WWOX: a fragile tumor suppressor.
WWOX: a fragile tumor suppressor.
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DOI：
10.1177/1535370214561590
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Huebner K
中科院分区：
文献类型：
--
作者：
Schrock MS;Huebner K
WWOX是位于染色体16q23.3-q24.1区含有WW结构域的氧化还原酶基因，跨越染色体脆弱位点FRA16D，编码46 kDa的WWOX蛋白。WWOX是一种肿瘤抑制因子，在包括乳腺癌、前列腺癌、卵巢癌和肺癌在内的多种癌症中表达缺失或减少。WWOX作为肿瘤抑制因子的功能表明它在预防癌变中起着重要的作用。事实上，体外研究表明，Wwox蛋白与许多结合伙伴相互作用，调节细胞凋亡、增殖和/或成熟。据报道，新生的Wwox基因敲除小鼠表现出新生骨肉瘤，而Wwox+/-小鼠表现出自发和诱导肿瘤的发生率增加。此外，在小鼠异种移植模型中，Wwox表达的缺失或减少会导致肿瘤发生的增加，这可以通过Wwox的重新表达来挽救，尽管研究人员对Wwox缺失在这些实验模型中的作用尚未达成普遍共识。尽管提出了这种肿瘤抑制功能，但WWOX与FRA16D的重叠使该基因对复制应激引起的蛋白质失活缺失敏感。在各种类型的癌症中，WWOX基因座的高频率缺失，没有“经典”肿瘤抑制因子的标志性蛋白质失活相关突变，导致人们提出，癌症中的WWOX缺失是由于遗传位点的脆弱性而发生在早期癌症祖细胞中的乘客事件，而不是为癌细胞提供选择优势的驱动事件。最近，一项提出的染色体脆性的表观遗传原因提出了早期脆性位点不稳定的新机制，并暗示了肿瘤抑制基因在CFSs中参与癌症。在这篇综述中，我们概述了WWOX作为肿瘤抑制基因的证据，并将其置于与FRA16D位点相关的脆弱性背景下。
WWOX, the WW domain-containing oxidoreductase gene at chromosome region 16q23.3-q24.1, spanning chromosomal fragile site FRA16D, encodes the 46 kDa Wwox protein. WWOX is a tumor suppressor that is lost or reduced in expression in a wide variety of cancers, including breast, prostate, ovarian, and lung. The function of WWOX as a tumor suppressor implies that it serves an essential function in the prevention of carcinogenesis. Indeed, in vitro studies show that Wwox protein interacts with many binding partners to regulate cellular apoptosis, proliferation and/or maturation. It has been reported that newborn Wwox knockout mice exhibit nascent osteosarcomas while Wwox+/- mice exhibit increased incidence of spontaneous and induced tumors. Furthermore, absence or reduction of Wwox expression in mouse xenograft models results in increased tumorigenesis, which can be rescued by Wwox re-expression, though there is not universal agreement among investigators regarding the role of Wwox loss in these experimental models. Despite this proposed tumor suppressor function, the overlap of WWOX with FRA16D sensitizes the gene to protein-inactivating deletions caused by replication stress. The high frequency of deletions within the WWOX locus in cancers of various types, without the hallmark protein inactivation-associated mutations of ‘classical’ tumor suppressors, has led to the proposal that WWOX deletions in cancers are passenger events that occur in early cancer progenitor cells due to fragility of the genetic locus, rather than driver events which provide the cancer cell a selective advantage. Recently, a proposed epigenetic cause of chromosomal fragility has suggested a novel mechanism for early fragile site instability and has implications regarding the involvement of tumor suppressor genes at CFSs in cancer. In this review, we provide an overview of the evidence for WWOX as a tumor suppressor gene and put this into the context of fragility associated with the FRA16D locus.
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