JP6298178B2 - 子宮頸癌の誘導に関与するアクチニン−4の薬剤学的用途 - Google Patents
子宮頸癌の誘導に関与するアクチニン−4の薬剤学的用途 Download PDFInfo
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Description
また、本発明は、アクチニン−4(actinin−4)阻害剤を含む子宮頸癌の予防または治療用薬学組成物を提供する。
本発明は、アクチニン−4(actinin−4)遺伝子のmRNAまたはそのタンパク質水準を測定する製剤を含む子宮頸癌診断用組成物に関する。
前記キットは、アクチニン−4遺伝子の発現水準またはタンパク質の量を測定できるプライマー、プローブまたは抗体を含むことができ、これらの定義は、前述した通りである。
前記薬剤学的に許容可能な担体は、医薬分野で通常使用される担体及びビヒクルを含み、具体的に、イオン交換樹脂、アルミナ、アルミニウムステアレート、レシチン、血清タンパク質(例えば、ヒト血清アルブミン)、緩衝物質(例えば、各種リン酸塩、グリシン、ソルビン酸、カリウムソルベート、飽和植物性脂肪酸の部分的なグリセリド混合物)、水、塩または電解質(例えば、プロタミンスルフェート、リン酸水素二ナトリウム、リン酸水素カリウム、塩化ナトリウム及び亜鉛塩)、膠質性シリカ、マグネシウムトリシリケート、ポリビニルピロリドン、セルロース系基質、ポリエチレングリコール、ナトリウムカルボキシメチルセルロース、ポリアリレート、ワックス、ポリエチレングリコールまたは羊毛脂等を含むが、これに制限されない。
Dulbecco’s modified Eagle’s medium(DMEM)、ウシ胎児血清(fetal bovine serum(FBS))、ペニシリン、ストレプトマイシン、Lipofectamine 2000 reagentは、Invitrogen(Carlsbad、CA)から購入した。
多様な癌細胞におけるアクチニン−4の発現量を比較するために、ウェスタンブロットを利用してタンパク質発現量を比較した。
先行研究報告において、MDCK細胞でアクチニン−4の発現によるAKT−Snailの信号機作を確認したことがある。したがって、子宮頸癌細胞でも、同じ機作が起きるかを確認した。
実施例1でアクチニン−4は、HeLa、SiHa、ME−180の順に少なく発現された。したがって、HeLa及びSiHa細胞では、アクチニン−4の発現抑制細胞を製作し、アクチニン−4の発現がほとんどないME−180細胞には、過発現細胞を製作した。
子宮頸癌細胞でアクチニン−4の過発現による細胞の移動性を確認するために、創傷傷治癒分析(wound healing assay)を進行した。
創傷傷治癒分析のために、6−ウェルプレートに各ウェル当たりHeLa及びSiHa 5×105細胞をシーディングしてアクチニン−4(1μg)をトランスフェクションした後、各ウェルの細胞を200pチップを利用して直線で細胞を掻き出した後、細胞が除去された位置に各表面の細胞が移動する程度を比較した(HeLa 24h、SiHa48h)。
移動性と浸潤性は、癌細胞の転移において非常に重要な過程中の1つである。したがって、アクチニン−4の発現が癌細胞の移動性及び浸潤性に関与するかを確認するために、アクチニン−4発現抑制細胞でトランスウェル移動(transwell migration)及びマトリゲル浸潤分析(matrigel invasionassay)を進行した。
アクチニン−4の過発現細胞であるMDCK細胞でβ−カテニンの発現を調査するために、MDCK細胞でアクチニン−4の過発現安定化細胞を製作した。このために、Flag−ACTN4プラスミドをトランスフェクションした後、2週間G−418(400μg/mL;Sigma)を処理することによって選別した。当該細胞でRIPAライシスを進行して、タンパク質を抽出した後、30μgのタンパク質を使用してウェスタンブロットでβ−カテニン(BD Biosceinces)とそのターゲット遺伝子であるビメンチン(Santa Cruz)の発現を確認した。それぞれの抗体は、1:3000比率で確認した。
β−カテニン及びそのターゲットタンパク質であるサイクリンD1の増加は、細胞の増殖を誘導するので、アクチニン−4の発現は、細胞増殖に関与するものと考えられ、HeLaとSiHaのアクチニン−4発現抑制安定化細胞(HeLa−KD、SiHa−KD)の増殖をコロニー形成分析を利用して確認した。12−ウェルプレートにそれぞれの細胞を3×103数をシーディングして、5日間維持した後、コロニーが形成された数を確認した。また、アクチニン−4の過発現安定化細胞であるME−180−OV#3細胞を利用して細胞増殖程度をコロニー形成実験を通じて確認した。このために、12−ウェルプレートにそれぞれの細胞を3×103数をシーディングして、5日間維持した後、コロニーが形成された数を確認した。コロニーの染色は、0.05%クリスタルバイオレット(crystal violet)で24時間染色後、蒸留水(DW)で洗浄した後、Nikon COOLPIX P300 digital camera(12.2 Mega−pixel;Nikon Corp.、Tokyo、Japan)で写真を撮った。
前記実施例6でアクチニン−4の過発現が細胞の成長を増加させるので、マウスモデルでこの効果を実験した。
Claims (7)
- アクチニン−4(actinin−4)遺伝子のmRNAまたはそのタンパク質水準を測定する製剤を含むヒトパピローマウイルス16または18型陽性子宮頸癌診断用組成物。
- 前記遺伝子のmRNAを測定する製剤は、前記遺伝子のmRNAに相補的な配列を有するオリゴヌクレオチドを含む、請求項1に記載の子宮頸癌診断用組成物。
- 前記タンパク質の水準を測定する製剤は、前記タンパク質に特異的な抗体を含む、請求項1に記載の子宮頸癌診断用組成物。
- アクチニン−4(actinin−4)阻害剤を含むヒトパピローマウイルス16または18型陽性子宮頸癌の予防または治療用薬学組成物。
- アクチニン−4阻害剤は、アンチセンス−オリゴヌクレオチド、siRNA、shRNA、miRNAまたはこれを含むベクター;または、抗体のうちいずれか1つである、請求項4に記載の子宮頸癌の予防または治療用薬学組成物。
- アクチニン−4(actinin−4)遺伝子を候補物質と人体外で接触させ、前記候補物質が前記遺伝子の発現を促進するかまたは抑制するかを判断し、ヒトパピローマウイルス16または18型陽性子宮頸癌を予防または治療するための薬剤として、アクニチン−4遺伝子の発現を抑制する候補物質を選択することを含むヒトパピローマウイルス16または18型陽性子宮頸癌の予防または治療用医薬のスクリーニング方法。
- アクチニン−4(actinin−4)タンパク質を候補物質と人体外で接触させ、前記候補物質が前記タンパク質の機能または活性を増進するかまたは抑制するかを判断し、ヒトパピローマウイルス16または18型陽性子宮頸癌を予防または治療するための薬剤として、アクニチン−4タンパク質の機能または活性を抑制する候補物質を選択することを含むヒトパピローマウイルス16または18型陽性子宮頸癌の予防または治療用医薬のスクリーニング方法。
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