WASF3調(diào)控KISS1致MMP9的下降（圖片由騰勇博士提供）
生物谷Bioon.com 訊 乳腺癌是女性惡性腫瘤的罪魁禍?zhǔn)字?，全世界每年約有一百多萬女性患有乳腺癌，男性也有患乳腺癌的風(fēng)險(xiǎn),。迄今,，乳腺癌仍然是科學(xué)家們未攻克的一座"堡壘"。近期,，國(guó)際著名癌癥雜志Internatiaonal Jounral of Cancer (IJC) 在"癌癥遺傳"專欄中重點(diǎn)介紹了美國(guó)NIH癌癥遺傳學(xué)術(shù)委員會(huì)主席Cowell 博士研究小組關(guān)于在乳腺癌細(xì)胞中原癌基因WASF3如何調(diào)控抑癌基因KISS1的最新研究結(jié)果,。
該文第一作者，美國(guó)喬治亞醫(yī)學(xué)院的滕勇博士（生物谷旗下生命科學(xué)論壇資深版主）認(rèn)為,，腫瘤侵染和轉(zhuǎn)移是影響惡性腫瘤患者預(yù)后的關(guān)鍵因素,，它是一個(gè)多步驟，多因素參與的復(fù)雜過程,，涉及腫瘤細(xì)胞的生物學(xué)特性和結(jié)構(gòu)變化等。WASF3和WASF1,、WASF2同屬于WASP家族Verprolin同源蛋白,， 它是參與調(diào)控細(xì)胞骨架的重要肌動(dòng)蛋白，具有促進(jìn)腫瘤遷移的功能,。實(shí)驗(yàn)小鼠模型和臨床樣本顯示W(wǎng)ASF3可高表達(dá)于惡性乳腺癌和前列腺癌組織,，如果敲除WASF3基因可顯著抑制腫瘤的發(fā)生和發(fā)展。其可能作用機(jī)制之一為WASF3可通過減少細(xì)胞應(yīng)力纖維,，刺激形成一種叫Lamellipodia的細(xì)胞膜亞結(jié)構(gòu)從而促進(jìn)腫瘤細(xì)胞的遷移,。KISS1是近年克隆的一個(gè)新型腫瘤轉(zhuǎn)移抑制基因，其表達(dá)缺失與人類乳腺癌等多種惡性腫瘤的轉(zhuǎn)移有關(guān),。在腫瘤細(xì)胞中WASF3和KISS1這兩個(gè)具有相反功能的基因究竟有怎樣的內(nèi)在聯(lián)系呢,？如果有，那么會(huì)不會(huì)存在一條相互調(diào)控的信號(hào)通路呢,？"Functional interrelationship between the WASF3 and KISS1 metastasis associated genes in breast cancer cells"一文數(shù)據(jù)顯示在WASF3基因沉默的乳腺癌細(xì)胞系中,，與細(xì)胞遷移和黏附有關(guān)的基質(zhì)金屬蛋白酶MMP9的表達(dá)量顯著降低，而這一結(jié)果是因?yàn)閃ASF3可負(fù)調(diào)控于KISS1,，而后者表達(dá)量的劇增可顯著抑制NFκB通路活性,，從而通過阻斷NFκB p65/50亞基團(tuán)從細(xì)胞質(zhì)轉(zhuǎn)移到細(xì)胞核內(nèi)的進(jìn)程，導(dǎo)致無法啟動(dòng)由p65/50主導(dǎo)調(diào)控的包括MMP9在內(nèi)的眾多原癌基因的轉(zhuǎn)錄和表達(dá),。結(jié)果還顯示,，WASF3可通過抑制KISS1的胞外分泌增強(qiáng)腫瘤細(xì)胞對(duì)TNFα刺激的敏感性，加快細(xì)胞的遷移和侵染。
該文是當(dāng)前世界上僅有的幾個(gè)報(bào)道原癌基因調(diào)控抑癌基因的研究案例,，將在腫瘤研究領(lǐng)域影響深遠(yuǎn),。（生物谷Bioon.com）
生物谷推薦原文摘要：
International Journal of Cancer DOI: 10.1002/ijc.25964
Functional interrelationship between the WASF3 and KISS1 metastasis associated genes in breast cancer cells
Yong Teng, Mingyao Liu and John K Cowell
Loss of WASF3 function in breast cancer cells results in loss of invasion phenotypes and reduced metastatic potential. Using oligonucleotide arrays we now demonstrate that knockdown of WASF3 leads to the upregulation of the KISS1 metastasis suppressor gene with concomitant reduced invasion and loss of MMP9 activity. Using a luciferase reporter, KISS1 transcription is significantly increased in the absence of WASF3. Knockdown of KISS1 in WASF3 silenced cells resulted in the recovery of the invasion phenotype. WASF3 knockdown also resulted in elevated IκBα levels in the cytoplasm and reduced levels of NFκB p65/50 subunits in the nucleus. TNFα has been associated with cell invasion through induction of MMP9 production via KISS1 regulation of the NFκB pathway. When WASF3 knockdown cells are treated with TNFα, no effect is seen on invasion or nuclear translocation of NFκB. Thus, coordinated expression patterns of the WASF3 metastasis promoter gene and the KISS1 metastasis suppressor gene appear to exert their influence through inhibition of NFκB signaling which in turn regulates MMP9 production facilitating invasion.
