美國哥倫比亞大學(xué)放射學(xué)研究所,，Herbert Irving綜合癌癥研究中心,，臨床腫瘤系，洛克菲勒大學(xué)分子生物學(xué)實驗室,，中國醫(yī)學(xué)科學(xué)院基礎(chǔ)醫(yī)學(xué)研究所生物化學(xué)與分子生物學(xué)系等處的研究人員在最新一期的《癌癥研究》（Cancer Research）上發(fā)表關(guān)于TGFBI與癌癥發(fā)生的相關(guān)文章,。
TGFBI基因表達(dá)的TGFBI蛋白是一種由轉(zhuǎn)化生長因子β誘導(dǎo)的分泌蛋白，在早期的報道中發(fā)現(xiàn)該蛋白與癌癥有關(guān)聯(lián),，很可能成為癌癥的一種生物學(xué)標(biāo)記物,。
體外實驗研究發(fā)現(xiàn)如果細(xì)胞缺失TGFBI會導(dǎo)致細(xì)胞過度增殖，促進(jìn)腫瘤血管生成，促成癌癥發(fā)生,。因此說,，TGFBI蛋白具有抗腫瘤的功能，但是,，TGFBI蛋白如何在活體內(nèi)發(fā)揮作用,，其作用的分子機(jī)制如何一直鮮為人知。為了深入了解TGFBI蛋白的作用機(jī)制,，研究小組開展了下面的研究工作,。
以小鼠為模型，將小鼠的TGFBI基因剔除掉,，小鼠成為不表達(dá)TGFBI的缺陷型小鼠，結(jié)果表明,，缺陷型小鼠更易罹患癌癥,，在7，12-二甲苯恩的作用下更易自發(fā)形成皮膚癌,。研究者還發(fā)現(xiàn),，缺陷型的小鼠胚胎成纖維細(xì)胞更易發(fā)生染色體畸變，細(xì)胞增殖活性增強(qiáng),，細(xì)胞復(fù)制過程中過早進(jìn)入S期（這些都有可能增強(qiáng)癌變的幾率）,。缺失TGFBI可能導(dǎo)致轉(zhuǎn)錄因子CREB激活，上調(diào)cyclin D1蛋白的表達(dá),。研究者發(fā)現(xiàn),，如果用遺傳技術(shù)在小鼠的胚胎成纖維細(xì)胞中再導(dǎo)入TGFBI，可有效地逆轉(zhuǎn)癌變的過程,。
研究小組的實驗結(jié)果首次證實TGFBI在活體內(nèi)具有腫瘤抑制子的活性,。該研究成果提示TGFBI可能成為診斷和治療的靶位。（生物谷Bioon.com）
生物谷推薦原始出處：
Cancer Research,，doi: 10.1158/0008-5472.CAN-08-1648,，Tom K. Hei，Yongliang Zhao
TGFBI Deficiency Predisposes Mice to Spontaneous Tumor Development
Ye Zhang1,5, Gengyun Wen1, Genze Shao1,6, Cuidong Wang4, Chyuansheng Lin2, Hongbo Fang5, Adayabalam S. Balajee1, Govind Bhagat3, Tom K. Hei1 and Yongliang Zhao1
1 Center for Radiological Research, 2 Herbert Irving Comprehensive Cancer Center, and 3 Department of Clinical Pathology, Columbia University; 4 Laboratory of Molecular Biology, The Rockefeller University, New York, New York; 5 Department of Biochemistry and Molecular Biology, Chinese Academy of Medical Sciences and Peking union Medical College, Beijing, China; and 6 Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania
Loss of TGFBI, a secreted protein induced by transforming growth factor-β, has been implicated in cell proliferation, tumor progression, and angiogenesis by in vitro studies. However, in vivo antitumor functions of TGFBI as well as the underlying molecular mechanism are not well understood. To these aims, we have generated a mouse model with disruption of TGFBI genomic locus. Mice lacking TGFBI show a retarded growth and are prone to spontaneous tumors and 7,12-dimethylbenz(a)anthracene–induced skin tumors. In relation to wild-type (WT) mouse embryonic fibroblasts (MEF), TGFBI–/– MEFs display increased frequencies of chromosomal aberration and micronuclei formation and exhibit an enhanced proliferation and early S-phase entry. Cyclin D1 is up-regulated in TGFBI–/– MEFs, which correlates with aberrant activation of transcription factor cyclic AMP–responsive element binding protein (CREB) identified by chromatin immunoprecipitation and luciferase reporter assays. TGFBI reconstitution in TGFBI–/– cells by either retroviral infection with WT TGFBI gene or supplement with recombinant mouse TGFBI protein in the culture medium leads to the suppression of CREB activation and cyclin D1 expression, and further inhibition of cell proliferation. Cyclin D1 up-regulation was also identified in most of the tumors arising from TGFBI–/– mice. Our studies provide the first evidence that TGFBI functions as a tumor suppressor in vivo.
