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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).

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