JPWO2018079689A1 - バイオマーカー、疾患関連遺伝子の探索方法、及び腎がんマーカー - Google Patents
バイオマーカー、疾患関連遺伝子の探索方法、及び腎がんマーカー Download PDFInfo
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Abstract
Description
(2)前記切除された疾患組織の周囲の正常組織を浸漬液に浸漬し、浸漬液中の前記正常組織から滲出した正常組織由来の滲出成分を解析し、前記正常組織由来バイオマーカー及び/又は疾患関連遺伝子を同定し、前記疾患組織由来のバイオマーカー及び/又は疾患関連遺伝子と前記正常組織由来のバイオマーカー及び/又は疾患関連遺伝子を比較検討し疾患特異的なバイオマーカー及び/又は疾患関連遺伝子を選択することを特徴とする(1)記載の探索方法。
(3)前記滲出成分が、細胞外小胞、タンパク質、核酸、脂質であることを特徴とする(1)又は(2)記載の探索方法。
(4)前記滲出成分が細胞外小胞であり、細胞外小胞に含まれる前記バイオマーカー及び/又は疾患関連遺伝子が、タンパク質、核酸、脂質であることを特徴とする(1)〜(3)いずれか1つ記載の探索方法。
(5)前記疾患が、がん、神経変性疾患、多発性硬化症、糖尿病、肝疾患、自閉症、脳梗塞であることを特徴とする(1)〜(4)いずれか1つ記載の探索方法。
(6)体液に含まれる細胞外小胞を分離し、前記細胞外小胞に含まれる表1、表2、表4に記載のバイオマーカーの少なくとも1つを検出し、所定値と比較することを特徴とする腎細胞がんの検査方法。
(7)前記バイオマーカーが、AZU1、CA9、STBD1、COMT、GYG1であることを特徴とする(6)記載の腎細胞がんの検査方法。
(8)前記体液が血液又は尿であることを特徴とする(6)又は(7)記載の腎細胞がんの検査方法。
(9)表1、表2、表4に記載の腎細胞がんのバイオマーカー。
(10)AZU1、CA9、STBD1、COMT、GYG1を指標として、候補化合物を選択することを特徴とするAZU1、CA9、STBD1、COMT、GYG1を標的とする腎細胞がんの治療薬スクリーニング方法。
図1は疾患組織から組織滲出性の細胞外小胞(tissue−exudative EVs、以下、Te-EVsと記載することもある。)を単離し、バイオマーカーを解析する方法の概要を示したものである。手術により切除した組織は、疾患組織、正常組織を切り出し、直ちに浸漬液に浸漬する。腎細胞がんの場合には、浸漬液として無血清DMEMを用いているが、浸漬液は、Te-EVsを抽出する組織によって適宜選択することができる。血清中には細胞外小胞が含まれるため、浸漬液としては無血清培地を使用することが好ましいが、予め細胞外小胞を除去すれば、血清を含有した培地を使用してもよい。
20名の腎細胞がん患者から、がん組織、正常組織(非がん部)、両者が得られたものについてTe-EVsを採取し解析を行った。腎細胞がんの組織診断は、ヘマトキシリン・エオジン染色により行った。AJCC TNM第6版に基づいて分類した患者の病期は、T1a〜T3cまでであった。
20人の患者から得られたがん組織、及び対になるがん部周辺の正常組織由来のTe-EVsを用いて上記と同様にしてLC/MS解析を行った(図4)。合計で3871のタンパク質が同定され、そのうち160は正常組織由来のTe-EVs、253はがん組織由来のTe-EVsに特異的な発現であり、3458は両者に共通して発現していた(図4A)。
以下に、volcano plotの原点からの距離が最も離れているAZU1(p=2.85×10−3、fold−change=31.59、図5において矢印AZU1で示す。)について詳細な解析を行った結果を示すが、上記で示した他のタンパク質についても同様にマーカーとして用いることができることは言うまでもない。
AZU1の発現が腎細胞がん組織に特異的に検出されたことから、AZU1の生物学的作用の検討を行った。腎細胞がんでは、多くの血管新生が生じ、がん組織の微小環境を構築していることが知られている(非特許文献14〜17)。そこで、AZU1が血管内皮細胞の形態に及ぼす影響を検討した。
(試料ウェルの電気抵抗(Ω)−空のウェルの電気抵抗(Ω))×培養面積(cm2)=TEER(Ωcm2)
血清中のEVsで腎細胞がん患者に特徴的なタンパク質を検出することができれば、腎細胞がんの早期発見に有用なマーカーとすることができる。そこで、血清中に含まれるEVs中において、腎細胞がん患者と健常者とで差が見られるタンパク質を探索した。表4は、血清中のEVsにおいて、腎細胞がん患者では検出できるが、健常者では検出できなかったタンパク質のうち、表1及び表2に示すTe−EVsの解析結果により検出されたものを除いて記載している。
Claims (10)
- 切除された疾患組織を浸漬液に浸漬し、
浸漬液中の前記疾患組織から滲出した疾患組織由来の滲出成分を解析し、
前記疾患組織由来のバイオマーカー及び/又は疾患関連遺伝子を同定することを特徴とする探索方法。 - 前記切除された疾患組織の周囲の正常組織を浸漬液に浸漬し、
浸漬液中の前記正常組織から滲出した正常組織由来の滲出成分を解析し、
前記正常組織由来バイオマーカー及び/又は疾患関連遺伝子を同定し、
前記疾患組織由来のバイオマーカー及び/又は疾患関連遺伝子と前記正常組織由来のバイオマーカー及び/又は疾患関連遺伝子を比較検討し疾患特異的なバイオマーカー及び/又は疾患関連遺伝子を選択することを特徴とする請求項1記載の探索方法。 - 前記滲出成分が、
細胞外小胞、タンパク質、核酸、脂質であることを特徴とする請求項1又は2記載の探索方法。 - 前記滲出成分が細胞外小胞であり、
細胞外小胞に含まれる前記バイオマーカー及び/又は疾患関連遺伝子が、
タンパク質、核酸、脂質であることを特徴とする請求項1〜3いずれか1項記載の探索方法。 - 前記疾患が、
がん、神経変性疾患、多発性硬化症、糖尿病、肝疾患、自閉症、脳梗塞であることを特徴とする請求項1〜4いずれか1項記載の探索方法。 - 体液に含まれる細胞外小胞を分離し、
前記細胞外小胞に含まれる表1、表2、表4に記載のバイオマーカーの少なくとも1つを検出し、
所定値と比較することを特徴とする腎細胞がんの検査方法。 - 前記バイオマーカーが、
AZU1、CA9、STBD1、COMT、GYG1であることを特徴とする請求項6記載の腎細胞がんの検査方法。 - 前記体液が血液又は尿であることを特徴とする
請求項6又は7記載の腎細胞がんの検査方法。 - 表1、表2、表4に記載の腎細胞がんのバイオマーカー。
- AZU1、CA9、STBD1、COMT、GYG1を指標として、
候補化合物を選択することを特徴とするAZU1、CA9、STBD1、COMT、GYG1を標的とする腎細胞がんの治療薬スクリーニング方法。
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