近日,，《生物化學(xué)雜志》(Journal of Biological Chemistry) 在線發(fā)表了中科院上海生科院營養(yǎng)科學(xué)研究所方靖研究組有關(guān)腸癌研究的最新進(jìn)展：Pax2 induces expression of cyclin D1 through activating AP-1 and promotes proliferation of colon cancer cells,，研究揭示了Pax2在結(jié)腸癌中的作用和分子機(jī)制。
Pax2 (Paired box 2)是轉(zhuǎn)錄因子,，在胚胎發(fā)育和細(xì)胞分化過程中發(fā)揮重要作用,。一般情況下,，發(fā)育結(jié)束后Pax2的表達(dá)變?nèi)酢Ｈ绻诎l(fā)育成熟組織中異常表達(dá),，Pax2則表現(xiàn)出癌基因的作用，目前已經(jīng)在幾種癌癥（如乳腺癌,，前列腺癌等）中發(fā)現(xiàn)Pax2的表達(dá)升高,。因此，Pax2成為癌癥治療一個(gè)潛在的靶標(biāo),。目前,，Pax2在腫瘤中發(fā)揮什么樣的作用、它是如何推動(dòng)腫瘤發(fā)展的,、其中的分子機(jī)制是什么,？這些問題還不清楚。
結(jié)腸癌是人類常見的消化道腫瘤,，全球每年有近50萬人死于結(jié)腸癌,，居癌癥死因第3位。在我國,，結(jié)腸癌居惡性腫瘤發(fā)病率第4位,，且近年呈明顯上升趨勢。營養(yǎng)所博士研究生張海生等在方靖研究員的指導(dǎo)下,，開展了Pax2在結(jié)腸癌中作用與機(jī)制研究,，發(fā)現(xiàn)Pax2在結(jié)腸癌中的表達(dá)也異常增高。體內(nèi),、外實(shí)驗(yàn)顯示,，Pax2具有促進(jìn)結(jié)腸癌細(xì)胞增殖和腫瘤生長的作用。
研究表明,，Pax2促進(jìn)細(xì)胞周期蛋白cyclin D1的表達(dá),。進(jìn)一步的機(jī)制研究發(fā)現(xiàn)，Pax2通過激活轉(zhuǎn)錄因子AP-1來提高cyclin D1的表達(dá),。Pax2阻止JunB與c-Jun的結(jié)合,，促進(jìn)了c-Jun和c-Fos的結(jié)合以及c-Jun的磷酸化，導(dǎo)致AP-1活力的升高和cyclin D1轉(zhuǎn)錄的增加,。這些結(jié)果提示Pax2通過激活A(yù)P-1來誘導(dǎo)cyclin D1的表達(dá),，進(jìn)而促進(jìn)結(jié)腸癌細(xì)胞的生長。這些發(fā)現(xiàn)為深入認(rèn)識(shí)Pax2在腫瘤生長過程中的作用機(jī)理和今后的疾病治療提供了理論依據(jù),。
該研究受到國家自然科學(xué)基金委和中國科學(xué)院的經(jīng)費(fèi)支持,。(生物谷Bioon.com)
doi: 10.1074/jbc.M112.401521
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PAX2 Protein Induces Expression of Cyclin D1 through Activating AP-1 Protein and Promotes Proliferation of Colon Cancer Cells
Hai-Sheng Zhang‡, Bing Yan‡, Xue-Bing Li‡, Li Fan‡, Yun-Fang Zhang‡, Guo-Hao Wu§, Min Li¶ and Jing Fang‡,1
Paired box (PAX) 2, a transcription factor, plays a critical role in embryogenesis. When aberrantly expressed in adult tissues, it generally exhibits oncogenic properties. However, the underlying mechanisms remain unclear. We reported previously that the expression of PAX2 was up-regulated in human colon cancers. However, the role of PAX2 in colon cancer cells has yet to be determined. The aim of this study is to determine the function of PAX2 in colon cancer cells and to investigate the possible mechanisms underlain. We find that knockdown of PAX2 inhibits proliferation and xenograft growth of colon cancer cells. Inhibition of PAX2 results in a decreased expression of cyclin D1. Expression of cyclin D1 is found increased in human primary colon malignant tumors, and its expression is associated with that of PAX2. These data indicate that PAX2 is a positive regulator of expression of cyclin D1. We find that knockdown of PAX2 inhibits the activity of AP-1, a transcription factor that induces cyclin D1 expression, implying that PAX2 induces cyclin D1 through AP-1. PAX2 has little effect on expression of AP-1 members including c-Jun, c-Fos, and JunB. Our data show that PAX2 prevents JunB from binding c-Jun and enhances phosphorylation of c-Jun, which may elevate the activity of AP-1. Taken together, these results suggest that PAX2 promotes proliferation of colon cancer cells through AP-1.
