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IJC:原癌基因调控抑癌基因的新案例

来源:生物谷 2011-04-12 09:21


WASF3调控KISS1致MMP9的下降(图片由腾勇博士提供)

生物谷Bioon.com 讯 乳腺癌是女性恶性肿瘤的罪魁祸首之一,全世界每年约有一百多万女性患有乳腺癌,男性也有患乳腺癌的风险。迄今,乳腺癌仍然是科学家们未攻克的一座"堡垒"。近期,国际著名癌症杂志Internatiaonal  Jounral of Cancer (IJC) 在"癌症遗传"专栏中重点介绍了美国NIH癌症遗传学术委员会主席Cowell 博士研究小组关于在乳腺癌细胞中原癌基因WASF3如何调控抑癌基因KISS1的最新研究结果。

该文第一作者,美国乔治亚医学院的滕勇博士(生物谷旗下生命科学论坛资深版主)认为,肿瘤侵染和转移是影响恶性肿瘤患者预后的关键因素,它是一个多步骤,多因素参与的复杂过程,涉及肿瘤细胞的生物学特性和结构变化等。WASF3和WASF1、WASF2同属于WASP家族Verprolin同源蛋白, 它是参与调控细胞骨架的重要肌动蛋白,具有促进肿瘤迁移的功能。实验小鼠模型和临床样本显示WASF3可高表达于恶性乳腺癌和前列腺癌组织,如果敲除WASF3基因可显着抑制肿瘤的发生和发展。其可能作用机制之一为WASF3可通过减少细胞应力纤维,刺激形成一种叫Lamellipodia的细胞膜亚结构从而促进肿瘤细胞的迁移。KISS1是近年克隆的一个新型肿瘤转移抑制基因,其表达缺失与人类乳腺癌等多种恶性肿瘤的转移有关。在肿瘤细胞中WASF3KISS1这两个具有相反功能的基因究竟有怎样的内在联系呢?如果有,那么会不会存在一条相互调控的信号通路呢?"Functional interrelationship between the WASF3 and KISS1 metastasis associated genes in breast cancer cells"一文数据显示在WASF3基因沉默的乳腺癌细胞系中,与细胞迁移和黏附有关的基质金属蛋白酶MMP9的表达量显着降低,而这一结果是因为WASF3可负调控于KISS1,而后者表达量的剧增可显着抑制NFκB通路活性,从而通过阻断NFκB p65/50亚基团从细胞质转移到细胞核内的进程,导致无法启动由p65/50主导调控的包括MMP9在内的众多原癌基因的转录和表达。结果还显示,WASF3可通过抑制KISS1的胞外分泌增强肿瘤细胞对TNFα刺激的敏感性,加快细胞的迁移和侵染。

该文是当前世界上仅有的几个报道原癌基因调控抑癌基因的研究案例,将在肿瘤研究领域影响深远。(生物谷Bioon.com)

生物谷推荐原文摘要:

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.

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