JP6143920B1 - 卵巣がんの予後診断マーカーとしてのmmp1遺伝子転写産物と検査法 - Google Patents
卵巣がんの予後診断マーカーとしてのmmp1遺伝子転写産物と検査法 Download PDFInfo
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Abstract
Description
卵巣がん予後予測マーカーとしては,卵巣がん組織におけるDNAメチル化プロファイルを特定の遺伝子領域について解析することにより,高メチル化,低メチル化の群間において,カプランマイヤー生存曲線等に差が確認されている(特許文献1)。しかしながら,DNAメチル化解析は一般の診断技術に活用するには解析の原理上操作が煩雑となり,検査費の高コスト化等の課題を残していることや,良性腫瘍と悪性腫瘍の識別力に不備があるため,疑陽性の問題が懸念されることなどから,がん発症後の予後予測マーカー技術については,さらなる技術的躍進が必要とされている。
本明細書において「MMP1遺伝子」とは,マトリックスメタロプロテイナーゼ1タンパク質をコードする遺伝子である。MMP1遺伝子は,I型,II型,及びIII型の間質コラーゲンを分解できる分泌型酵素をコードする。この遺伝子は,ヒト染色体11q22.3に座上するMMP遺伝子クラスターの一部である。
を増幅するためのフォワードプライマー,及びリバースプライマーの例は,以下のものである。すなわち,配列番号3及び4のプライマー対,及び配列番号5及び6のプライマー対である。
境界型悪性腫瘍と悪性腫瘍の卵巣がん患者,および良性腫瘍を卵巣に生じた患者における,MMP1遺伝子転写産物発現解析を実施した。その結果を図1に示す。
配列番号2)GAPDH-Rv: tggtgaagacgccagtgga
配列番号3)MMP1-Fw: aggtctctgagggtcaagca
配列番号4)MMP1-Rv: ctggttgaaaagcatgagca
50℃/2min
↓ 95℃/2min
↓(95℃/15sec→60℃/30sec)×40サイクル
種々のがん臨床検体における遺伝子発現解析データを提供する公的なマイクロアレイデータセットを提供するカプランマイヤープロッターにおいて,1582名の卵巣がん患者の中で,卵巣がん病期がステージIの74名の患者群を抽出し,MMP1遺伝子転写産物カプランマイヤー生存曲線解析を実施した(MMP1プローブ:204475_at)。その結果を図2に示す。ステージI卵巣がん患者において,腫瘍組織にけるMMP1遺伝子の高発現は,その後の予後悪化と極めて強い相関性を見出した(ハザード比:3.6×108,ログランクテスト:p=0.014)。
ルシフェラーゼ遺伝子を導入したヒト卵巣がん細胞株のRMG−1およびES−2を,CB17/icr−scid/scidJclマウスの左卵巣へ正所移植を行ない,最大8週間まで経時的にIVISシステムを用いてインビボイメージングを行なった。それにより,非転移株のRMG−1と,高転移株のES−2のマウスにおける増殖性と浸潤性を評価した。
転移における悪性度が異なる卵巣がん細胞株と,ヒト卵巣表層上皮細胞に由来するエクソソームによる,卵巣がん細胞の転移浸潤に与える影響を評価した。
卵巣がん細胞株およびそれらに由来するエクソソーム画分に含まれるMMP1遺伝子転写産物の発現量比較を実施した。
細胞の調製:ヒト卵巣表層上皮細胞(HOSE1)およびRGM−1は,10%非動化FBSおよび1% antibiotic−antimycotic solution(インビトロジェン社)を添加したDMEM/F12 培地で培養し, ES−2細胞株は,10%非動化FBSおよび1% antibiotic−antimycotic solution(インビトロジェン社)を添加したMcCoy’s 5A培地で培養した。培養条件は37℃/5% CO2濃度で設定した。
配列番号2)GAPDH−Rv: tggtgaagacgccagtgga
配列番号3)MMP1−Fw: aggtctctgagggtcaagca
配列番号4)MMP1−Rv: ctggttgaaaagcatgagca
PCR反応条件は,下記で実施した。
50℃/2min
↓ 95℃/2min
↓(95℃/15sec→60℃/30sec)×40
配列番号6)MMP1−Full−Rv: caccttctttggactcacac
(98℃/10sec→60℃/30sec→72℃/2min)×30サイクル
その結果,ES2由来エクソソームには全長型のMMP1遺伝子転写産物が含有されることが明らかとなった。
配列表フリーテキスト
SEQ ID NO:2 ; A PCR primer specific to transcriptional product of GAPDH gene
SEQ ID NO:3 ; A PCR primer specific to transcriptional product of MMP-1 gene.
SEQ ID NO:4 ; A PCR primer specific to transcriptional product of MMP-1 gene.
SEQ ID NO:5 ; A PCR primer specific to transcriptional product of MMP-1 gene.
SEQ ID NO:6 ; A PCR primer specific to transcriptional product of MMP-1 gene.
Claims (2)
- 卵巣がんの予後を予測するための方法であって,
被検者から採取した腹水又は腹水から回収されるエクソソームにおける全長型のマトリックスメタロプロテアーゼ(MMP)1遺伝子の転写産物の検出値を得ることにより,全長型のマトリックスメタロプロテアーゼ(MMP)1遺伝子の発現レベルを測定する工程を含む,方法。 - 請求項1に記載の方法であって,
前記全長型のマトリックスメタロプロテアーゼ(MMP)1遺伝子の転写産物の検出値と,前記被検者から採取した腹水又は腹水から回収されるエクソソームにおける内部標準遺伝子転写物の検出値とを比較し,前記全長型のマトリックスメタロプロテアーゼ(MMP)1遺伝子の転写産物の検出値が前記被検者から採取した腹水又は腹水から回収されるエクソソームにおける内部標準遺伝子転写物の検出値より所定比率以上である場合に,前記全長型のマトリックスメタロプロテアーゼ(MMP)1遺伝子の転写産物の検出値を陽性と判断する工程を,さらに含む,
方法。
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JP2016121392A JP6143920B1 (ja) | 2016-06-20 | 2016-06-20 | 卵巣がんの予後診断マーカーとしてのmmp1遺伝子転写産物と検査法 |
US16/312,093 US20190316205A1 (en) | 2016-06-20 | 2017-06-20 | Mmp1 gene transcript for use as a marker for diagnosis of ovarian cancer prognosis, and test method |
SG11201811433TA SG11201811433TA (en) | 2016-06-20 | 2017-06-20 | Mmp1 gene transcript for use as marker for diagnosis of ovarian cancer prognosis, and test method |
CN201780043531.0A CN110023510A (zh) | 2016-06-20 | 2017-06-20 | 作为卵巢癌预后诊断标志物的mmp1基因转录产物和检测方法 |
EP17815395.3A EP3473729A4 (en) | 2016-06-20 | 2017-06-20 | GENE TRANSCRIPTION PRODUCT (MMP1) FOR USE AS OVARIAN CANCER PROGNOSTIC DIAGNOSTIC MARKER, AND TEST METHOD |
CA3067527A CA3067527A1 (en) | 2016-06-20 | 2017-06-20 | Mmp1 gene transcript for use as marker for diagnosis of ovarian cancer prognosis, and test method |
AU2017282420A AU2017282420A1 (en) | 2016-06-20 | 2017-06-20 | MMP1 gene transcript for use as marker for diagnosis of ovarian cancer prognosis, and test method |
PCT/JP2017/022680 WO2017221927A1 (ja) | 2016-06-20 | 2017-06-20 | 卵巣がんの予後診断マーカーとしてのmmp1遺伝子転写産物と検査法 |
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