JP2017529831A - Met阻害剤に対する感受性予測用の新規なバイオマーカー及びその用途 - Google Patents
Met阻害剤に対する感受性予測用の新規なバイオマーカー及びその用途 Download PDFInfo
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Abstract
Description
ference RNA)、shRNA(short hairpin RNA)、miRNA(microRNA)、リボザイム(ribozyme)、DNAzyme、PNA(peptide nucleic acids)、アンチセンスオリゴヌクレオチド、抗体、アブタマー、天然抽出物及び化学物質からなる群より選択された1種以上である。より望ましくは、前記遺伝子のmRNAに特異的に結合するアンチセンスオリゴヌクレオチド、アブタマー、siRNA(small interference RNA)、shRNA(short hairpin RNA)又はmiRNA(microRNA)であり、最も望ましくは、siRNA(small interference RNA)、shRNA(short hairpin RNA)又はmiRNA(microRNA)である。
carcinoma)、子宮頸ガン(cervical cancer)、小腸ガン(small intestine cancer)、
内分泌ガン(endocrine cancer)、甲状腺ガン(thyroid cancer)、副甲状線ガン
(parathyroid cancer)、腎ガン(adrenal cancer)、軟組織腫瘍(soft tissue tumor)、尿道ガン(urethral cancer)、前立腺ガン(prostate cancer)、気管支ガン(bronchogenic cancer)、骨髓ガン(bone marrow tumor)などを含むが、それに限定されるものではない。
前記(b)段階において、IGSF1遺伝子の発現水準又はそのタンパク質の発現水準が対照群に比べて高発現の場合、対象のMET阻害剤に対する感受性があると判定する。
HGF-非依存的METリン酸化誘導
HGF-非依存的ヒト胃ガン細胞株AGS細胞株に、MET野生型構造物(plasmid)を、48時間の間形質感染(transfection)させた後、細胞培養液を収去して、HGF elisa assay(R&D Systems、Inc、Minneapolis、MN, USA)を行った。細胞溶解物は収去して、METとIGSF1タンパク質の変化をウエスタンブロットで検証した。
HGF-非依存的なMET活性化に関連した遺伝子を同定するために、ヒト胃ガンAGS細胞株に、MET野生型プラスミドを、48時間の間過発現させた後、細胞溶解物を収去した。ヒト胃ガン細胞株の溶解液500μgを、抗-pMET抗体1μgと混合した後、4℃で12時間の間培養した後、Protein-Sepharose bead(Santa Cruz Biotehcnology、 Santa Cruz、CA、USA)20μlを添加した後、2時間の間追加反応した。免疫沈降物を緩衝液(Nondiet P-40 lysis buffer)で5回洗浄した後、2XSDSサンプル溶液を20μl添加して加熱した後、SDS-PAGEを行った後、銀染色キット(GE Healthcare Bio-Sciences Corp、NJ、USA)を使用して染色した。HGF-非依存的MET活性化に関連したタンパク質を同定するために、銀染色法(Silver staining)を通じて確認されたタンパク質を、質量分析法(Mass Spectrometry)を通じて同定した。
ウエスタンブロットを行うために、各細胞から分離したタンパク質を、SDS-PAGEを通じて分離した後、それをメンブレン(PolyScreen membranes(New England Nuclear、Boston、MA、USA)に移した後、多様な抗体(anti-phospho MET、E-cadherin、(Cell signaling Technology、Beverly、MA、USA)、anti-MET、anti-r-tubulin(Santa Cruz Biotechnology、Santa Cruz、CA、USA)、anti-IGSF1(Abnova、Jhouzih、Taipei、Taiwan)を用いて、4℃で12時間の間反応させた後、1XTBS-T緩衝液で10分間3回洗浄した。適切な抗rabbit-HRP或いは抗mouse-HRP secondary抗体を、常温で2時間反応させた後に、1XTBS-T緩衝液で10分間 3回洗浄した後、ECL solution(GE Healthcare Bio-Sciences Corp)を使用して、タンパク質の発現を検証した。
HGF-非依存的ヒト胃ガン細胞株MKN45、SNU638及び肺ガンHCC827 細胞株に、IGSF1 siRNA或いはMET siRNAを、48時間の間形質感染させた。24 ウェルプレートに8mm細孔サイズのインサートプレート(BD Biosceinces)を入れ、インサートプレートマトリゲル200μg /ml(BD Biosciences)の濃度で100μlずつ株分けした後、CO2インキュベータで30分間反応させた。MET或いはIGSF1 siRNAを形質感染させた2.5X104細胞を、無血清培地に全容積を100μlに調整してインサートプレートに入れた。ボトムプレートに増殖培地(RPMI1640+10%FBS)を400μl株分けした後、CO2インキュベータで24時間培養した。24時間の後に、インサートプレートをPBSで洗浄した後、上に残っている細胞を綿棒で拭き取った後に、10%のホルマリンで20分間固定した。二次水で洗浄した後に、0.01%の クリスタルバイオレット溶液で20分間染色した後に、温水で洗浄後、乾燥してから、移動した細胞数を測定した。細胞移動測定法(migration assay)の場合には、インサートプレートをコート(coating)することなく、前記と同一の方法で進行した。コントロール(control)とMET或いはIGSF1 siRNAを形質感染させた胃ガン及び肺ガン細胞株において、インサートプレートを通過して移動した細胞数を測定して検証した。
siRNA及びshRNAの製造方法
HGF-非依存的ヒト胃ガン細胞株MKN45、SNU638及び肺ガンHCC827細胞株に、IGSF1 siRNA(配列番号3のIGSF1#1; 5'-GCAGGUCUUUACCGGUGCU-3'、配列番号4のIGSF1#2; 5'-GGUGCUGCUACUGGAAGGA-3')、MET siRNA(配列番号5; 5'-AAAGATAAACCTCTCATAATG-3')、IGSF1 shRNA(配列番号6; 5'-CAAAGAUGGAAGUGAAAUA UCUCUAUUUCACUUCCAUCUUUGUU-3')、及び/又は、MET shRNA(配列番号7; 5'- GCCAGCCUGAAUGAUGACAUCUCUGUCAUCAUUCAGGCUGGCUU-3')を、48時間の間形質感染させた後、細胞溶解物は収去して、METとIGSF1タンパク質の変化をウエスタンブロットで検証した。
ヒトmiRNA34a(配列番号1; UGGCAGUGUCUUAGCUGGUUGU)又はmiRNA34c(配列番号2; AGGCAGUGUAGUUAGCUGAUUGC)を、 サーモフィッシャーサイエンティフィック(Thermo Fisher Scientific)社から購入して使用した。HGF-非依存的ヒト胃ガンSNU638細胞4X105cellsを、シード処理(seeding)した後、miRNA34a或いはmiRNA34cを300nM形質感染させた後、0日、1日、2日、3日の間、トリパンブルー色素排除試験法(trypan blue exclusion method)を使用して細胞数を測定した。
HGF-非依存的ヒト胃ガン SNU638 細胞4X105cell或いはMKN45細胞3X105cellを シード処理した後、miRNA34a(配列番号1)又はmiRNA34c(配列番号2)を300nM形質感染させた後、0日、1日、2日、3日の間、トリパンブルー色素排除試験法を使用して細胞数を測定した。
ヒト miRNA34aとmiRNA34cのアンタゴミルをサーモフィッシャーサイエンティフィック社から購入して使用した。HGF-非依存的ヒト胃ガン SNU638 細胞4X105cells或いはMKN45細胞3X105cellsをシード処理した後、miRNA34a或いはmiRNA34cを300nM形質感染させた後、0日、1日、2日、3日の間、トリパンブルー色素排除試験法を使用して細胞数を測定した。
本発明者等は、HGF-非依存的METリン酸化誘導マーカーを同定する目的で、HGF-陰性のヒト胃ガン細胞株AGSに、MET野生型DNAを過発現させることで、HGF-非依存的METリン酸化を誘導させた(図1a中の左側グラフ)。それに、p-MET抗体を用いて免疫沈降法(immunoprecipitation)を実施した後、METと結合するタンパク質を同定するために、銀染色法(silver staining)を実施した(図1a中の右側ゲルイメージ)。
2-1. ヒト胃ガン細胞株でのHGF-非依存的METリン酸化誘導マーカーIGSF1とMETリン酸化間の発現分析
本発明者等は、ヒト胃ガン細胞株において、HGF-非依存的METリン酸化誘導マーカーIGSF1とMETリン酸化間の連関性を分析する目的で、全8種の胃ガン細胞株に、IGSF1、pMET(リン酸化された活性型MET)抗体を用いて、ウエスタンブロットを実施した。
本発明者等は、ヒト肺ガン細胞株でのHGF-非依存的METリン酸化誘導マーカーIGSF1とMETリン酸化間の発現を分析する目的で、全9種の肺ガン細胞株に、IGSF1、pMET(リン酸化された活性型MET)抗体を用いて、ウエスタンブロットを実施した。
本発明者等は、ヒト胃ガン細胞株でのHGF-非依存的METリン酸化誘導マーカーIGSF1とMETタンパク質間の結合を分析する目的で、ヒト胃ガン細胞株AGSにMETとIGSF1とを過発現させ、pMET抗体を用いて免疫沈降法を実施した後、IGSF1との結合をウエスタンブロットで確認した。
本発明者等は、ヒト胃ガン細胞株(AGS、MKN45、SNU638)及び肺ガン細胞株(HCC827)でのHGF-非依存的METリン酸化誘導マーカーIGSFの発現抑制時におけるMETリン酸化の変化を分析する目的で、ヒト胃ガン及び肺ガン細胞株に、IGSF1又はMETをsiRNA方法で発現を抑制させた後、METタンパク質のリン酸化の変化をウエスタンブロットで確認した。
本発明者等は、ヒト胃ガン細胞株であるSNU638とMKN45に、IGSF1又はMETをshRNAで抑制させた後、各遺伝子の発現変化をリアルタイムPCRで確認した。
ロイペプチン(Leupeptin) & NH4Cl: リソソームタンパク質分解酵素(lysosomal protease)抑制剤)
3-1. ヒト胃ガン細胞株でのHGF-非依存的METリン酸化誘導マーカーIGSF1の発現抑制時における細胞成長抑制能の分析
本発明者等は、ヒト胃ガン細胞株SNU638とMKN45とにおいて、IGSF1の発現或いはMETの発現をshRNA技法で抑制させた後、細胞成長抑制能を分析した。
本発明者等は、ヒト肺ガン細胞株HCC827とHCC1944とにおいて、IGSF1の発現或いはMETの発現をshRNA技法で抑制させた後、細胞成長抑制能を分析した。
4-1. ヒト胃ガン細胞株でのHGF-非依存的METリン酸化誘導マーカーIGSF1の発現抑制時におけるガン細胞の転移性及び移動性抑制の分析
本発明者等は、ヒト胃ガン細胞株SNU638とMKN45とにおいて、IGSF1の発現をsiRNA技法で抑制させた後、転移性と移動性抑制の程度を細胞浸潤測定法(invasion chamber assay)と創傷治癒測定法(wound healing assay)で分析した。
本発明者等は、ヒト肺ガン細胞株HCC827とH1944とにおいて、IGSF1の発現をshRNA技法で抑制させた後、ガン細胞の転移性及び移動性抑制の程度を、細胞浸潤測定法(invasion chamber assay)及び細胞移動測定法(migration assay)で分析した。
5-1. 胃ガン細胞株でのIGSF1発現有無に応じるMET阻害剤の効能比較分析
本発明者等は、胃ガン細胞株であるSNU638とMKN45とにおいてIGSF1を抑制した時、MET阻害剤に対する反応性が増加することを確認した。図5aに示したように、MET阻害剤であるPHA665752を濃度別に処理した時、細胞 luciferase 誘導されることをトリパンブルー排除(trypan blue exclusion)方法で確認したし、その時にcleaved caspase 3の発現が増加することを証明した。
本発明者等は、肺ガン細胞株であるHCC827においてIGSF1の発現を抑制したところ、細胞死滅が増加し、MET阻害剤に対する反応性も増加することを確認した。
6-1. HGF-非依存的METリン酸化誘導マーカーIGSF1及びc-METを同時抑制するmiR34a及びmiR34cによるIGSF1とMETとの抑制能分析
本発明者等は、HGF-非依存的METリン酸化誘導マーカーIGSF1及びMETを同時抑制するmiR34a及びmiR34cによる抑制の程度を分析する目的で、ヒト293細胞株においてそれぞれ、野生型IGSF1、野生型MET、それらの3'UTR部位を変異(mutation)させたルシフェラーゼ(luciferase)プラスミドを用いて、miR34a又はmiR34cと共に形質感染(transfection)させた。
本発明者等は、HGF-非依存的METリン酸化誘導マーカーIGSF1及びMETを同時抑制するmiR34a及びmiR34cによるIGSF1とMETとの発現変化の程度を分析する目的で、ヒト胃ガン細胞株MKN45及びSNU638にmir34a又はmiR34cを形質感染させた後、METの発現とIGSF1の発現とをリアルタイムPCR方法で確認した。
本発明者等は、HGF-非依存的METリン酸化誘導マーカーIGSF1及びMETを同時抑制するmiR34a及びmiR34cによる細胞成長を分析する目的で、ヒト胃ガン細胞株SNU638にmiR34a又はmiR34cを形質感染させた後、ガン細胞の成長を確認した。
図6dの上段パネルに示したように、本発明者等は、胃ガン細胞株であるSNU638とMKN45とにmir-34a 又はmir-34cを形質感染させた時、細胞移動性が抑制されることを確認した。
図6eの上段パネルに示したように、本発明者等は、胃ガン細胞株であるSNU638にant-mir34a或いはanti-mir34cを形質感染させた時、mir-34a又はmir-34cにより抑制されていたMETとIGSF1との発現が回復することを、RNA水準(左側)とタンパク質水準(右側)で確認した。
本発明者等は、実際胃ガン患者組織でのMET活性、IGSF1及びHGFの発現水準を確認するために、 US Biomax社よりTMA(tissue microarray)スライドを購入した後、免疫化学染色法を実施した。
Claims (21)
- IGSF1(Immunoglobulin Superfamily member 1、NM_001555.2)遺伝子を含む、
MET(Mesenchymal-Epithelial Transition factor)阻害剤に対する感受性予測用バイオマーカー。 - 前記METは、HGF(Hepatocyte Growth Factor)-非依存的(independent)に活性化されたことを特徴とする、
請求項1に記載のMET阻害剤に対する感受性予測用バイオマーカー。 - 前記活性化は、IGSF1(Immunoglobulin Superfamily member 1)及びMET(Mesenchymal-Epithelial Transition factor、 NM001127500.1)遺伝子の同時発現により METリン酸化が誘導されたことを特徴とする、
請求項2に記載のMET阻害剤に対する感受性予測用バイオマーカー。 - IGSF1(Immunoglobulin Superfamily member 1、M_001555.2)遺伝子の発現水準;
又は、そのタンパク質の発現水準を測定する製剤を含む、
MET(Mesenchymal-Epithelial Transition factor)阻害剤に対する感受性予測用組成物。 - 前記METは、HGF(Hepatocyte Growth Factor)-非依存的(independent)に活性化されたことを特徴とする、
請求項4に記載のMET阻害剤に対する感受性予測用組成物。 - 前記活性化は、IGSF1(Immunoglobulin Superfamily member 1、NM_001555.2)及びMET(Mesenchymal-Epithelial Transition factor、NM_001127500.1)遺伝子の同時発現によりMETリン酸化が誘導されたことを特徴とする、
請求項5に記載のMET阻害剤に対する感受性予測用組成物。 - 前記MET阻害剤は、ACTH(adrenocorticotropic hormone)生成腫瘍、急性リンパ球性又はリンパ芽球性白血病、急性又は慢性のリンパ球性白血病、急性非リンパ球性白血病、膀胱ガン、脳腫瘍、乳ガン、子宮頸ガン、慢性骨髓性白血病、リンパ腫、子宮内膜症、食道ガン、膀胱ガン、ユーイング肉腫(Ewing's sarcoma)、舌ガン、ホプキンスリンパ腫、カポジ肉腫、腎ガン、肝(肝臓)ガン、肺ガン、中皮腫、多発性骨髓腫、神経芽細胞腫、 非ホプキンスリンパ腫、骨肉腫、卵巣ガン、乳腺ガン、前立腺ガン、膵腸ガン、大腸ガン、ペニスガン、網膜芽細胞腫(retinoblastoma)、皮膚ガン、胃ガン、甲状腺ガン、子宮ガン、精巣ガン、ウィルムス腫瘍及び栄養膜腫瘍(Trophoblastoma)からなる群より選択された1種以上に対する治療剤であることを特徴とする、
請求項4に記載のMET阻害剤に対する感受性予測用組成物。 - 前記MET阻害剤は、抗-MET抗体、誘引 MET受容体、METペプチド拮抗剤、優性(dominant)ネガティブMET突然変異、MET特異的アンチセンスオリゴヌクレオチド及びリボザイム、及び選択的小分子METキナーゼ抑制剤からなる群より選択された1種以上であることを特徴とする、
請求項7に記載のMET阻害剤に対する感受性予測用組成物。 - 前記遺伝子の発現水準を測定する製剤は、前記遺伝子のmRNAに特異的に結合するアンチセンスオリゴヌクレオチド、プライマー対又はプロブを含むことを特徴とする、
請求項4に記載のMET阻害剤に対する感受性予測用組成物。 - 前記タンパク質の発現水準を測定する製剤は、前記タンパク質に特異的に結合する抗体、ペプチド又はヌクレオチドを含むことを特徴とする、
請求項4に記載のMET阻害剤に対する感受性予測用組成物。 - 請求項4乃至10 のいずれか一項に記載の組成物を含む、MET阻害剤に対する感受性予測用キット。
- IGSF1(Immunoglobulin Superfamily member 1、NM_001555.2)遺伝子の発現; 又は、前記遺伝子のタンパク質の発現或いは活性を抑制する抑制剤を有効成分として含む、対象のMET(Mesenchymal-Epithelial Transition factor)阻害剤に対する感受性増進剤。
- 前記増進剤は、MET(Mesenchymal-Epithelial Transition factor、NM_0011275
00.1)遺伝子の発現; 又は、前記遺伝子のタンパク質の発現或いは活性を抑制する抑制剤をさらに含むことを特徴とする、
請求項12に記載の増進剤。 - 前記抑制剤は、siRNA(small interference RNA)、shRNA(short hairpin RNA)、miRNA(microRNA)、リボザイム(ribozyme)、DNAzyme、PNA(peptide nucleic acids)、アンチセンスオリゴヌクレオチド、抗体、アブタマー、天然抽出物及び化学物質からなる群より選択された1種以上であることを特徴とする、
請求項12又は13に記載の増進剤。 - 前記miRNA(microRNA)は、配列番号1の塩基配列を含むMiR34a; 又は配列番号2の塩基配列を含むmiR34cであることを特徴とする、
請求項14に記載の増進剤。 - 前記siRNA(small interference RNA)は、配列番号3の塩基配列を含むIGSF1 siRNA、配列番号4の塩基配列を含むIGSF1 siRNA又は配列番号5の塩基配列を含むMET siRNAであり; 前記shRNA(short hairpin RNA)は、配列番号6の塩基配列を含むIGSF1 shRNA又は配列番号7の塩基配列を含むMET shRNAであることを特徴とする、
請求項14に記載の増進剤。 - (a)対象から生物学的試料を用意する段階と;
(b)前記生物学的試料内のIGSF1(Immunoglobulin Superfamily member 1、NM_001555.2)遺伝子又はそのタンパク質の発現水準を測定する段階と;
を含むMET(Mesenchymal-Epithelial Transition factor)阻害剤に対する感受性予測方法であって、
前記(b)段階において、IGSF1遺伝子又はそのタンパク質の発現水準が、対照群に比べて高発現の場合、対象のMET阻害剤に対する感受性があると判定することを特徴とする方法。 - 前記対象は、HGF遺伝子又はそのタンパク質の発現水準が、対照群と比較して低発現又は非発現されたことを特徴とする、
請求項17に記載の予測方法。 - 前記対象は、MET(Mesenchymal-Epithelial Transition factor、NM_001127500.
1)遺伝子又はそのタンパク質の発現水準が、対照群に比べて高発現されたことを特徴とする、
請求項17に記載の予測方法。 - 請求項12乃至16のいずれか一項に記載のMET(Mesenchymal-Epithelial Transition factor)阻害剤に対する感受性増進剤及びMET阻害剤を、対象に共同投与する段階を含む、
MET阻害剤に対する感受性の増進方法。 - 請求項12乃至16のいずれか一項に記載のMET(Mesenchymal-Epithelial Transition factor)阻害剤に対する感受性増進剤及びMET阻害剤を有効成分として含む、
METシグナル伝達経路の調節異常に関連した疾患の予防又は治療用薬学的組成物。
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