俄亥俄州州立大学综合癌症中心(Ohio State University Comprehensive Cancer Center)的研究人员在动物模式中发现，若丧失了Wwox对偶基因的其中一个，将使其提高得到肺癌的风险。此研究发表于近期的PNAS期刊。
本文的第一作者Rami I. Aqeilan教授说：典型的肿瘤抑制基因(tumor-suppressor genes)会等到细胞丧失两个对偶基因或两个对偶基因都突变了，才会提高罹癌的风险。而Wwox只要丧失对偶基因中的一个，正常的细胞就倾向于癌化，显示Wwox应该是致癌的初始因子。
研究人员也发现当Wwox基因遗失后，会造成严重的软骨瘤(chondroid osteosarcoma)。Aqeilan表示：软骨瘤好发于儿童，是由于其骨骼细胞过于快速生长所致。虽然软骨瘤发生于人类的比例很少，但却是骨癌中最常出现的类型，占儿童癌症致死率的第二位，仅次于血癌(leukemia)。
研究人员先证明Wwox确实是一个肿瘤抑制基因，当缺乏此基因时，有85%的机会会得到肺癌，65%的机会会得到乳癌，也有很高的机率很罹患胃癌、大肠癌、前列腺癌以及淋巴癌。Wwox基因位于第十六号染色体，横跨在染色体的易脆区(fragile site)，在此区域的染色体在环境压力大时，特别容易发生断裂及异常。当环境压力过大将导致Wwox对偶基因中的一个缺失，得到肺癌的机会就变高。
Aqeilan团队制造了Wwox基因缺陷小鼠，若小鼠的两个Wwox基因都缺失，牠们4周内就会死亡。这些小鼠中共有13只完成实验，其中有4只在幼鼠期就得到软骨瘤，大约占了31%。而在58只缺乏一个Wwox基因的小鼠中，约16%的小鼠罹患肺癌，相较于正常鼠则只有3%，罹癌机率提高了5倍之多。
研究人员也将这些基因缺陷鼠曝露于致癌物ethyl nitrosourea中，以观察Wwox能抑制何种癌症。在46只基因缺陷小鼠中有80%罹癌，大部份的小鼠得到的是肺癌及淋巴癌，少数则有肝癌及鳞状细胞癌。Aqeilan教授说：Wwox基因缺陷小鼠的动物模式，有助于了解Wwox基因缺失会导致何种癌症，也提供研究人员一个研发抗癌药的目标。
(资料来源 : Bio.com)
PNAS | March 6, 2007 | vol. 104 | no. 10 | 3949-3954
Targeted deletion of Wwox reveals a tumor suppressor function
Rami I. Aqeilan*,, Francesco Trapasso*, Sadiq Hussain, Stefan Costinean*, Dean Marshall*, Yuri Pekarsky*, John P. Hagan*, Nicola Zanesi*, Mohamed Kaou*, Gary S. Stein, Jane B. Lian, and Carlo M. Croce*
*Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210; and Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655
Edited by George F. Vande Woude, Van Andel Research Institute, Grand Rapids, MI, and approved January 11, 2007 (received for review November 3, 2006)
Abstract
The WW domain-containing oxidoreductase (WWOX) spans the second most common fragile site of the human genome, FRA16D, located at 16q23, and its expression is altered in several types of human cancer. We have previously shown that restoration of WWOX expression in cancer cells suppresses tumorigenicity. To investigate WWOX tumor suppressor function in vivo, we generated mice carrying a targeted deletion of the Wwox gene and monitored incidence of tumor formation. Osteosarcomas in juvenile Wwox–/– and lung papillary carcinoma in adult Wwox+/– mice occurred spontaneously. In addition, Wwox+/– mice develop significantly more ethyl nitrosourea-induced lung tumors and lymphomas in comparison to wild-type littermate mice. Intriguingly, these tumors still express Wwox protein, suggesting haploinsuffiency of WWOX itself is cancer predisposing. These results indicate that WWOX is a bona fide tumor suppressor.
common fragile site | FHIT | knockout | osteosarcoma | lung cancer
The WW domain-containing oxidoreductase (WWOX) encodes a 46-kDa protein that contains two WW domains and a short-chain dehydrogenase/reductase domain (1–3). The WWOX gene is altered by deletions or translocations in a large fraction of many cancer types including breast, prostate, esophageal, lung, stomach, and pancreatic carcinomas (2, 4–9). WWOX protein is lost or reduced in the majority of these cancers and in a large fraction of other cancer types (10, 11). WWOX spans the second most active common fragile sites, FRA16D (reviewed in ref. 12). Common fragile sites are large regions of profound genomic instability found in all individuals. Following partial inhibition of DNA synthesis, those regions show site-specific gaps or breaks on metaphase chromosomes. In addition, common fragile sites exhibit induction of sister chromatid exchange and show a high rate of translocations and deletions in somatic cell hybrids (13). Because FRA16D maps within regions of frequent loss of heterozygosity, and is associated with homozygous deletions in various adenocarcinomas and with chromosomal translocations in multiple myeloma (2), these rearrangements have been suggested to inactivate the WWOX gene. On the other hand, ectopic overexpression of WWOX in cancer cells lacking expression of endogenous WWOX results in significant growth inhibition and prevents the development of tumors in athymic nude mice (14, 15). In addition, we reported that restoration of WWOX expression in cancer cells results in caspase-mediated apoptosis (15). Thus, these data suggest that WWOX may act as a tumor suppressor
Biochemical and functional characterization of WWOX has shown that it interacts with proline-tyrosine rich motif-containing proteins. WWOX associates via its first WW domain with p73 and enhances p73-mediated apoptosis (16). WWOX also binds to the PPPY motif of AP2 and ErbB4, established oncogenes in breast cancer (17, 18). Interestingly, WWOX suppresses the transcriptional ability of these target proteins by sequestering them in the cytoplasm (16–18). Taken together, accumulating evidence, both in cell culture and in nude mice, suggests that WWOX functions as a tumor suppressor, although no direct in vivo proof has yet been reported to verify WWOX as a bona fide tumor suppressor. To define the role of WWOX protein in cancer development, we generated mice carrying a targeted deletion of the Wwox gene. The murine Wwox locus is similar to its human homolog (19), spans the Fra8E1 common fragile site, and is highly conserved. Here, we demonstrate that the loss of both alleles of Wwox results in osteosarcomas in some early postnatal mice, whereas loss of one allele significantly increases the incidence of spontaneous and chemically induced tumors. Altogether, our results provide the first in vivo evidence of WWOX tumor suppressor function.
