Cell Markers)

及能大輔, 廣橋良彦, 和田朝香, 島宏彰, 九冨五郎, 真柄和史, 高澤久美, 高澤啓, 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 ) 82回 2116 - 2116 2023年09月

Emerging roles of transmembrane-type tight junction proteins in cancers.

Akira Takasawa, Kumi Takasawa, Masaki Murata, Makoto Osanai, Norimasa Sawada

Pathology international 73 ( 8 ) 331 - 340 2023年08月 [国際誌]

Tight junctions (TJs) are the most apical components of the cell-cell adhesion machinery in epithelial and endothelial cells and they play essential roles in homeostasis. Recent studies have revealed that aberrant expression of tight junction proteins (TJPs) is frequently observed in various type of cancers. Here we review cancer-associated aberrant expression of TJPs with focus on transmembrane-type TJPs including claudins, junctional adhesion molecule-A (JAM-A), and occludin. Some transmembrane-type TJPs are upregulated at the early neoplastic stage and their expression persists during dedifferentiation. Aberrant expression of TJPs contributes to proliferation, invasion, and dysregulated signaling of cancer cells. In addition to an increase in their expression level, their localization is altered from a TJ-restricted pattern to distribution throughout the whole cell membrane, making them suitable as therapeutic targets. Extracellular domains of transmembrane-type TJPs can be approached by target drugs not only from the lumen side (apical side) but also from the extracellular matrix side (basal side), including blood vessels. Aberrantly expressed TJPs are potential useful diagnostic markers as well as therapeutic targets for cancers.

MPNSTにおけるPVR発現の意義

中橋尚也, 高澤啓, 江森誠人, 高澤久美, 太田未咲, 真柄和史, 小野佑輔, 及能大輔, 杉田真太朗, 長谷川匡, 小山内誠

日本整形外科学会雑誌 ( (公社)日本整形外科学会 ) 97 ( 8 ) S1975 - S1975 2023年08月

Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, SMU-DDCS, harboring an IDH1 mutation

Makoto Emori, Naoya Nakahashi, Akira Takasawa, Kenji Murata, Yasutaka Murahashi, Junya Shimizu, Tomohide Tsukahara, Shintaro Sugita, Kohichi Takada, Tadashi Hasegawa, Makoto Osanai, Kosuke Iba

Human Cell ( Springer Science and Business Media LLC ) 2023年07月

A novel approach to diagnosing crystal-storing histiocytosis: utility of scanning electron microscopy for formalin-fixed paraffin-embedded tissue specimens.

Kazufumi Magara, Akira Takasawa, Keisuke Kikuchi, Taro Sugawara, Taro Murakami, Daisuke Kyuno, Yusuke Ono, Kumi Takasawa, Yasunao Numata, Shigeru Sasaki, Hiroshi Nakase, Tadashi Hasegawa, Makoto Osanai

Medical molecular morphology 2023年07月 [国内誌]

Crystal-storing histiocytosis (CSH) is a rare disorder that shows infiltration of histiocytes with an aberrant cytoplasmic accumulation of crystalline structures and is often accompanied by lymphoproliferative-plasma cell disorders (LP-PCD) as background diseases. The diagnosis of CSH requires identification of crystalline structures that accumulate in the infiltrating histiocytes, which may be challenging by optical microscopy alone. In this case report, we describe an atypical course of systemic CSH with multifocal fibrosclerosis of an unknown background disease that was diagnosed by ultrastructural observation, including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), in pathological autopsy. In addition, crystalline structures were successfully identified by scanning electron microscopic observations using formalin-fixed and paraffin-embedded (FFPE) tissue from biopsy specimens taken before death. Since CSH was identified by SEM in a tiny biopsy specimen, observation of histiocytic infiltrative lesions by SEM using FFPE tissue may lead to early detection of and initiation of treatment for CSH.

Suppression of the vitamin D metabolizing enzyme CYP24A1 provides increased sensitivity to chemotherapeutic drugs in breast cancer.

Sakura Kamiya, Yuna Nakamori, Akira Takasawa, Kumi Takasawa, Daisuke Kyuno, Yusuke Ono, Kazufumi Magara, Makoto Osanai

Oncology reports 49 ( 5 ) 2023年05月 [国際誌]

Vitamin D is an essential nutrient for the human body not only for the metabolism of calcium but also for homeostasis. Vitamin D contributes to cell fate decisions, including cell proliferation, differentiation and viability. Accumulated epidemiological data suggest a relationship between vitamin D deficiency and carcinogenesis in numerous organs. Furthermore, it is known that the expression of the vitamin D metabolizing enzyme, cytochrome P450 family 24 subtype A1 (CYP24A1), is increased in different types of human malignancy including breast carcinoma. However, the pathological relevance of elevated CYP24A1 expression level requires further clarification. In the present study, it was demonstrated that CYP24A1 promoted the oncogenic property of breast carcinoma cells. Consistent with previous reports, it was demonstrated that the expression of CYP24A1 was elevated in invasive breast carcinoma and significantly decreased the overall survival of patients with invasive breast carcinoma. Importantly, suppression of CYP24A1 expression significantly enhanced cell death sensitivity to two anticancer drugs with pharmacologically different modes of action, cisplatin and gefitinib. The results of the present study suggest the possibility of CYP24A1‑inhibiting therapy as a novel therapy in breast cancer with overexpression of CYP24A1.

Elevated expression of endocan in the development of cervical squamous neoplasia of the uterus.

Midori Sato, Ayano Inoue, Akira Takasawa, Kumi Takasawa, Daisuke Kyuno, Yusuke Ono, Kazufumi Magara, Makoto Osanai

Medical molecular morphology 2023年04月 [国内誌]

Accumulated evidence has shown that endocan, which was originally called endothelial cell-specific molecule-1, is an attractive prognostic factor in a variety of cancers. However, the relevance of endocan expression in human malignancies remains to be clarified. In the present study, the expression of endocan in cervical squamous neoplasia of the uterus, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as in invasive squamous cell carcinoma was examined by immunohistochemistry. Endocan was not sufficiently expressed in the normal cervical epithelium. Endocan expression was present in LSIL cases but was limited to basal and parabasal areas of the cells. HSIL cases exhibited strong expression of endocan with widely distributed expression toward the epithelial surface. In contrast, further strong expression of endocan was not observed in patients with invasive carcinoma. This study is the first study showing increased expression of endocan in precancerous dysplastic lesions and malignancy of the cervix. The data suggest that a high expression level of endocan potentially contributes to the development of cervical squamous neoplasia of the uterus.

レチノイン酸代謝酵素CYP26A1の異常発現は、舌癌の悪性化に関与する

桑原未羽, 黒田睦喜, 小野佑輔, 高澤啓, 仲盛優菜, 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 ) 112 ( 1 ) 386 - 386 2023年03月

舌扁平上皮がんで異常高発現するPVRはがん悪性化に寄与する

永井佐和, 高澤啓, 永井美佐, 小野佑輔, 真柄和史, 青山智志, 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 ) 112 ( 1 ) 382 - 383 2023年03月

MPNSTにおけるPVR発現の意義

中橋尚也, 高澤啓, 高澤久美, 太田未咲, 真柄和史, 小野祐輔, 及能大輔, 杉田真太朗, 長谷川匡, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 346 - 346 2023年03月

乳がんにおけるタイト結合関連タンパク質LSRの膜型エストロゲン受容体GPR30を介した発現調節とその意義

太田未咲, 高澤啓, 高澤久美, 青山智志, 小野祐輔, 及能大輔, 小山内誠, 長谷川匡

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 303 - 303 2023年03月

子宮頸部腺癌で異所性高発現するclaudin-6はがん悪性化に寄与する

高澤啓, 伊藤祐衣, 高澤久美, 村上太朗, 太田未咲, 青山智志, 小野祐輔, 及能大輔, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 255 - 255 2023年03月

乳がんにおけるタイト結合分子JAM-Aの役割

真柄和史, 高澤啓, 高澤久美, 小野佑輔, 及能大輔, 仲盛優菜, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 240 - 240 2023年03月

膵臓がんで高発現する解糖系酵素ALDOAはがん悪性化に関与する

永井美佐, 高澤啓, 永井佐和, 小野佑輔, 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 ) 112 ( 1 ) 378 - 378 2023年03月

舌扁平上皮がんで異常高発現するPVRはがん悪性化に寄与する

永井佐和, 高澤啓, 永井美佐, 小野佑輔, 真柄和史, 青山智志, 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 ) 112 ( 1 ) 382 - 383 2023年03月

レチノイン酸代謝酵素CYP26A1の異常発現は、舌癌の悪性化に関与する

桑原未羽, 黒田睦喜, 小野佑輔, 高澤啓, 仲盛優菜, 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 ) 112 ( 1 ) 386 - 386 2023年03月

膵臓がんで高発現する解糖系酵素ALDOAはがん悪性化に関与する

永井美佐, 高澤啓, 永井佐和, 小野佑輔, 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 ) 112 ( 1 ) 378 - 378 2023年03月

乳がんにおけるタイト結合関連タンパク質LSRの膜型エストロゲン受容体GPR30を介した発現調節とその意義

太田未咲, 高澤啓, 高澤久美, 青山智志, 小野祐輔, 及能大輔, 小山内誠, 長谷川匡

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 303 - 303 2023年03月

子宮頸部腺癌で異所性高発現するclaudin-6はがん悪性化に寄与する

高澤啓, 伊藤祐衣, 高澤久美, 村上太朗, 太田未咲, 青山智志, 小野祐輔, 及能大輔, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 255 - 255 2023年03月

MPNSTにおけるPVR発現の意義

中橋尚也, 高澤啓, 高澤久美, 太田未咲, 真柄和史, 小野祐輔, 及能大輔, 杉田真太朗, 長谷川匡, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 346 - 346 2023年03月

乳がんにおけるタイト結合分子JAM-Aの役割

真柄和史, 高澤啓, 高澤久美, 小野佑輔, 及能大輔, 仲盛優菜, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 112 ( 1 ) 240 - 240 2023年03月

Invasive pulmonary aspergillosis with candidiasis: usefulness of molecular and ultrastructural morphological analysis on FFPE tissue for invasive fungal infections.

Yusaku Kubota, Akira Takasawa, Yusuke Ono, Tomoyuki Aoyama, Kumi Takasawa, Akinori Tada, Kazufumi Magara, Taro Murakami, Fuminori Daimon, Soh Yamamoto, Shota Sato, Yutaro Hiratsuka, Daisuke Kyuno, Makoto Osanai

Medical molecular morphology 56 ( 2 ) 1 - 8 2023年02月 [国内誌]

Invasive pulmonary aspergillosis (IPA) is one of the most frequent forms of invasive fungal infections (IFI); however, it is often difficult to identify the pathogenic fungal species and to select appropriate treatments for patients with IFI including IPA. Here, we describe the detailed pathophysiology of an autopsy case of severe respiratory failure due to IPA with candidiasis. The patient developed severe respiratory failure after influenza infection and died, and the autopsy revealed a mixed disease of IPA with candidiasis. In this study, in addition to the routine pathological examination, we further examined formalin-fixed paraffin-embedded (FFPE) tissues by scanning electron microscopy (SEM) and partial genomic DNA sequencing. Although optical microscopy alone was insufficient to identify the pathogenic organisms, SEM clearly depicted the characteristic morphology of Aspergillus sp. and Candida sp. as closely overlapping in a nested fashion, providing evidence of mixed infection of both fungal species in a focal site. The technique using FFPE tissue in combination with ultrastructural observation by SEM, elemental analysis by SEM-EDX, and DNA sequencing is promising for analyzing the pathophysiology of IFI.

Vitamin D metabolism in cancer: potential feasibility of vitamin D metabolism blocking therapy.

Sakura Kamiya, Yuna Nakamori, Akira Takasawa, Kumi Takasawa, Daisuke Kyuno, Yusuke Ono, Kazufumi Magara, Makoto Osanai

Medical molecular morphology 56 ( 2 ) 85 - 93 2023年02月 [国内誌]

In this review, we discuss the possibility of the vitamin D metabolizing enzyme CYP24A1 being a therapeutic target for various tumors including breast, colorectal and prostate tumors. Given the pleiotropic cellular activity of vitamin D, its deficiency impairs its physiological function in target cells and results in various pathologies including cancer. In addition, accumulated data have shown that elevated expression of CYP24A1 promotes carcinogenesis in various cancer subtypes by decreasing the bioavailability of vitamin D metabolites. Thus, we propose the potential feasibility of vitamin D metabolism-blocking therapy in various types of human malignancies that express constitutive CYP24A1.

Retinoic acid metabolism in cancer: potential feasibility of retinoic acid metabolism blocking therapy.

Makoto Osanai, Akira Takasawa, Kumi Takasawa, Daisuke Kyuno, Yusuke Ono, Kazufumi Magara

Medical molecular morphology 56 ( 1 ) 1 - 10 2023年01月 [国内誌]

Retinoic acid (RA) is an active metabolite of vitamin A, which is an essential signaling molecule involved in cell fate decisions, such as differentiation, proliferation, and apoptosis, in a wide variety of cell types. Accumulated data have demonstrated that expression of RA-metabolizing enzymes, CYP26A1, B1, and C1 (cytochrome P450, family 26A1, B1, and C1, respectively), protects cells and tissues from exposure to RA through restriction of RA access to transcriptional machinery by converting RA to rapidly excreted derivatives. CYP26 enzymes play similar but separate roles in limiting the consequences of fluctuations in nutritional vitamin A. Recently, we found that RA depletion caused by expression of CYP26A1 promotes malignant behaviors of tumor cells derived from various tissues, implicating CYP26A1 as a candidate oncogene. We also showed that the expression levels of CYP26 enzymes are elevated in various types of cancer. We have provided evidence for oncogenic and cell survival properties of CYP26 enzymes, indicating that these molecules are possible therapeutic targets for CYP26-expressing malignancies.

CXCL12 is expressed by skeletal muscle cells in tongue oral squamous cell carcinoma.

Akira Yorozu, Shohei Sekiguchi, Akira Takasawa, Fumika Okazaki, Takeshi Niinuma, Hiroshi Kitajima, Eiichiro Yamamoto, Masahiro Kai, Mutsumi Toyota, Yui Hatanaka, Koyo Nishiyama, Kazuhiro Ogi, Hironari Dehari, Kazufumi Obata, Makoto Kurose, Atsushi Kondo, Makoto Osanai, Akihiro Miyazaki, Kenichi Takano, Hiromu Suzuki

Cancer medicine 12 ( 5 ) 5953 - 5963 2022年10月 [国際誌]

BACKGROUND: The CXCL12/CXCR4 axis plays a pivotal role in the progression of various malignancies, including oral squamous cell carcinoma (OSCC). In this study, we aimed to clarify the biological and clinical significance of CXCL12 in the tumor microenvironment of OSCCs. METHODS: Publicly available single-cell RNA-sequencing (RNA-seq) datasets were used to analyze CXCL12 expression in head and neck squamous cell carcinomas (HNSCC). Immunohistochemical analysis of CXCL12, α-smooth muscle antigen (α-SMA), fibroblast activation protein (FAP) and CD8 was performed in a series of 47 surgically resected primary tongue OSCCs. Human skeletal muscle cells were co-cultured with or without OSCC cells, after which CXCL12 expression was analyzed using quantitative reverse-transcription PCR. RESULTS: Analysis of the RNA-seq data suggested CXCL12 is abundantly expressed in stromal cells within HNSCC tissue. Immunohistochemical analysis showed that in grade 1 primary OSCCs, CXCL12 is expressed in both tumor cells and muscle cells. By contrast, grade 3 tumors were characterized by disruption of muscle structure and reduced CXCL12 expression. Quantitative analysis of CXCL12-positive areas within tumors revealed that reduced CXCL12 expression correlated with poorer overall survival. Levels of CXCL12 expression tended to inversely correlate α-SMA expression and positively correlate with infiltration by CD8+ lymphocytes, though these relations did not reach statistical significance. CXCL12 was significantly upregulated in muscle cells co-cultured with OSCC cells. CONCLUSION: Our results suggest that tongue OSCC cells activate CXCL12 expression in muscle cells, which may contribute to tumor progression. However, CXCL12 is reduced in advanced OSCCs due to muscle tissue destruction.

COVID-19-associated disseminated mucormycosis: An autopsy case report.

Daisuke Kyuno, Terufumi Kubo, Mitsuhiro Tsujiwaki, Shintaro Sugita, Michiko Hosaka, Hazuki Ito, Keisuke Harada, Akira Takasawa, Yusaku Kubota, Kumi Takasawa, Yusuke Ono, Kazufumi Magara, Eichi Narimatsu, Tadashi Hasegawa, Makoto Osanai

World journal of clinical cases 10 ( 28 ) 10358 - 10365 2022年10月 [国際誌]

BACKGROUND: Reports of mucormycosis, an infectious disease that commonly affects immunocompromised individuals, have increased during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Disseminated mucormycosis associated with COVID-19 is rare but fatal and is characterized by an aggressive clinical course and delayed diagnosis. Our report documents a case of disseminated mucormycosis after COVID-19 infection. This is a rare pathological autopsy report on COVID-19-associated mucormycosis. CASE SUMMARY: A 58-year-old man was transferred to our hospital with severe COVID-19 pneumonia. During treatment for acute respiratory distress syndrome, he developed intra-abdominal bleeding that required a right hemicolectomy and ileostomy for hemostasis. The ileostoma and surgical wound developed necrosis followed by sepsis and multi-organ failure, which led to death. An autopsy revealed multiple thrombi associated with Rhizopus oryzae infection, which led to the necrosis of multiple infected organs. CONCLUSION: Early suspicion and diagnosis followed by treatment are keys to better outcomes of mucormycosis in patients with severe COVID-19.

膵癌患者の予後と癌進展におけるJAM-Aの役割(Junctional Adhesion Molecule-A may play a role in the progression of pancreatic cancer)

及能大輔, 高澤啓, 高澤久美, 真柄和史, 小山内誠

日本癌学会総会記事 ( (一社)日本癌学会 ) 81回 J - 2053 2022年09月

タイト結合分子JAM-Aの異常高発現が乳がんの悪性化に関与する(Elevated expression of JAM-A contributes malignant progression of breast cancer)

真柄和史, 高澤啓, 高澤久美, 及能大輔, 小山内誠

日本癌学会総会記事 ( (一社)日本癌学会 ) 81回 P - 3247 2022年09月

Pathological classification of desmoplastic reaction is prognostic factor in cervical adenocarcinoma.

Taishi Akimoto, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Motoki Matsuura, Masato Tamate, Masahiro Iwasaki, Shutaro Habata, Taro Murakami, Makoto Osanai, Tsuyoshi Saito

Medical molecular morphology 55 ( 4 ) 275 - 282 2022年07月 [国内誌]

Desmoplastic reaction (DR) and inflammation are significant pathological manifestations of tumorigenesis in several cancers. However, the correlation between these stromal reactions and cervical adenocarcinoma has been poorly documented. This investigation elucidated whether DR is a prognostic indicator in early cervical adenocarcinoma patients. Fifty-nine patients with early stage cervical adenocarcinoma (stages I/II) were included in the study. DR was divided into three groups, mature, intermediate, and immature, based on the presence of myxoid stroma and hyalinized keloid-like collagen. Inflammatory cell responses were classified as mild, moderate, and severe. Those stromal reactions were separately evaluated in the invasion front stroma and intratumoral stroma. In both the intratumor and invasion front stroma, intermediate/immature DR was correlated with tumor size, T stage, N stage, lymphovascular invasion, and parametrial infiltration (p < 0.001 to p < 0.05). In addition, in the intratumoral stroma, intermediate/immature DR led to short relapse-free survival and overall survival (p < 0.001). In the invasion front stroma, inflammatory cell responses were associated with DR immaturity and FIGO stage (p < 0.01). These results suggest that the classification of DR maturity is a potential prognostic biomarker in early stage cervical adenocarcinoma patients. DR can be evaluated by routine H&E staining without immunohistochemistry, making it convenient and economical in clinical practice.

免疫チェックポイント阻害薬による偽増悪および免疫関連有害事象を併発した肺多形癌の一剖検例

多田聡法, 真柄和史, 高澤啓, 久保田雄策, 小野佑輔, 及能大輔, 高澤久美, 廣橋良彦, 小山内誠

日本病理学会会誌 ( (一社)日本病理学会 ) 111 ( 1 ) 357 - 358 2022年03月

膵臓癌におけるALDOA発現とその意義

永井美佐, 小野佑輔, 高澤啓, 永井佐和, 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 ) 352 - 352 2022年03月

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]

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.

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]

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.

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]

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.

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]

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.

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]

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.

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]

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.

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]

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.

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]

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.

頭頸部扁平上皮がんの微小環境におけるAEBP1の解析

萬顕, 関口翔平, 山本英一郎, 新沼猛, 高澤啓, 須藤豪太, 畠中柚衣, 北嶋洋志, 甲斐正広, 小山内誠, 宮崎晃亘, 高野賢一, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 79回 PJ14 - 6 2020年10月

早期大腸がん浸潤先進部の分子解析

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, 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 ) 79回 PJ14 - 8 2020年10月

Aldolase A promotes epithelial-mesenchymal transition to increase malignant potentials of cervical adenocarcinoma.

Yuki Saito, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Taishi Akimoto, Misaki Ota, Kazufumi Magara, Masaki Murata, Yoshihiko Hirohashi, Tadashi Hasegawa, Norimasa Sawada, Tsuyoshi Saito, Makoto Osanai

Cancer science 111 ( 8 ) 3071 - 3081 2020年08月 [国際誌]

Recent studies have revealed that metabolic reprogramming is closely associated with epithelial-mesenchymal transition (EMT) during cancer progression. Aldolase A (ALDOA) is a key glycolytic enzyme that is highly expressed in several types of cancer. In this study, we found that ALDOA is highly expressed in uterine cervical adenocarcinoma and that high ALDOA expression promotes EMT to increase malignant potentials, such as metastasis and invasiveness, in cervical adenocarcinoma cells. In human surgical specimens, ALDOA was highly expressed in cervical adenocarcinoma and high ALDOA expression was correlated with lymph node metastasis, lymphovascular infiltration, and short overall survival. Suppression of ALDOA expression significantly reduced cell growth, migration, and invasiveness of cervical cancer cells. Aldolase A expression was partially regulated by hypoxia-inducible factor-1α (HIF-1α). Shotgun proteome analysis revealed that cell-cell adhesion-related proteins were significantly increased in ALDOA-overexpressing cells. Interestingly, overexpression of ALDOA caused severe morphological changes, including a cuboidal-to-spindle shape shift and reduced microvilli formation, coincident with modulation of the expression of typical EMT-related proteins. Overexpression of ALDOA increased migration and invasion in vitro. Furthermore, overexpression of ALDOA induced HIF-1α, suggesting a positive feedback loop between ALDOA and HIF-1α. In conclusion, ALDOA is overexpressed in cervical adenocarcinoma and contributes to malignant potentials of tumor cells through modulation of HIF-1α signaling. The feedback loop between ALDOA and HIF-1α could become a therapeutic target to improve the prognosis of this malignancy.

Elevated expression of G protein-coupled receptor 30 (GPR30) is associated with poor prognosis in patients with uterine cervical adenocarcinoma.

Yoshihiko Ino, Taishi Akimoto, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Asako Ueda, Misaki Ota, Kazufumi Magara, Yohei Tagami, Masaki Murata, Tadashi Hasegawa, Tsuyoshi Saito, Norimasa Sawada, Makoto Osanai

Histology and histopathology 35 ( 4 ) 351 - 359 2020年04月 [国際誌]

Uterine cervical adenocarcinoma has a worse prognosis than that of squamous cell carcinoma and useful diagnostic and prognostic markers are needed. Estrogen is one of the key regulators of several cancers, however, the estrogen signaling has not been focused on in cervical adenocarcinoma. Here, we shows expression profile of classical estrogen receptor (ER) and a novel membrane type estrogen receptor, G protein-coupled receptor 30 (GPR30), in surgical specimens (n=53). GPR30 was strongly expressed on the cell membrane and in the cytoplasm in adenocarcinoma in situ (AIS) and adenocarcinoma, and its expression was especially strong at the invasion front in most of the cases of GPR30-positive adenocarcinoma. Nuclear staining of ER was strong in non-neoplastic glands, whereas it was almost absent in most of the AIS and adenocarcinoma cases. There was a weak but statistically significant negative correlation between immunoreactivity of GPR30 and that of ER in cervical AIS and adenocarcinoma lesions (Spearman's correlation, r=-0.324, p=0.017). ROC curve analysis revealed that immunoreactivity of GPR30 successfully distinguished neoplasms from non-neoplastic glands with high specificity (100%) and sensitivity (75.5%). GPR30 positivity was significantly correlated with histological type (p=0.009), tumor diameter (p=0.003), tumor size (p<0.001), lymphovascular infiltration (p=0.005) and UICC stage (p<0.001). ER expression was correlated only with tumor factor (p=0.047). GPR30-high patients had poor prognosis with a significantly shorter overall survival (OS) period (p=0.0309). GPR30 expression is a potential diagnostic and prognostic marker.

Immunoreactivity patterns of tight junction proteins are useful for differential diagnosis of human salivary gland tumors.

Tomoyuki Aoyama, Akira Takasawa, Masaki Murata, Makoto Osanai, Kenichi Takano, Tadashi Hasagawa, Norimasa Sawada

Medical molecular morphology 52 ( 1 ) 23 - 35 2019年03月 [国内誌]

The expression pattern of tight junction proteins (TJPs) varies among organs and tumor types. In this study, we examined the immunoreactivity of claudin (CLDN)-1, -4, and -7, and JAM-A in salivary gland tumors (SGTs) by histological types and cell types to estimate their usefulness as differential diagnostic markers. Immunoreactivity of CLDN1 was higher in ductal epithelium cells of SGTs than in non-tumor tissues. Conversely, immunoreactivity of CLDN1 was significantly decreased in basal/myoepithelium cells of SGTs compared with that in non-tumor tissues. There was no significant difference between the immunoreactivity of CLDN1 in benign tumors and that in malignant tumors. Immunoreactivity of CLDN4, CLDN7, and JAM-A in ductal epithelium cells was higher in many SGTs than in non-tumor tissues. There was a difference depending on the histological type of SGT in immunoreactivity of CLDN4, CLDN7, and JAM-A in basaloid/myoepithelial cells. It was possible to classify SGTs by a hierarchical clustering using immunoreactivity of TJPs. The results suggest that an immunohistochemical marker panel including these TJPs may be useful for differential diagnosis of SGTs and that CLDN1 is associated with tumorigenesis of SGTs.

Identification of Coiled-Coil Domain-Containing Protein 180 and Leucine-Rich Repeat-Containing Protein 4 as Potential Immunohistochemical Markers for Liposarcoma Based on Proteomic Analysis Using Formalin-Fixed, Paraffin-Embedded Tissue.

Aoyama T, Takasawa A, Takasawa K, Ono Y, Emori M, Murata M, Hayasaka T, Fujitani N, Osanai M, Yamashita T, Hasegawa T, Sawada N

The American journal of pathology 2019年02月 [査読有り]

Cytotoxicity of Clostridium perfringens enterotoxin depends on the conditions of claudin-4 in ovarian carcinoma cells.

Satoshi Tanaka, Tomoyuki Aoyama, Marie Ogawa, Akira Takasawa, Masaki Murata, Makoto Osanai, Tsuyoshi Saito, Norimasa Sawada

Experimental cell research 371 ( 1 ) 278 - 286 2018年10月 [国際誌]

Currently, Clostridium perfringens enterotoxin (CPE) is being investigated as an anti-cancer drug for tumors expressing the tight junction (TJ) transmembrane proteins claudin-3 and/or claudin-4. However, the optimal conditions for CPE cytotoxicity are still unclear. Our objectives were to determine the optimal conditions for CPE as an anti-cancer drug for treating ovarian cancer in vitro and in vivo. In our experiments, cells at low culture density showed higher sensitivity to CPE, suggesting that claudins at TJs were poorly accessible to CPE compared with those at the edge of cell colonies. Ovarian cancer cells cultured under calcium-depleted pretreatment conditions to disrupt TJs and to knock-down TJ proteins and E-cadherin production altered CPE cytotoxicity, which was mainly dependent on claudin-4 expression. These results suggest that the condition of claudin-4 at the cell surface is important for CPE cytotoxicity. Our in vivo experiments showed that a high dose of CPE is required for the effective treatment of peritoneal dissemination of ovarian cancer cells. Here, we suggest that the accessibility of CPE to claudins is important for its cytotoxicity and depends on the conditions of claudin-4 in vitro. In addition, E-cadherin expression in ovarian cancer cells affects the efficiency of CPE in vivo.

Estrogen/GPR30 Signaling Contributes to the Malignant Potentials of ER-Negative Cervical Adenocarcinoma via Regulation of Claudin-1 Expression.

Taishi Akimoto, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Masaki Murata, Makoto Osanai, Tsuyoshi Saito, Norimasa Sawada

Neoplasia (New York, N.Y.) 20 ( 10 ) 1083 - 1093 2018年10月 [国際誌]

Cervical adenocarcinomas are believed to lose estrogen response on the basis of no expression of a nuclear estrogen receptor such as ERα in clinical pathology. Here, we demonstrated that cervical adenocarcinoma cells respond to a physiological concentration of estrogen to upregulate claudin-1, a cell surface molecule highly expressed in cervical adenocarcinomas. Knockout of claudin-1 induced apoptosis and significantly inhibited proliferation, migration, and invasion of cervical adenocarcinoma cells and tumorigenicity in vivo. Importantly, all of the cervical adenocarcinoma cell lines examined expressed a membrane-bound type estrogen receptor, G protein-coupled receptor 30 (GPR30/GPER1), but not ERα. Estrogen-dependent induction of claudin-1 expression was mediated by GPR30 via ERK and/or Akt signaling. In surgical specimens, there was a positive correlation between claudin-1 expression and GPR30 expression. Double high expression of claudin-1 and GPR30 predicts poor prognosis in patients with cervical adenocarcinomas. Mechanism-based targeting of estrogen/GPR30 signaling and claudin-1 may be effective for cervical adenocarcinoma therapy.

Retinoic acid-metabolizing enzyme cytochrome P450 26A1 promotes skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene.

Makoto Osanai, Akira Takasawa, Kumi Takasawa, Masaki Murata, Norimasa Sawada

Oncology letters 15 ( 6 ) 9987 - 9993 2018年06月 [国際誌]

Elevated expression of the retinoic acid-metabolizing enzyme cytochrome P450 26A1 (CYP26A1) has been demonstrated to have an oncogenic function in carcinogenesis. In order to address the oncogenic capacity of CYP26A1 in vivo, transgenic mice that ubiquitously overexpressed CYP26A1 driven by the cytomegalovirus promoter were generated in the present study. Since the growth of these animals was normal for ≤15 months and they presented no evident abnormalities, a two-stage skin carcinogenesis analysis was performed. In the CYP26A1 transgenic mice, papilloma formation was observed within 7 weeks after administration of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Development of papillomas in these animals was significantly accelerated when compared with that observed in the control mice following treatment with DMBA in combination with the chemical tumor promoter 12-O-tetradecanoylphorbol-13-acetate. In addition, constitutive expression of CYP26A1 increased the susceptibility of these mice to the generation of squamous cell carcinomas caused by treatment with the carcinogen alone. It is thus concluded that CYP26A1 expression promotes skin carcinogenesis initiated by DMBA.

Occludin induces microvillus formation via phosphorylation of ezrin in a mouse hepatic cell line.

Masaki Murata, Makoto Osanai, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Yuka Kawada, Akihiro Yamamoto, Yusuke Ono, Yutaro Hiratsuka, Takashi Kojima, Norimasa Sawada

Experimental cell research 366 ( 2 ) 172 - 180 2018年05月 [国際誌]

Apical and basolateral cell membranes are separated by tight junctions (TJs). Microvilli are limited to the apical cell membrane. TJs and microvilli are the landmarks for epithelial cell polarity. However, the direct relationship between TJ proteins (TJPs) and the components of microvilli remains unclear. In this study, we investigated whether occludin, which is considered to be a functional TJP, is involved in microvillus formation. In occludin knockout mouse hepatic cells (OcKO cells), the microvillus density was less than that in wild-type (WT) cells and the length of microvilli was short. Immunoreactivity of ezrin was decreased in OcKO cells compared with that in WT cells. Although there was no change in the expression level of ezrin, phosphorylation of ezrin was decreased in OcKO cells. The microvillus density and the length of microvilli were increased in OcKO cells by transfection of full-length mouse occludin and COOH-terminal domains of occludin. These results suggested that occludin induced microvillus formation via phosphorylation of ezrin and that the COOH-terminal domain of occludin, which is localized in non-TJ areas, might be able to induce microvilli formation. Our results provide new insights into the function of occludin.

Elevated expression of JAM-A promotes neoplastic properties of lung adenocarcinoma.

Kazufumi Magara, Akira Takasawa, Makoto Osanai, Misaki Ota, Yohei Tagami, Yusuke Ono, Kumi Takasawa, Masaki Murata, Yoshihiko Hirohashi, Masahiro Miyajima, Gen Yamada, Tadashi Hasegawa, Norimasa Sawada

Cancer science 108 ( 11 ) 2306 - 2314 2017年11月 [国際誌]

A cell-cell adhesion protein, junctional adhesion molecule-A (JAM-A), has been shown to be involved in neoplasia of various organs. However, the fundamental role of JAM-A in tumorigenesis is still under debate because dysregulated expression of this protein has distinct effects, playing opposite roles in carcinogenesis depending on the target tissues. In the present study, we found elevated levels of JAM-A expression in lung adenocarcinoma and its preinvasive lesions, including atypical adenomatous hyperplasia and adenocarcinoma in situ by immunohistochemistry. We also showed that suppression of constitutive JAM-A expression conferred target cells with increased susceptibility to apoptosis in lung adenocarcinoma cells. Consequently, inhibition of JAM-A activity decreased colony-forming capability in vitro and tumorigenicity in vivo. The transformed phenotype following suppression of JAM-A expression was sufficient to reduce motile and invasive capacities. Importantly, knockout of JAM-A had striking effects on cells. Our observations suggest that increased expression of JAM-A promotes neoplasia of lung adenocarcinoma. In addition, an anti-JAM-A antibody efficiently reduced cell proliferation and provoked apoptosis, indicating the potential feasibility of JAM-A-inhibitory cancer therapy.

Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer

Kumi Takasawa, Akira Takasawa, Makoto Osanai, Tomoyuki Aoyama, Yusuke Ono, Tsuyoshi Kono, Yoshihiko Hirohashi, Masaki Murata, Norimasa Sawada

CANCER LETTERS ( ELSEVIER IRELAND LTD ) 403 66 - 73 2017年09月 [査読有り]

Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy. (C) 2017 Elsevier B.V. All rights reserved.

Prognostic significance of the co-expression of EGFR and HER2 in adenocarcinoma of the uterine cervix.

Ueda A, Takasawa A, Akimoto T, Takasawa K, Aoyama T, Ino Y, Nojima M, Ono Y, Murata M, Osanai M, Hasegawa T, Saito T, Sawada N

PLOS ONE 12 ( 8 ) e0184123 2017年 [査読有り]

CYP24A1-induced vitamin D insufficiency promotes breast cancer growth

Makoto Osanai, Gang-Hong Lee

ONCOLOGY REPORTS ( SPANDIDOS PUBL LTD ) 36 ( 5 ) 2755 - 2762 2016年11月 [査読有り]

Vitamin D plays a critical role in tissue homeostasis by regulating the expression of genes affecting cell proliferation, differentiation, and apoptosis. The vitamin D 24-hydroxylase CYP24A1 functions in vitamin D target tissues to degrade the hormonal form of vitamin D. Existing knowledge regarding dysregulated CYP24A1 expression supports its candidacy as a putative oncogene. Here, we found that the suppression of constitutive CYP24A1 expression conferred target cells with increased susceptibility to apoptosis and consequently inhibited anchorage-independent growth in breast carcinoma cells. In addition, suppression of vitamin D metabolism following knockdown of CYP24A1 significantly reduced tumor growth in vivo. These data provide substantial evidence for a pro-survival and stimulatory oncogenic effect of CYP24A1 in breast carcinoma cells.

Claudins-4 and -7 might be valuable markers to distinguish hepatocellular carcinoma from cholangiocarcinoma

Ono Y, Hiratsuka Y, Murata M, Takasawa A, Fukuda R, Nojima M, Tanaka S, Osanai M, Hirata K, Sawada N

Virchows Archiv 469 ( 4 ) 417 - 426 2016年10月 [査読有り]

Nuclear localization of tricellulin promotes the oncogenic property of pancreatic cance

Takasawa A, Murata M, Takasawa K, Ono Y, Osanai M, Tanaka S, Nojima M, Kono T, Hirata K, Kojima T, Sawada N

Scientific Reports 6 33582 2016年09月 [査読有り]

Analysis of the expression and localization of tight junction transmembrane proteins, claudin-1, -4, -7, occludin and JAM-A, in human cervical adenocarcinoma.

Taishi Akimoto, Akira Takasawa, Masaki Murata, Yui Kojima, Kumi Takasawa, Masanori Nojima, Tomoyuki Aoyama, Yutaro Hiratsuka, Yusuke Ono, Satoshi Tanaka, Makoto Osanai, Tadashi Hasegawa, Tsuyoshi Saito, Norimasa Sawada

Histology and histopathology 31 ( 8 ) 921 - 31 2016年08月 [国際誌]

OBJECTIVE: Tight junction proteins have recently been reported to be useful for distinguishing between neoplastic and non-neoplastic tissues. In this study, we evaluated the expression and localization of tight junction transmembrane proteins in human cervical adenocarcinoma and adenocarcinoma in situ (AIS), and we determined whether their expression patterns could distinguish cervical adenocarcinoma from non-neoplastic cervical glands. METHODS: Fifty-five patients with cervical adenocarcinoma or AIS were included in this study. Surgical specimens were immunohistochemically stained for claudin (CLDN) -1, -4, -7, occludin, and JAM-A. RESULTS: Significantly higher expression levels of CLDNs and JAM-A were found in cervical AIS and adenocarcinoma than in non-neoplastic glands. In cervical AIS and adenocarcinoma, localization of CLDN1 and JAM-A was extended throughout the whole cell membranes, whereas they were predominantly expressed at the most apical cell-cell junction in non-neoplastic glands. ROC curve analysis revealed that immunoreactivities of CLDN-1 or JAM-A successfully distinguished neoplasms from non-neoplastic cervical glands with high specificity (CLDN-1, 79.1%; JAM-A, 79.1%) and high sensitivity (CLDN-1, 84.1%; JAM-A, 95.5%). CONCLUSIONS: As expected, there were immunohistochemical differences between cervical adenocarcinoma and non-neoplastic cervical glands by using antibodies against tight junction transmembrane proteins. These results suggest that CLDN-1 and JAM-A are potential biomarkers for cervical adenocarcinoma.

NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells.

Hayashi Y, Osanai M, Lee GH

Oncology reports 34 ( 4 ) 1650 - 1658 2015年08月 [査読有り]

Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases.

Hayashi Y, Osanai M, Lee GH

Cancer science ( 6 ) 102 ( 6 ) 1228 - 1235 2011年06月 [査読有り]

Nicotine-mediated suppression of the retinoic acid metabolizing enzyme CYP26A1 limits the oncogenic potential of breast cancer

Makoto Osanai, Gang-Hong Lee

CANCER SCIENCE ( WILEY-BLACKWELL ) 102 ( 6 ) 1158 - 1163 2011年06月 [査読有り]

Tobacco smoke influences cancer development in tissues that are not directly exposed, and epidemiological studies have indicated that smoking women might experience decreased risk of breast cancer as a result of antiestrogenic effects. However, it remains to be clarified whether nicotine, one of the major addictive and best-investigated constituents of tobacco smoke, has any effect on breast cancer. Our recent work demonstrated that the retinoic acid metabolizing enzyme CYP26A1 enhances oncogenic and cell survival properties of breast carcinoma cells, implying a role as an oncogene. Here, we present evidence that nicotine significantly suppresses constitutive expression of CYP26A1, and that cells treated with nicotine exhibit enhanced sensitivity to apoptosis. In addition, nicotine may inhibit anchorage independent growth, cellular invasiveness and motility. These data show that nicotine can limit CYP26A1-mediated oncogenic characteristics, and suggest mechanisms by which nicotine might inhibit breast cancer development. (Cancer Sci 2011; 102: 1158-1163).

Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice

Kohtaro Yamasaki, Yoshihiro Hayashi, Sumika Okamoto, Makoto Osanai, Gang-Hong Lee

CANCER SCIENCE ( WILEY-BLACKWELL PUBLISHING, INC ) 101 ( 1 ) 65 - 72 2010年01月 [査読有り]

Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F(1) littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration. (Cancer Sci 2009).

Expression of fascin-1, an actin-bundling protein, in migrating hepatoblasts during rat liver development

Yoshihiro Hayashi, Katsumi Toda, Toshiji Saibara, Sumika Okamoto, Makoto Osanai, Hideaki Enzan, Gang-Hong Lee

CELL AND TISSUE RESEARCH ( SPRINGER ) 334 ( 2 ) 219 - 226 2008年11月 [査読有り]

Fascin-1 is an actin-bundling protein localized at the core actin bundles within microvillar projections and filopodial extensions in migrating cells. It is expressed at a low level in normal epithelial cells, but at a high level in tumor cells, indicating its importance in the invasion and motility of tumor cells. In addition, fascin-1 is expressed in human and murine embryos, occurring at high levels especially in developing nervous tissues. In this study, we have investigated the expression patterns of fascin-1 immunohistochemically during the early stages of rat hepatogenesis. A high expression of fascin-1 was detected in the liver bud and hepatoblasts at embryonic day (ED) 10.5, ED11.5, and ED12.5. Expression fell by ED13.5 and was not detectable at ED14.5. These observations demonstrate that the expression of fascin-1 is correlated with the migration activity of hepatoblasts during the early stages of liver development in rats.

IGF-I regulates tight-junction protein claudin-1 during differentiation of osteoblast-like MC3T3-E1 cells via a MAP-kinase pathway.

Hatakeyama N, Kojima T, Iba K, Murata M, Thi MM, Spray DC, Osanai M, Chiba H, Ishiai S, Yamashita T, Sawada N

Cell and tissue research ( 2 ) 334 243 - 254 2008年11月 [査読有り]

Protein kinase C enhances tight junction barrier function of human nasal epithelial cells in primary culture by transcriptional regulation.

Koizumi J, Kojima T, Ogasawara N, Kamekura R, Kurose M, Go M, Harimaya A, Murata M, Osanai M, Chiba H, Himi T, Sawada N

Molecular pharmacology ( 2 ) 74 432 - 442 2008年08月 [査読有り]

Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca<sup>2+</sup>absorption between enterocytes

Hiroki Fujita, Kotaro Sugimoto, Shuichiro Inatomi, Toshihiro Maeda, Makoto Osanai, Yasushi Uchiyama, Yoko Yamamoto, Takuro Wada, Takashi Kojima, Hiroshi Yokozaki, Toshihiko Yamashita, Shigeaki Kato, Norimasa Sawada, Hideki Chiba

Molecular Biology of the Cell 19 1912 - 1921 2008年05月 [査読有り]

Transforming growth factor-beta induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes.

Kojima T, Takano K, Yamamoto T, Murata M, Son S, Imamura M, Yamaguchi H, Osanai M, Chiba H, Himi T, Sawada N

Liver international : official journal of the International Association for the Study of the Liver ( 4 ) 28 534 - 545 2008年04月 [査読有り]

Transmembrane proteins of tight junctions.

Chiba H, Osanai M, Murata M, Kojima T, Sawada N

Biochimica et biophysica acta ( 3 ) 1778 588 - 600 2008年03月 [査読有り]

Induction of claudins in passaged hTERT-transfected human nasal epithelial cells with an extended life span.

Kurose M, Kojima T, Koizumi J, Kamekura R, Ninomiya T, Murata M, Ichimiya S, Osanai M, Chiba H, Himi T, Sawada N

Cell and tissue research ( 1 ) 330 63 - 74 2007年10月 [査読有り]

Changes of gap and tight junctions during differentiation of human nasal epithelial cells using primary human nasal epithelial cells and primary human nasal fibroblast cells in a noncontact coculture system.

Koizumi J, Kojima T, Kamekura R, Kurose M, Harimaya A, Murata M, Osanai M, Chiba H, Himi T, Sawada N

The Journal of membrane biology ( 1-3 ) 218 1 - 7 2007年08月 [査読有り]

A novel monoclonal antibody against the second extracellular loop of occludin disrupts epithelial cell polarity.

Tokunaga Y, Kojima T, Osanai M, Murata M, Chiba H, Tobioka H, Sawada N

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society ( 7 ) 55 735 - 744 2007年07月 [査読有り]

Inhibitory effects of retinoic acid receptor alpha stimulants on murine cataractogenesis through suppression of deregulated calpains

Nami Nishikiori, Makoto Osanai, Hideki Chiba, Takashi Kojima, Hiroshi Ohguro, Norimasa Sawada

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE ( ASSOC RESEARCH VISION OPHTHALMOLOGY INC ) 48 ( 5 ) 2224 - 2229 2007年05月 [査読有り]

PURPOSE. To determine whether retinoic acid (RA)-mediated inhibition of deregulated calpains had any effect on the development of cataract given that accumulating evidence has demonstrated a possible relationship between cataractogenesis and inappropriate activation of calpains. METHODS. The authors examined for Ca2+ influx and expression alteration of calpains in F9 cells with or without RAs, such as all-trans retinoic acid (ATRA), and specific stimulant of retinoic acid receptor alpha (RAR alpha; Am580) in the presence of oxidative stress, such as mediated by H2O2. They next examined the clinical relevance of RAs by applying these agents to a murine diabetic cataract and observed the development of the disease. RESULTS. F9 cells constitute a well-established autonomous cell model for investigating retinoid signaling, partially representing the lens epithelial phenotype, as determined by the expression of aquaporin 0, a specific differentiation marker for lens cells. Treatment with ATRA and Am580 significantly decreased the influx of Ca2+ into the cells, causally resulting in decreased mRNA expression and inhibited activation of calpains. In addition, RAR alpha agonists significantly abrogated the upregulation of calpain 2 induced by H2O2, which is a potential etiological contributor to the diabetic cataract, whereas H2O2 had no effect on calpain 1. Importantly, this RA-mediated gene-expression alteration was sufficient for dramatically inhibiting the development of lens opacity in mice with diabetes. CONCLUSIONS. Results showed that a certain type of RA inhibits Ca2+ elevation and subsequent overactivation of calpains, suggesting the potential feasibility of calpain-targeting therapies mediated by RA for cataract.

Oncostatin M induces upregulation of claudin-2 in rodent hepatocytes coinciding with changes in morphology and function of tight junctions.

Imamura M, Kojima T, Lan M, Son S, Murata M, Osanai M, Chiba H, Hirata K, Sawada N

Experimental cell research ( 9 ) 313 1951 - 1962 2007年05月 [査読有り]

Expression patterns of claudin family of tight-junction proteins in the mouse prostate

Naoyuki Sakai, Hideki Chiba, Hiroki Fujita, Yushi Akashi, Makoto Osanai, Takashi Kojima, Norimasa Sawada

HISTOCHEMISTRY AND CELL BIOLOGY ( SPRINGER ) 127 ( 4 ) 457 - 462 2007年04月 [査読有り]

Claudins are the transmembrane proteins forming the backbone of tight junctions, and consist of over 20 members of a gene family. Claudins are expressed in a tissue- and cell-type specific fashion, and changes in their abundance and/or distribution are proposed to play important roles in the pathophysiology of numerous disorders. In the prostate, claudin-1, -3, -4 and -7 transcripts are known to be expressed, but it is unknown regarding mRNA expression of other claudins or concerning expression and localization of claudin proteins in this organ. We herein show, by RT-PCR and Western blotting analyses, that not only these four claudins but also claudin-5, -8 and -10 are expressed in the normal mouse prostate. Claudin-3, -4, -5, -8 and -10 were primarily localized at the apicalmost sites of lateral membranes of luminal epithelial cells in the prostate gland, whereas claudin-1 and -7 were distributed along the basolateral membranes of the epithelium. These findings provide basic information for elucidating the significance of claudins in prostate diseases, including prostate cancers.

The nuclear receptor hepatocyte nuclear factor 4alpha acts as a morphogen to induce the formation of microvilli.

Chiba H, Sakai N, Murata M, Osanai M, Ninomiya T, Kojima T, Sawada N

The Journal of cell biology ( 6 ) 175 971 - 980 2006年12月 [査読有り]

Connexin 26 expression prevents down-regulation of barrier and fence functions of tight junctions by Na+/K+-ATPase inhibitor ouabain in human airway epithelial cell line Calu-3.

Go M, Kojima T, Takano K, Murata M, Koizumi J, Kurose M, Kamekura R, Osanai M, Chiba H, Spray DC, Himi T, Sawada N

Experimental cell research ( 19 ) 312 3847 - 3856 2006年11月 [査読有り]

タイト結合による上皮細胞極性維持にはoccludinの細胞外第2ループが重要である

徳永祐一, 小島隆, 飛岡弘敏, 村田雅樹, 小山内誠, 千葉英樹, 澤田典均

日本癌学会総会記事 ( (一社)日本癌学会 ) 65回 242 - 242 2006年09月

病態発生とタイト結合とギャップ結合の役割黄疸と血液胆汁関門

小島隆, 村田雅樹, 小山内誠, 千葉英樹, 澤田典均

日本病理学会会誌 ( (一社)日本病理学会 ) 95 ( 1 ) 155 - 155 2006年04月

肝細胞のバリア機能におけるタイト結合蛋白claudin-2の役割

今村将史, 小島隆, 孫誠一, 村田雅樹, 小山内誠, 千葉英樹, 平田公一, 澤田典均

日本病理学会会誌 ( (一社)日本病理学会 ) 95 ( 1 ) 191 - 191 2006年04月

Glial cell line-derived neurotrophic factor in the vitreous of patients with proliferative diabetic retinopathy

N Nishikiori, Y Mitamura, A Tashimo, Y Nakamura, T Harada, M Osanai, N Sawada, K Ohtsuka

DIABETES CARE ( AMER DIABETES ASSOC ) 28 ( 10 ) 2588 - 2588 2005年10月 [査読有り]

タイト結合蛋白occludinは肝細胞において生存シグナルの伝達に重要な役割を有する

村田雅樹, 小島隆, 高野賢一, 畠山尚子, 小山内誠, 千葉英樹, 澤田典均

日本癌学会総会記事 ( (一社)日本癌学会 ) 64回 368 - 368 2005年09月

細胞間の接着とシグナル Hepatocyte nuclear factor(HNF)-4αはタイト結合分子の発現を制御し,上皮の分化と極性形成を誘導する

千葉英樹, 郷久晴朗, 小島隆, 菊地慶介, 小山内誠, 澤田典均

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 56回 18 - 18 2003年05月

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