JPWO2016143697A1 - Syt13、syt8、anos1発現量による胃癌腹膜播種の検査方法、検査キット、分子標的治療薬スクリーニング方法、及び治療薬 - Google Patents
Syt13、syt8、anos1発現量による胃癌腹膜播種の検査方法、検査キット、分子標的治療薬スクリーニング方法、及び治療薬 Download PDFInfo
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- syt13
- syt8
- anos1
- gastric cancer
- peritoneal dissemination
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Abstract
Description
(1)胃切除術後の腹膜播種を予測するための検査方法であって、対象から採取された患者血清、胃切除術における腹腔洗浄液、胃癌組織の少なくともいずれか1つの試料におけるSYT13、SYT8、ANOS1の少なくともいずれか1つの発現量を測定し、試料中のSYT13、SYT8、ANOS1の少なくともいずれか1つの発現量が所定値より高い場合には、腹膜播種のリスクが高いと判定することを特徴とする検査方法。
(2)(1)に記載の検査方法であって、SYT13、SYT8、ANOS1の発現量の測定方法が、SYT13、SYT8、ANOS1のmRNA及び/又はタンパク質発現量を測定することを特徴とする検査方法。
(3)(2)記載の検査方法であって、SYT13、SYT8、ANOS1のmRNA発現量の測定方法が定量的PCRによるものであることを特徴とする検査方法。
(4)胃切除術後の腹膜播種を診断又は予測するためのキットであって、SYT13、SYT8、ANOS1の発現量を測定するための定量的PCR用のプライマー、抗SYT8抗体、抗SYT13抗体、抗ANOS1抗体のいずれか1つ以上を含むことを特徴とする検査キット。
(5)SYT13、SYT8、ANOS1の少なくともいずれか1つの発現、又は機能の抑制を指標として物質をスクリーニングすることを特徴とするSYT13、SYT8、ANOS1を標的とする分子標的治療薬スクリーニング方法。
(6)胃癌の腹膜播種を治療もしくは予防するための分子標的治療薬であって、(5)記載の分子標的治療薬スクリーニング方法によって得られることを特徴とする治療薬。
(7)SYT13、SYT8、ANOS1の少なくともいずれか1つのsiRNAを含む胃切除術後の腹膜播種による転移を抑制するための医薬組成物。
これまでに名古屋大学医学部において胃切除術を行った進行胃癌症例を5年以上の長期無再発群、腹膜播種再発群、肝転移再発群、リンパ節再発群の4群に分け解析を行った。まず、胃癌再発群の約半数を占め、効果的な治療法の確立されていない腹膜播種再発に着目し、腹膜播種再発例において特異的に高発現を示す分子の検出を行うことにした。具体的には、ステージIII胃癌で治癒切除術が施行され、術後補助療法としてS−1内服を行った症例を経過に応じて群分けした。5年以上の長期無再発群、腹膜播種再発群、肝転移再発群、リンパ節再発群の4群に分け、各4例の胃癌原発巣組織から得られたRNAを対象にトランスクリプトーム解析による発現プロファイリングを行った。
胃癌細胞株11種類と非癌上皮細胞株FHs74についてPCRアレイ解析を行った。Human Epithelial to Mesenchymal Transition (EMT) RT2 Profiler PCR Array (Qiagen社製)を用いて、12種の細胞株を対象に84遺伝子(EMT、転写因子、細胞外マトリックス、接着因子、癌関連主要経路に関与する遺伝子)の発現を網羅的に解析した。この結果と各細胞株におけるSYT8、SYT13との発現度との間で相関性検定を行った。SYT8の結果を図1A、Bに、SYT13の結果を図1C、Dに示す。
手術の際に目視では腹膜播種が認められない症例において、SYT8、SYT13発現と、潜在的腹膜播種の相関を解析した。
SYT8 :Forward GCTTCTCTCTCCGGTACGTG(配列番号1)
Reverse AGGAAGGTGAAGGCCTCATT(配列番号2)
SYT13:Forward ACCTGGAGAAGGCGAAGC(配列番号3)
Reverse TCTGGGAACTTGAGGAGGG(配列番号4)
GAPDH:Forward GAAGGTGAAGGTCGGAGTC(配列番号5)
Reverse GAAGATGGTGATGGGATTTC(配列番号6)
SYT8、SYT13ともに60症例の患者組織を用い検討を行った。抗SYT8抗体(LifeSpan BioSciences社製)、又は抗SYT13抗体(Aviva Systems Biology社製)を用い、ビオチン標識2次抗体キットとしてHistofine SAB‐POキット(ニチレイ社製)を使用し、DAB基質キット(ニチレイ社製)で染色を行った。図3は抗体により染色を行った後、ヘマトキシリン染色を行った像を示している。
200例の胃癌切除患者から得た組織中のmRNAについて、定量的PCR法によりSYT13 mRNAを測定し、発現量の比較を行った。
上記の200例の胃癌患者とは異なる患者集団182例から得た腹水検体中のSYT13 mRNA量を、定量的PCR法で測定した。腹水中の細胞から得たmRNAを用い、SYT13 mRNA発現量を測定し、腹膜播種への相関をROC曲線により解析した(図6A)。Area under the curve値が0.698と、SYT13 mRNA発現と腹膜播種再発は強い相関性を示した。SYT13発現量の至適カットオフ値は2.21×10−7と算出された。また、図6Bに示すように、腹水中SYT13陽性症例では、有意に腹膜播種陽性症例の頻度が高かった。
次に、胃癌切除患者から得た組織中のSYT8 mRNAの解析結果を示す。200例の胃癌切除患者から得た組織中のmRNAについて、実施例5と同様にして定量的PCR法によりSYT8 mRNAを測定し、発現量の比較を行った(図7)。
SYT8、SYT13の発現と腹膜播種との強い相関がみられたことから、in vitroでSYT8、SYT13の高発現胃癌細胞株(MKN1、MKN45)を用いて、各遺伝子の選択的発現阻害(ノックダウン)実験を行い、胃癌細胞の増殖能、浸潤能、遊走能を評価した。SYT8のsiRNAを用いた結果を図9A〜Cに、SYT13のsiRNAを用いた結果を図9D〜Fに示す。なお、図9に示すのはMKN1を用いて得られた結果であるが、MKN45でも同様の結果が得られている。
培養細胞を用いた結果から、SYT8、SYT13発現が腹膜播種転移の原因となる可能性が示唆された。そこでSYT8、SYT13発現をsiRNAによって抑制し、腹膜播種再発が抑制されるかマウスモデルを用いて解析を行った。
実施例9と同様にしてSYT8 siRNA腹腔内投与の治療効果を検証した。上記と同様のマウス腹膜播種モデルに、SYT8 siRNAを週に2回、6週間投与した。siRNAは、実施例8と同様Dharmacon社製のものを用いた。コントロール群、siRNA腹腔内投与群それぞれ9匹ずつのマウスを用いて解析を行った。
(2)ANOS1と腹膜播種との相関
次に、ANOS1についての解析結果を示す。ANOS1(NCBI RefSeq IDアクセッション番号:XM_006190153.1)のmRNA発現と腹膜播種との関係を解析した。上述のように、ANOS1発現は、癌細胞の増殖性や、上皮間葉転換(EMT)との関連について示唆されているものの、相反するデータもある。そこで、胃癌におけるANOS1と腹膜播種の相関について解析を行った。
ANOS1:Forward AACAATGGTTCCCTGGTTTG(配列番号7)
Reverse TCACAAAAGCTTTGGCACTG(配列番号8)
実施例2と同様にして胃癌細胞株11種類と非癌上皮細胞株FHs74についてPCRアレイ解析を行った。この結果と各細胞株におけるANOS1との発現度との間で相関性検定を行った。結果を図16に示す。
実施例8と同様にして、in vitroでANOS1の高発現胃癌細胞株(MKN1、MKN45)を用いて、ANOS1の選択的発現阻害(ノックダウン)実験を行い、胃癌細胞の増殖能、浸潤能、遊走能を評価した。結果を図17A−Cに示す。
実施例3と同様にして、60症例の患者組織を用いてANOS1タンパク質発現の検討を行った。抗ANOS1抗体(Millipore社製)を用いた他は実施例3と同様にして免疫組織染色を行った。ANOS1の発現強度を染色無(図18中 No staining)、最小限(同 Minimal(<30%))、限局性(Focal(30−70%))、広範性(Difuse(>70%))に分類した。代表的な染色像を図18Aに示す。ANOS1 mRNA発現レベルと組織染色像との関係を図18Bに示す。ANOS1 mRNA発現レベルは、mRNAの発現量をGAPDHのmRNAの発現量で正規化した値である。
組織中のANOS1の発現量と予後との相関を解析した。表2と同様にして、胃癌組織中のmRNAのANOS1発現から、ANOS1高発現者、低発現者に分類し、術後からの生存者数をプロットした(図19A)。ANOS1の高発現者は低発現者に比べ、有意に予後不良であることが明らかである。
60名の健常者及び146名の胃癌患者の血清中のANOS1をELISAにより解析した。血清サンプルは術前7日以内に採取し、急速に凍結し−80℃に保存して用いた。血清ANOS1レベルはhuman ANOS1 ELISA kit(CUSABIO社製)を用いて測定した。
Claims (7)
- 胃切除術後の腹膜播種を予測するための検査方法であって、
対象から採取された患者血清、胃切除術における腹腔洗浄液、胃癌組織の少なくともいずれか1つの試料におけるSYT13、SYT8、ANOS1の少なくともいずれか1つの発現量を測定し、
試料中のSYT13、SYT8、ANOS1の少なくともいずれか1つの発現量が所定値より高い場合には、腹膜播種のリスクが高いと判定することを特徴とする検査方法。 - 請求項1に記載の検査方法であって、
SYT13、SYT8、ANOS1の発現量の測定方法が、
SYT13、SYT8、ANOS1のmRNA及び/又はタンパク質発現量を測定することを特徴とする検査方法。 - 請求項2記載の検査方法であって、
SYT13、SYT8、ANOS1のmRNA発現量の測定方法が定量的PCRによるものであることを特徴とする検査方法。 - 胃切除術後の腹膜播種を診断又は予測するためのキットであって、
SYT13、SYT8、ANOS1の発現量を測定するための定量的PCR用のプライマー、抗SYT8抗体、抗SYT13抗体、抗ANOS1抗体のいずれか1つ以上を含むことを特徴とする検査キット。 - 胃切除後の腹膜播種を治療するための分子標的治療薬をスクリーニングする方法であって、
SYT13、SYT8、ANOS1の少なくともいずれか1つの発現、又は機能の抑制、を指標として物質をスクリーニングすることを特徴とするSYT13、SYT8、ANOS1を標的とする分子標的治療薬スクリーニング方法。 - 胃癌の腹膜播種を治療もしくは予防するための分子標的治療薬であって、請求項5記載の分子標的治療薬スクリーニング方法によって得られることを特徴とする治療薬。
- SYT13、SYT8、ANOS1の少なくともいずれか1つのsiRNAを含む胃切除術後の腹膜播種による転移を抑制するための医薬組成物。
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