佐久間 裕司 (サクマ ユウジ)

写真a

所属

附属免疫学研究所 分子医学部門

職名

准教授

ホームページ

http://kaken.nii.ac.jp/d/r/10364514.ja.html

学位 【 表示 / 非表示

  • 自治医科大学   博士(医学)

経歴 【 表示 / 非表示

  • 2012年
     
     

    地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所)   がん分子病態学部   副技幹

    副技幹

研究分野 【 表示 / 非表示

  • ライフサイエンス   人体病理学  

researchmapの所属 【 表示 / 非表示

  • 札幌医科大学医学部   附属フロンティア医学研究所分子医学部門   准教授  

 

研究キーワード 【 表示 / 非表示

  • 分子標的治療

  • メチル化

  • 脈管浸潤

  • 顕微鏡的

  • KIT陰性化

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論文 【 表示 / 非表示

  • The HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin- resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway

    Takashi Ui, Kazue Morishima, Shin Saito, Yuji Sakuma, Hirofumi Fujii, Yoshinori Hosoya, Shumpei Ishikawa, Hiroyuki Aburatani, Masashi Fukayama, Toshiro Niki, Yoshikazu Yasuda

    ONCOLOGY REPORTS ( SPANDIDOS PUBL LTD )  31 ( 2 ) 619 - 624  2014年02月  [査読有り]

     概要を見る

    Although cisplatin (CDDP) is a key drug in the treatment of esophageal squamous cell carcinoma (ESCC), acquired chemoresistance remains a major problem. Combination therapy may represent one strategy to overcome this resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of cancer cells, and its inhibition by small molecules, either alone or in combination, has shown promise in the treatment of solid malignancies. In the present study, we evaluated the synergistic effects of combining CDDP with the HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) on two CDDP-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150. The results obtained demonstrated the synergistic inhibitory effects of CDDP and 17-AAG on the growth of KYSE30 and KYSE150 cells. Cell growth and cell number were more effectively reduced by the combined treatment with CDDP and 17-AAG than by the treatment with either CDDP or 17-AAG alone. Western blotting revealed that the combined action of CDDP and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3, which demonstrated that the reduction in both cell growth and cell number was mediated by apoptosis. Time-course experiments showed that reduction in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis. The results of the present study demonstrate that 17-AAG synergizes with CDDP and induces apoptosis in CDDP-resistant ESCC cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect. Combination therapy with CDDP and an HSP90 inhibitor may represent a promising strategy to overcome CDDP resistance in ESCC.

    DOI PubMed

  • Annexin A4 Is Involved in Proliferation, Chemo-Resistance and Migration and Invasion in Ovarian Clear Cell Adenocarcinoma Cells

    Tae Mogami, Naho Yokota, Mikiko Asai-Sato, Roppei Yamada, Shiro Koizume, Yuji Sakuma, Mitsuyo Yoshihara, Yoshiyasu Nakamura, Yasuo Takano, Fumiki Hirahara, Yohei Miyagi, Etsuko Miyagi

    PLOS ONE ( PUBLIC LIBRARY SCIENCE )  8 ( 11 ) e80359  2013年11月  [査読有り]

     概要を見る

    Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca++-binding annexin A4 (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

    DOI PubMed

  • Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

    Yuji Sakuma, Shoichi Matsukuma, Yoshiyasu Nakamura, Mitsuyo Yoshihara, Shiro Koizume, Hironobu Sekiguchi, Haruhiro Saito, Haruhiko Nakayama, Yoichi Kameda, Tomoyuki Yokose, Sachiko Oguni, Toshiro Niki, Yohei Miyagi

    Laboratory Investigation ( 10 )  93 ( 10 ) 1137 - 1146  2013年10月  [査読有り]

     概要を見る

    Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated. © 2013 USCAP.

    DOI PubMed

  • Downregulation of ALDH1A1 expression in non-small cell lung carcinomas - its clinicopathologic and biological significance

    Koji Okudela, Tetsukan Woo, Hideaki Mitsui, Takeshisa Suzuki, Michihiko Tajiri, Yuji Sakuma, Yohei Miyagi, Yoko Tateishi, Shigeaki Umeda, Munetaka Masuda, Kenichi Ohashi

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY ( E-CENTURY PUBLISHING CORP )  6 ( 1 ) 1 - 12  2013年  [査読有り]

     概要を見る

    ALDH1A1 metabolizes a variety of endogenous and exogenous aldehyde, and also oxidizes retinol to synthesize retinoic acid and modulate cell differentiation. Moreover, ALDH1A1 is also suggested to participate in the maintenance of cancer stem cells. To investigate the potential role of ALDH1A1 in carcinogenesis of the lung, the present study examined two hundred and sixty eight cases of non-small cell lung carcinoma (NSCLC) for its immunohistochemical expression and analyzed associations between ALDH1A1 levels and a series of clinicopathologic parameters. Also, the biological significance of the aberrant expression of ALDH1A1 was investigated in vitro. ALDH1A1 expression was markedly reduced in 39.9% (107/268) of NSCLCs. The incidence of this reduction was significantly higher in adenocarcinomas (ADC: 41.6%, 85/207) and large cell carcinomas (61.1%, 11/18) than squamous cell carcinomas (25.5%, 11/43). Among ADCs, the downregulation tended to be more remarkable in high grade, poorly differentiated tumors, and tumors with stronger proliferating activity. It also occurred with a significantly higher incidence in smokers than non-smokers. Forced expression of ALDH1A1 in NSCLC cell lines, which had lost ALDH1A1 expression, markedly attenuated their growth. Taken together, loss of ALDH1A1 expression is suggested to promote carcinogenesis especially in the smoking-related ADCs.

    PubMed

  • Prognostic value of preoperative FDG-PET in stage IA lung adenocarcinoma

    Shuji Murakami, Haruhiro Saito, Yuji Sakuma, Tetsuro Kondo, Fumihiro Oshita, Hiroyuki Ito, Masahiro Tsuboi, Chikako Hasegawa, Tomoyuki Yokose, Youichi Kameda, Haruhiko Nakayama, Kouzo Yamada

    EUROPEAN JOURNAL OF RADIOLOGY ( ELSEVIER IRELAND LTD )  81 ( 8 ) 1891 - 1895  2012年08月  [査読有り]

     概要を見る

    Background: Maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been found to have prognostic value. We previously reported the correlation between SUVmax and pathological invasive area, and determined an SUVmax cut-off value of 2.15 for predicting the recurrence potential of an invasive area of diameter 5 mm. Here, we evaluate the validity of FDG-PET for prediction of recurrence in pathological stage IA lung adenocarcinoma. Methods: From February 2006 to May 2008, 100 patients with pathological stage IA lung adenocarcinoma underwent complete resection at our hospital. Tumors were classified as air-type or solid-type based on thin-section computed tomography (TS-CT) findings and the influence of TS-CT classification, SUVmax, and clinicopathologic features were evaluated in terms of the incidence of recurrence. Results: Unlike air-type adenocarcinomas, recurrent disease was detected in 8 of 62 solid-type adenocarcinomas. SUVmax and diameter of invasive area were significantly correlated with recurrence and a shorter time to recurrence. All 8 recurrent cases had pathological invasive area >5 mm. All except one case of recurrence were solid-type adenocarcinomas with SUVmax >= 2.15. Three-year disease-free survival rates were 100% in air-type adenocarcinomas, 97.1% in solid-type adenocarcinomas with SUVmax < 2.15, and 74.1% in solid-type adenocarcinoma with SUVmax >= 2.15. Conclusion: Combined evaluation of TS-CT classification and SUVmax had significant value in predicting recurrence in stage IA lung adenocarcinoma, reflecting the aggressiveness of primary lung adenocarcinoma. Prediction of tumor aggressiveness could contribute to decision-making regarding the choice of surgical procedure and treatment after surgery. (c) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI PubMed

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