JP2022522660A - Tut4/7発現調節因子を含む癌予防又は治療用薬学的組成物 - Google Patents
Tut4/7発現調節因子を含む癌予防又は治療用薬学的組成物 Download PDFInfo
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Abstract
Description
本発明は、TUT4/7発現調節因子を含む癌予防又は治療用薬学的組成物に関し、より詳細には、TUT4/7発現を調節する核酸配列を含む癌予防又は治療用薬学的組成物に関する。
〔背景技術〕
マイクロRNA(micro RNA;miRNA)の生成過程は、ドロシャ(Drosha)とダイサー(Dicer)による切断過程によって二重螺旋RNAを作り、これを構成する2本の鎖(5pと3p)からいずれかの鎖を選択する過程を伴う。2本の鎖は厳格に異なる配列を持っており、異なる遺伝子の発現を調節できるため、いずれの鎖が選択されるかを決定する鎖選択(strand selection)過程は生物学的に重要である。
〔発明の概要〕
〔発明が解決しようとする課題〕
本発明者らは、TUT4及びTUT7(TUT4/7)によるウリジン化現象がpre-mir-324のダイサー切断位置を調節することによって機能の異なる3種のマイクロRNA(5p及び23p異型体)を生成することを確認し、TUT4/7の機能を抑制させて細胞***を防ぎ、癌発達を阻害させることができ、miR-324-5pの量を増やし、miR-324-3p.1の機能を抑制させて同一の効果を示すことができることを糾明し、本発明を完成するに至った。
〔課題を解決するための手段〕
本発明者らは、TUT4及びTUT7(TUT4/7)によるウリジン化現象がpre-mir-324のダイサー切断位置を調節することによって機能の異なる3種のマイクロRNA(5p及び23p異型体)を生成することを確認し、TUT4/7の機能を抑制させて細胞***を防ぎ、癌発達を阻害させることができ、miR-324-5pの量を増やし、miR-324-3p.1の機能を抑制させて同一の効果を示すことができることを糾明した。
配列番号4の塩基配列からなる核酸;及び
配列番号5~20からなる群から選ばれる1個以上の塩基配列を含む短い干渉RNA(small interfering RNA;siRNA);からなる群から選ばれる1種以上を含む癌予防又は治療用薬学的組成物に関する。
〔発明の効果〕
本発明は、TUT4/7発現調節因子を含む癌予防又は治療用薬学的組成物に関し、本発明の薬学組成物は、TUT4/7の機能を抑制させることによって細胞***を防ぎ、癌発達を阻害させることができ、miR-324-5pの量を増やし、miR-324-3p.1の機能を抑制させることができるので、これを効果的に癌の予防、治療又は診断に用いることができる。
〔図面の簡単な説明〕
〔図1〕mir-324アームスイッチング(Arm switching)結果であり、図1AはmiRNAに対する5p比率の中間絶対偏差の散点度(豊富でどこにでもあるmiRNA(両データセットにおいて>100 median RPM、全てのサンプルにおいて>0 RPM)が分析に含まれる)、図1BはAQ-seqによって測定されたHEK293TにおけるmiR-324のIsomiRプロファイル(RPM正規化読み取り回数は左側、5p及び3pの参照シーケンスは灰色陰影で表示)、図1CはAQ-seqによって測定されたマウス組織の指示されたパネルに対するmir-324の鎖比(5p/3p.1)、及び図1Dはほ乳動物におけるmiR-324の5’-isomiRの保存、を示す。
〔発明を実施するための形態〕
以下、本発明を下記の実施例によってより詳細に説明する。ただし、これらの実施例は本発明を例示するためのものに過ぎず、本発明の範囲がこれらの実施例によって限定されるものではない。
[準備例]
1.AQ-seqライブラリー
AQ-seq(バイアスが最小化されたsRNA-seq)ライブラリーは、以前研究(Kim et al.,2019)に説明されている通り、15個のマウス組織の全RNAを用いて構成された。
マウスにおけるsRNA-seq結果の読取り値がマウスゲノム(mm10)にマップされた以外は、以前研究(Kim et al.,2019)に説明された通りにデータを処理した。
修正されたバージョンのAGO CLIP-seq(CLEAR-CLIP及びCLASH)の結果を分析して、miR-324標的(target)を識別した(Helwak et al.,2013;Moore et al.,2015)。
野生型(wild type)、5’ポケットダイサー突然変異体及び3’ポケットダイサー突然変異体の発現のためのプラスミドを構築するために、ヒトダイサーレファレンス(RefSeq NM_030621)のコーディング配列を、以前研究で導入された突然変異の存在又は不在の下に増幅させた(Park et al.2011)。増幅されたDNAをIn-Fusion HD Cloning Kit(Clontech)を用いてBamHI及びXhoI部位においてpCK-FLAGベクター(CMVプロモーター-駆動ベクター)でサブクローニングした。
A172及びU87MGは、韓国細胞株銀行から入手した。HEK293T、A172及びU87MGを10%ウシ胎児血清(WELGENE)が補充されたDMEM(WELGENE)で保持させた。膠芽細胞腫(glioblastoma)患者(TS13-64)から由来した1次腫瘍細胞は、延世大学校医科大学(4-2012-0212、4-2014-0649)の機関検討委員会によって承認された通り、新鮮な膠芽細胞腫組織標本から確立された。
TRIzol(Invitrogen)を用いて総RNAを分離し、mirVana miRNA Isolation Kit(Ambion)で短いRNA(small RNA)(<200nt)を濃縮した。その後、RNAを15%ウレア-ポリアクリルアミドゲルで分析した。合成mir-324二重複合体及びDecade Markers System(Ambion)をサイズマーカーとして用いた。RNAをHybond-NX膜(Amersham)に移し、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミドで膜に架橋させた。アンチセンスプローブ5’末端は、T4ポリヌクレオチド(Takara)によって[ γ-32P]ATPと放射性標識され、Performa Spinカラム(Edge BioSystems)を用いて精製された。膜を、PerfectHyb Plusハイブリッド化バッファーで変成されたUltraPure Salmon Sperm DNA溶液(Thermo Scientific)と共に培養し、アンチセンスプローブとハイブリッド化した後、マイルド(mild)洗浄バッファー(0.05% SDS及び2X SSC)で洗浄し、ストリンジェント(stringent)洗浄バッファー(0.1% SDS及び0.1X SSC)で洗浄した。放射能信号は、Typhoon FLA 7000(GE Healthcare)によって感知され、Multi Gaugeソフトウェア(FujiFilm)によって分析された。
マウス組織においてmRNAレベルを測定するために、RevertAid First Strand cDNA合成キット(Thermo Scientific)を用いてマウストータルRNAマスターパネル(Mouse Total RNA Master Panel)(Takara)のRNAを逆転写し、Power SYBR Green PCR Master Mix(Thermo Scientific)でStepOnePlus Real-Time PCRシステム(Thermo Scientific)で定量的実時間PCRを行った。内部対照群にはGAPDHが用いら、qPCRプライマーの配列は、下表4に示す。
pre-mir-324及びその変異体は、T4ポリヌクレオチドによって[γ-32P]ATPと放射性標識され、メーカーの指示にしたがってOligo Clean & Concentrator(Zymo Research)を用いて精製された。
miR-1-3p、miR-324-5p又はmiR-324-3p.1の3個の8mer標的部位を含有するpmirGLOを、対照miRNA又はmir-324二重複合体と共にリポフェクタミン3000を用いてHEK293T細胞に共同形質注入(co-transfected)した。形質注入2日後に細胞を収穫し、レポーター分析を行った。レポーター活性はメーカーの指示(Promega)にしたがってSpark(登録商標)マイクロプレートリーダー(TECAN)でデュアルルシフェラーゼレポーターアッセイシステム(Dual-Luciferase Reporter Assay System)を用いて測定された。miR-1-3pがHEK293Tでほとんど発現していないことを勘案し(AQ-seqで~8RPM)、miR-1-3pの3個の8mer標的部位を有するpmirGLOがプラスミド対照群として用いられた。追加標準化のために対照群miRNAが用いられた。
Oncopression(http://oncopression.com)からマイクロアレイを用いて前処理された遺伝子発現データを検索した(Lee and Choi,2017)。REMBRANDT遺伝子発現データセット(E-MTAB-3073)は、ArrayExpress(Madhavan et al.,2009)から入手した。
TCGA膠芽細胞腫患者に対するlevel 3 miRNA遺伝子定量化データ及び臨床データはそれぞれ、GDC legacy archive及びGDCデータポータルから獲得した。患者たちは、miR-324-5p/3p比によって階層化され、また、上位及び下位40%が分析に含まれた。患者の生存はKaplan-Meier方法で推定し、Rの生存パッケージを用いて両側ログランク検定(two-sided log-rank test)でテストした。
細胞をPBSで洗浄し、プロテアーゼ抑制剤カクテルセットIII(Merck Millipore)及びフォスファターゼ抑制剤カクテルII(AG Scientific)が補充されたRIPAバッファー(Thermo Scientific)に溶解させた。BCAタンパク質分析キット(Pierce Biotechnology)でタンパク質濃度を測定し、同一量のタンパク質を4~12%トリス-グリシンゲル(Thermo Scientific)から分離してImmobilon-P PVDF膜(Merck Millipore)に移した。膜を、5%脱脂乳が含まれたPBS-T(PBS(Amresco)+0.1%ツイン20(Anatrace))と共に培養した後、一次抗体で処理した。PBS-Tで3回洗浄した後、膜をHRP-接合二次抗体と共に培養した。タンパク質バンドは、SuperSignal West Pico PLUS Chemiluminescent Substrate(Thermo Scientific)によって検出され、ChemiDoc XRS+システム(Bio-Rad)によってスキャンされた。
細胞を3~8時間10μM BrdUと共に培養した後、冷たい(ice-cold)70%エタノールで固定した。固定された細胞をFITC接合抗BrdU抗体(11-5071-42、RRID:AB_11042627、Invitrogen)と共に培養し、10μg/mL RNase A(Thermo Scientific)の存在下に20μg/mLヨウ化プロピジウム(Sigma-Aldrich)で追加染色した。その後、BD Accuri C6 Plus流細胞分析機を用いて検出した。細胞周期は、BD Accuri C6システムソフトウェアによって分析された。
[実施例]
1.mir-324の代案的鎖選択(又は、アームスイッチング(Arm switching))
まず、鎖比率(strand ratio)に大きい変化が見られるmiRNAを検索した。鎖比率の正確な定量のために、AQ-seqライブラリープロトコルを用いた。鎖選択(strand selection)の変異(variation)は、15個の異なるマウス組織/発達段階によって推定された(図1Aのx軸)。また、ヒトの鎖使用を比較するために、9個のヒト細胞株から得たsRNA-seqデータセットを用いた。
[まとめ]
図7から確認できるように、末端ウリジン化酵素であるTUT4/7は、pre-mir-324をウリジン化することによって、mir-324代案的鎖選択に主要プレーヤーとして働く。すなわち、TUT4/7は、pre-mir-324をウリジン化させ、ウリジン化現象がpre-mir-324のダイサー切断位置を調節することによって、機能の異なる3種のマイクロRNA(5p及び23p異型体)間の比率を変化させる。したがって、ウリジン化によるmiR-324調節を阻害させると、細胞***関連遺伝子の発現を抑制でき、膠芽細胞腫の成長を抑制させることができる。
〔産業上の利用可能性〕
本発明は、TUT4/7発現調節因子を含む癌予防又は治療用薬学的組成物に関し、より詳細には、TUT4/7発現を調節する核酸配列を含む癌予防又は治療用薬学的組成物に関する。
Claims (14)
- 配列番号1及び2の塩基配列を含むマイクロRNA(micro RNA;miRNA);
配列番号4の塩基配列からなる核酸;及び
配列番号5~20からなる群から選ばれる1個以上の塩基配列を含む短い干渉RNA(small interfering RNA;siRNA);からなる群から選ばれる1種以上を含む癌予防又は治療用薬学的組成物。 - 前記マイクロRNAは、前記配列番号1の塩基配列を含むマイクロRNA及び前記配列番号2の塩基配列を含むマイクロRNAが互いに結合した複合体(duplex)形態である、請求項1に記載の癌予防又は治療用薬学的組成物。
- 前記短い干渉RNAは、配列番号5~8のいずれか一つの塩基配列を含む短い干渉RNA及び前記配列番号9~12のいずれか一つの塩基配列を含む短い干渉RNAが互いに結合した複合体の形態;又は配列番号13~16のいずれか一つの塩基配列を含む短い干渉RNA及び前記配列番号17~20のいずれか一つの塩基配列を含む短い干渉RNAが互いに結合した複合体の形態である、請求項1に記載の癌予防又は治療用薬学的組成物。
- 前記癌は、脳腫瘍、結腸癌、大腸癌、肺癌、肝癌、胃癌、食道癌、膵癌、胆嚢癌、腎臓癌、膀胱癌、前立腺癌、精巣癌、子宮頸癌、子宮内膜癌、絨毛癌、卵巣癌、乳癌、甲状腺癌、脳癌、頭頸部癌及び悪性黒色腫からなる群から選ばれる、請求項1に記載の癌予防又は治療用薬学的組成物。
- 前記癌は脳腫瘍である、請求項1に記載の癌予防又は治療用薬学的組成物。
- miR-324-5p及びmiR-324-3p.1からなる群から選ばれる1種以上のmiRNAの発現レベルを測定する製剤を含む癌診断用組成物。
- 前記製剤は、前記一つ以上のmiRNAに特異的に結合するプライマー又はプローブを含む、請求項6に記載の癌診断用組成物。
- 請求項6又は7の組成物を含む癌診断用キット。
- 前記キットは、RT-PCR、実時間RT-PCR、ノーザンブロッティング、RNA保護分析法又はマイクロアレイチップ用である、請求項8に記載の癌診断用キット。
- TUT4(Terminal uridylyl transferases 4)及びTUT7(Terminal uridylyl transferases 7)からなる群から選ばれる1種以上の遺伝子mRNA又はそのタンパク質のレベルを測定する製剤を含む癌診断用組成物。
- 前記遺伝子mRNAのレベルを測定する製剤は、前記TUT4及びTUT7のいずれか一つ以上のmRNAに特異的に結合するプライマー又はプローブを含む、請求項10に記載の癌診断用組成物。
- 前記タンパク質のレベルを測定する製剤は、前記TUT4及びTUT7のいずれか一つ以上のタンパク質に特異的に結合する抗体を含む、請求項10に記載の癌診断用組成物。
- 請求項10~12のいずれか一項の組成物を含む癌診断用キット。
- 前記キットは、RT-PCRキット、DNAチップキット又はタンパク質チップ用である、請求項13に記載の癌診断用キット。
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US20210363527A1 (en) | 2021-11-25 |
KR102424454B1 (ko) | 2022-07-22 |
KR20210042290A (ko) | 2021-04-19 |
JP2023098926A (ja) | 2023-07-11 |
KR102336744B1 (ko) | 2021-12-08 |
EP3904518A1 (en) | 2021-11-03 |
EP3904518A4 (en) | 2023-10-11 |
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