俄亥俄州州立大學綜合癌癥中心(Ohio State University Comprehensive Cancer Center)的研究人員在動物模式中發(fā)現(xiàn)，若喪失了Wwox對偶基因的其中一個,，將使其提高得到肺癌的風險,。此研究發(fā)表于近期的PNAS期刊,。
本文的第一作者Rami I. Aqeilan教授說：典型的腫瘤抑制基因(tumor-suppressor genes)會等到細胞喪失兩個對偶基因或兩個對偶基因都突變了，才會提高罹癌的風險,。而Wwox只要喪失對偶基因中的一個,，正常的細胞就傾向于癌化，顯示W(wǎng)wox應該是致癌的初始因子,。
研究人員也發(fā)現(xiàn)當Wwox基因遺失后,，會造成嚴重的軟骨瘤(chondroid osteosarcoma)。Aqeilan表示：軟骨瘤好發(fā)于兒童,，是由于其骨骼細胞過于快速生長所致,。雖然軟骨瘤發(fā)生于人類的比例很少，但卻是骨癌中最常出現(xiàn)的類型,，占兒童癌癥致死率的第二位,，僅次于血癌(leukemia)。
研究人員先證明Wwox確實是一個腫瘤抑制基因,，當缺乏此基因時,，有85%的機會會得到肺癌，65%的機會會得到乳癌,，也有很高的機率很罹患胃癌,、大腸癌、前列腺癌以及淋巴癌,。Wwox基因位于第十六號染色體,，橫跨在染色體的易脆區(qū)(fragile site)，在此區(qū)域的染色體在環(huán)境壓力大時,，特別容易發(fā)生斷裂及異常,。當環(huán)境壓力過大將導致Wwox對偶基因中的一個缺失，得到肺癌的機會就變高,。
Aqeilan團隊制造了Wwox基因缺陷小鼠,，若小鼠的兩個Wwox基因都缺失，牠們4周內(nèi)就會死亡,。這些小鼠中共有13只完成實驗,，其中有4只在幼鼠期就得到軟骨瘤，大約占了31%,。而在58只缺乏一個Wwox基因的小鼠中,，約16%的小鼠罹患肺癌，相較于正常鼠則只有3%,，罹癌機率提高了5倍之多,。
研究人員也將這些基因缺陷鼠曝露于致癌物ethyl nitrosourea中，以觀察Wwox能抑制何種癌癥,。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,，少數(shù)則有肝癌及鱗狀細胞癌。Aqeilan教授說：Wwox基因缺陷小鼠的動物模式,，有助于了解Wwox基因缺失會導致何種癌癥,，也提供研究人員一個研發(fā)抗癌藥的目標。
(資料來源 : 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.
