JP2019507594A - 大腸がん診断用組成物と診断マーカー検出方法 - Google Patents
大腸がん診断用組成物と診断マーカー検出方法 Download PDFInfo
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Abstract
KRS及びAIMP1からなる本発明の大腸がん診断マーカーは、大腸がん患者の血清から正常人対照群と比較してその発現水準が増加している。従って、KRS及びAIMP1からなる群から選ばれた一つ以上のマーカーの発現水準を測定することにより、大腸がんの有無を正確かつ迅速に判断することができる。
Description
[技術的課題]
そこで、本発明者らは、大腸がんを効果的に診断できるバイオマーカーを開発しようと鋭意努力した結果、大腸がん患者の血清から簡単かつ迅速に検出が可能で、敏感度及び特異度が高いバイオマーカーを発見して本発明を完成した。
(a)被検体からの試料の提供を受ける段階;
(b)前記試料からKRS及びAIMP1からなる群から選ばれた一つ以上のmRNAの発現水準又は蛋白質の発現水準を測定する段階;及び
(c)前記遺伝子のmRNAの発現水準又は蛋白質の発現水準を、正常対照試料の対応する遺伝子のmRNAの発現水準又は蛋白質の発現水準と較べて、発現水準が増加した被検体を、大腸がんに罹病したものと判定する段階を含む大腸がんのマーカーを検出する方法を提供することである。
(a)大腸がん患者から提供された試料に、大腸がんの治療候補物質を投与する段階;
(b)候補物質の存在又は非存在下で、前記の試料から、KRS及びAIMP1からなる群から選ばれた一つ以上のmRNAの発現水準又は蛋白質の発現水準を測定する段階;
(c)候補物質の存在下でのmRNAの発現水準又は蛋白質の発現水準と、候補物質の非存在下での対応するmRNAの発現水準又は蛋白質の発現水準とを比較する段階;
(d)候補物質の存在下でmRNAの発現水準又は蛋白質の発現水準を減少させる物質を選別する段階;及び
(e)選別された候補物質の抗がん活性を、細胞又は動物から確認する段階を含む、大腸がん治療薬のスクリーニング方法を提供することである。
前記の本発明の目的を達成するために、本発明は、KRS(lysyl-tRNA synthetase)及びAIMP1(aminoacyl-tRNA synthetase complex-interacting multifunctional Protein 1)からなる群から選ばれた一つ以上のmRNA又はその蛋白質の発現水準を測定する製剤を含む大腸がん診断用組成物を提供する。
(a)被検体からの試料の提供を受ける段階;
(b)前記試料から、KRS及びAIMP1からなる群から選ばれた一つ以上のmRNAの発現水準又は蛋白質の発現水準を測定する段階;及び
(c)前記遺伝子mRNAの発現水準又は蛋白質の発現水準を、正常対照試料の対応する遺伝子mRNAの発現水準又は蛋白質の発現水準と比べて、発現水準が増加した彼検体を大腸がんに罹病したものと判定する段階を含む大腸がんのマーカーを検出する方法を提供することである。
(a)大腸がん患者から提供された試料に、大腸がんの治療候補物質を投与する段階;
(b)候補物質の存在又は非存在下で、前記試料から、KRS及びAIMP1からなる群から選ばれた一つ以上のmRNAの発現水準又は蛋白質の発現水準を測定する段階;
(c)候補物質の存在下でのmRNAの発現水準又は蛋白質の発現水準と、候補物質非存在下でのmRNAの発現水準又は蛋白質の発現水準とを比較する段階;
(d)候補物質の存在下でmRNAの発現水準又は蛋白質の発現水準を減少させる物質を選別する段階;及び
(e)選別された候補物質の抗がん活性を、細胞又は動物から確認する段階を含む、大腸がん治療剤のスクリーニング方法を提供することである。
(a)被検体から試料の提供を受ける段階;
(b)前記試料から、KRS及びAIMP1からなる群から選ばれた一つ以上のmRNAの発現水準又は蛋白質の発現水準を測定する段階;及び
(c)前記各遺伝子mRNAの発現水準又は蛋白質の発現水準を、正常人対照群試料の対応する遺伝子mRNAの発現水準又は蛋白質の発現水準と比較して、発現水準が増加した被検体を大腸がんに罹病したと判定する段階を含む、大腸がんのマーカーを検出する方法を提供する。
(a)大腸がん患者から提供された試料に大腸がんの治療候補物質を投与する段階;
(b)候補物質の存在又は非存在下で、前記試料から、KRS及びAIMP1からなる群から選ばれた一つ以上のmRNAの発現水準又は蛋白質の発現水準を測定する段階;
(c)候補物質の存在下でのmRNAの発現水準又は蛋白質の発現水準と、候補物質非存在下での対応するmRNAの発現水準又は蛋白質の発現水準とを比較する段階;
(d)候補物質の存在下でmRNAの発現水準又は蛋白質の発現水準を減少させる物質を選別する段階;及び
(e)選別された候補物質の抗がん活性を、細胞又は動物から確認する段階を含む大腸がん治療剤のスクリーニング方法を提供する。
KRS及びAIMP1からなる本発明の大腸がん診断マーカーは、大腸がん患者の血清から、正常人対照群と比べて、その発現水準が増加している。従って、KRS及びAIMP1からなる群から選ばれた一つ以上のマーカーの発現水準を測定することにより、大腸がんの有無を正確かつ迅速に判断することができる。
1.実験試料の入手
正常人又は大腸がん患者の血清に分泌されたGRS(glycyl-tRNA synthetase)、KRS(lysyl-tRNA synthetase)、HRS(histidyl-tRNA synthetase)、WRS(tryptophanyl-tRNA synthetase)、AIMP-1(aminoacyl-tRNA synthetase complex-interacting multifunctional Protein 1)、TNF-α、IL-10及びCA-19-9の数値を、製造社の指示に従って、酵素免疫分析キットを利用して分析した。蛋白質の分泌量は、マイクロプレートリーダー(TECAN)を利用して測定した。それぞれの血清蛋白質の分析キットの製造社は次の通りである:
GRS、HRS、WRS ELISA kit(Cusabio、China)
AIMP1 ELISA kit(Elab science、China)
KRS ELISA kit(Mybiosource、USA)
TNF-α、IL-10(BD science、USA)
CA 19-9(Abnova、Taiwan)
正常人と大腸がん患者の血清から分泌された蛋白質の間のP値は、マン・ホイットニー検定/両側検定(Mann-Whitney test/Two-tailed test)で、XLASTATソフトウェアを利用して分析した。ドットブロットプロット、ROC曲線、AUC、標準偏差はGraphpad Prism 6ソフトウェアを利用して分析した。
<実施例1>
正常人と大腸がん患者の血清分析結果
大腸がんに特異的なマーカーを検索するために、正常人32人及び大腸がん患者164人の血清蛋白質を酵素免疫分析法(ELISA)で分析した。
ROC曲線分析
図2に示した通り、KRS、AIMP1のROCのAUCが0.6よりも大きく表れ、P値が0.01より小さく表れており、KRS、AIMP1の量について、大腸がん患者の血清内の数値が正常人の数値よりも統計学的に有意に大きいため、良いバイオマーカーであることが分かった。またKRS、AIMP1が従来の大腸がんのバイオマーカーであるCA-19-9よりも良いことを確認した。
Claims (15)
- KRS(lysyl-tRNA synthetase)及びAIMP1(aminoacyl-tRNA synthetase complex-interacting multifunctional Protein 1)からなる群から選ばれた一つ以上のmRNA又はその蛋白質の発現水準を測定する製剤を含む大腸がん診断用組成物。
- 前記遺伝子のmRNA発現水準を測定する製剤は、KRS mRNA又はAIMP1 mRNAに特異的に結合するプローブ又はプライマーセットであることを特徴とする請求項1記載の組成物。
- 前記蛋白質の発現水準を測定する製剤は、KRS蛋白質又はAIMP1蛋白質に特異的な抗体であることを特徴とする請求項1記載の組成物。
- KRS mRNAは配列番号1で表示される塩基配列を含み、AIMP1 mRNAは配列番号2で表示される塩基配列を含むことを特徴とする請求項1記載の組成物。
- 前記KRS蛋白質は配列番号3で表示されるアミノ酸配列を含み、AIMP1蛋白質は配列番号4で表示されるアミノ酸配列を含むことを特徴とする請求項1記載の組成物。
- KRS及びAIMP1からなる群から選ばれた一つ以上のmRNA又は蛋白質の発現水準を測定する製剤を含む大腸がん診断用キット。
- 前記キットは、RT-PCRキット、DNAチップキット又は蛋白質チップキットであることを特徴とする請求項6記載のキット。
- 大腸がんの診断に必要な情報を提供するために、
(a)被検体から試料の提供を受ける段階;
(b)前記試料から、KRS及びAIMP1からなる群から選ばれた一つ以上のmRNA発現水準又は蛋白質の発現水準を測定する段階;及び
(c)上記遺伝子mRNAの発現水準又は蛋白質の発現水準を、正常人対照群試料の対応する遺伝子mRNAの発現水準又は蛋白質の発現水準と比べて、発現水準が増加した被検体を、大腸がんに罹病したものと判定する段階を含む大腸がんのマーカーを検出する方法。 - 前記試料は、血液、血漿、血清、唾液、鼻液、喀痰、関節嚢液、羊水、腹水、子宮頸部又は膣分泌物、尿及び脳脊髄液からなる群から選ばれることを特徴とする請求項8記載の方法。
- 前記mRNAの発現水準を測定する方法は、逆転写ポリメラーゼ反応、競合的逆転写ポリメラーゼ反応、リアルタイム逆転写ポリメラーゼ反応、RNase保護分析法、ノーザンブロッティング及びDNAチップからなる群から選ばれたいずれか一つ以上を利用するものである請求項8記載の方法。
- 前記蛋白質の発現水準を測定するための方法は、ウエスタンブロット、ELISA、放射免疫分析、放射免疫拡散法、オクタロニー免疫拡散法、ロケット免疫電気泳動、組織免疫染色、免疫沈降分析法、補体固定分析法、FACS及び蛋白質チップの方法からなる群から選ばれたいずれか一つを利用するものである請求項8記載の方法。
- (a)大腸がん患者から提供された試料に大腸がんの治療候補物質を投与する段階;
(b)候補物質の存在又は非存在下で、前記試料から、KRS及びAIMP1からなる群から選ばれた一つ以上のmRNAの発現水準又は蛋白質の発現水準を測定する段階;
(c)候補物質存在下でのmRNAの発現水準又は蛋白質の発現水準と、候補物質非存在下での対応するmRNAの発現水準又は蛋白質の発現水準とを比較する段階;
(d)候補物質の存在下でmRNAの発現水準又は蛋白質の発現水準を減少させる物質を選別する段階;及び
(e)選別された候補物質の抗がん活性を、細胞又は動物から確認する段階を含む大腸がん治療剤のスクリーニング方法。 - 大腸がん診断用製剤を製造するための、KRS(lysyl-tRNA synthetase)及びAIMP1(aminoacyl-tRNA synthetase complex-interacting multifunctional Protein 1)からなる群から選ばれた一つ以上のmRNA又はその蛋白質の発現水準を測定する製剤の使用。
- 前記遺伝子のmRNA発現水準を測定する製剤は、KRS mRNA又はAIMP1 mRNAに特異的に結合するプローブ又はプライマーセットであることを特徴とする請求項13記載の使用。
- 前記蛋白質の発現水準を測定する製剤は、KRS蛋白質又はAIMP1蛋白質に特異的な抗体であることを特徴とする請求項13記載の使用。
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Also Published As
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US11360093B2 (en) | 2022-06-14 |
KR101851003B1 (ko) | 2018-04-20 |
JP6847972B2 (ja) | 2021-03-24 |
KR20170100206A (ko) | 2017-09-04 |
WO2017146529A1 (ko) | 2017-08-31 |
US20190018015A1 (en) | 2019-01-17 |
EP3409790A4 (en) | 2019-11-06 |
CN109312405A (zh) | 2019-02-05 |
EP3409790A1 (en) | 2018-12-05 |
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