研究者データベース

井平 圭(イヒラ ケイ)
北海道大学病院 小児・周産・女性科
助教

基本情報

所属

  • 北海道大学病院 小児・周産・女性科

職名

  • 助教

学位

  • PhD(北海道大学)

J-Global ID

研究活動情報

論文

  • Kei Ihira, Peixin Dong, Ying Xiong, Hidemichi Watari, Yosuke Konno, Sharon J. B. Hanley, Masayuki Noguchi, Noriyuki Hirata, Futoshi Suizu, Takahiro Yamada, Masataka Kudo, Noriaki Sakuragi
    ONCOTARGET 8 8 13509 - 13520 2017年02月 [査読有り][通常論文]
     
    EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.
  • Peixin Dong, Ying Xiong, Hidemichi Watari, Sharon J. B. Hanley, Yosuke Konno, Kei Ihira, Fumihiko Suzuki, Takahiro Yamada, Masataka Kudo, Junming Yue, Noriaki Sakuragi
    SCIENTIFIC REPORTS 6 35480  2016年10月 [査読有り][通常論文]
     
    Derepression of wild-type p53 by suppressing its negative inhibitor iASPP (Inhibitor of apoptosis-stimulating protein of p53) represents a potential therapeutic option for cervical cancer (CC). Here, we reported a novel functional significance of iASPP upregulation in cervical tumorigenesis: iASPP acts as a key promoter of CC cell proliferation, epithelial-mesenchymal transition, invasion and cancer stemness, by interacting with p53 to suppress p53-mediated transcription of target genes and reducing p53-responsive microRNA-34a levels. Moreover, we demonstrate that miR-124, directly targeting iASPP, reduces expression of iASPP and attenuates CC cell growth and invasiveness. Low miR-124 expression is inversely correlated with increased expression of iASPP mRNA in CC tissues. In a cohort of 40 patients with CC, the low miR-124 expression was correlated with poor 5-year overall survival (P = 0.0002) and shorter disease-free survival 5-year (P = 0006). Treatment with the DNA methyltransferase inhibitor Zebularine increases miR-124 expression and retards CC cell growth and invasion with minimal toxicity to normal cells. Even at a non-toxic concentration, Zebularine was effective in suppressing CC cell invasion and migration. Altogether, the restoration of miR-124 reduces iASPP expression and leads to p53-dependent tumor suppression, suggesting a therapeutic strategy to treat iASPP-associated CC.
  • Dong P, Xiong Y, Watari H, Hanley SJ, Konno Y, Ihira K, Yamada T, Kudo M, Yue J, Sakuragi N
    Journal of experimental & clinical cancer research : CR 35 1 132  2016年09月 [査読有り][通常論文]
  • Peixin Dong, Kei Ihira, Ying Xiong, Hidemichi Watari, Sharon J. B. Hanley, Takahiro Yamada, Masayoshi Hosaka, Masataka Kudo, Junming Yue, Noriaki Sakuragi
    ONCOTARGET 7 15 20260 - 20270 2016年04月 [査読有り][通常論文]
     
    Overexpression of IQGAP1 and microRNA (miRNA) dysregulation are frequent in human tumors, but little is known about the role of IQGAP1 and its relationship to miRNA in endometrial carcinogenesis. We demonstrate that IQGAP1 activates the epithelial-mesenchymal transition (EMT) program and that miR-124 directly represses IQGAP1 expression in endometrial cancer (EC) cells. The overexpression of IQGAP1 stimulates EMT features and enhances migration, invasion and proliferation of EC cells, whereas knocking down IQGAP1 expression reverses EMT and inhibits these malignant properties. Using miRNA microarray profiling, we identified 29 miRNAs (let-7b, let-7f, miR-10b, miR-15b, miR-23a, miR-24, miR-25, miR-27a, miR-29b, miR-30a-5p, miR-34a, miR-124, miR-127, miR-130b, miR-148a, miR-155, miR-191*, miR-194, miR-224, miR-362, miR-409-3p, miR-422b, miR-424, miR-453, miR-497, miR-518d, miR-518f*, miR-526a and miR-656) that are significantly down-regulated in an in vitro-selected highly invasive derivative cell line (HEC-50-HI) relative to the parental HEC-50 cells. We further identified miR-124 as a direct regulator of IQGAP1 in EC cells. Enforced expression of miR-124 suppresses EC cell invasion and proliferation. The expression of IQGAP1 mRNA was significantly elevated in EC tissues, while the expression of miR-124 was decreased. The downregulation of miR-124 correlates with a poor survival outcome for patients with EC. Treating EC cells with the demethylating agent 5-aza-2'-deoxycytidine increased miR-124 expression and down-regulated IQGAP1 levels. Our data suggest that IQGAP1 promotes EMT, migration and invasion of EC cells. MiR-124, a novel tumor suppressor miRNA that is epigenetically silenced in EC, can reverse EMT and the invasive properties, by attenuating the expression of the IQGAP1 oncogene.
  • Peixin Dong, Kei Ihira, Junichi Hamada, Hidemichi Watari, Takahiro Yamada, Masayoshi Hosaka, Sharon J. B. Hanley, Masataka Kudo, Noriaki Sakuragi
    ONCOTARGET 6 24 19968 - 19975 2015年08月 [査読有り][通常論文]
     
    Although mutational inactivation of p53 is found in 50% of all human tumors, a subset of tumors display defective p53 function, but retain wild-type (WT) p53. Here, direct and indirect mechanisms leading to the loss of WT p53 activities are discussed. We summarize the oncogenic roles of iASPP, an inhibitor of WT p53, in promoting proliferation, invasion, drug or radiation-resistance and metastasis. From the therapeutic view, we highlight promising perspectives of microRNA-124, peptide and small molecules that reduce or block iASPP for the treatment of cancer. High iASPP expression enhances proliferation, aggressive behavior, the resistance to radiation/chemotherapy and correlates with poor prognosis in a range of human tumors. Overexpression of iASPP accelerates tumorigenesis and invasion through p53-dependent and p53-independent mechanisms. MicroRNA-124 directly targets iASPP and represses the growth and invasiveness of cancer cells. The disruption of iASPP-p53 interaction by a p53-derived peptide A34 restores p53 function in cancer cells. The inhibition of iASPP phosphorylation with small molecules induces p53-dependent apoptosis and growth suppression. The mechanisms underlying aberrant expression of iASPP in human tumors should be further investigated. Reactivating WT p53 functions by targeting its novel inhibitor iASPP holds promise for potential therapeutic interventions in the treatment of WT p53-containing tumors.

講演・口頭発表等

  • Bevacizumab in ovarian and uterine cervical cancer treatment : 10 year's experience of a single center in Northern Japan  [通常講演]
    井平圭
    The 5th Biennial Meeting of Asian Society of Gynecologic Oncology 2017年10月 ポスター発表
  • EZH2 stimulates Twist expression by epigenetic silencing of its suppressor miR-361 through an YY1-dependent mechanism  [通常講演]
    井平圭
    The 4th Biennial Meeting of Asian Society of Gynecologic Oncology 2015年11月 ポスター発表

教育活動情報

主要な担当授業

  • 基本医学研究
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 女性特有の内分泌 妊娠の成立 妊娠・分娩の生理と病理 婦人科疾患 婦人科悪性腫瘍 Reproductive Endocrinology Establishment of pregnancy Physiology and pathology of pregnancy and labor Gynecologic diseases Gynecologic cancer
  • 医学総論
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 婦人科がん、化学療法、臨床試験、がんプロフェッショナル
  • 基盤医学研究
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 婦人科学 婦人科腫瘍、婦人科病理、卵巣内分泌、臨床遺伝 産科学 周産期、臨床遺伝
  • 臨床医学研究
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 婦人科学 婦人科腫瘍、婦人科病理、卵巣内分泌、臨床遺伝 産科学 周産期、臨床遺伝


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