JBC：研究揭示Pax2在结肠癌中作用机制

近日，《生物化学杂志》(Journal of Biological Chemistry) 在线发表了中科院上海生科院营养科学研究所方靖研究组有关肠癌研究的最新进展：Pax2 induces expression of cyclin D1 through activating AP-1 and promotes proliferation of colon cancer cells，研究揭示了Pax2在结肠癌中的作用和分子机制。

Pax2 (Paired box 2)是转录因子，在胚胎发育和细胞分化过程中发挥重要作用。一般情况下，发育结束后Pax2的表达变弱。如果在发育成熟组织中异常表达，Pax2则表现出癌基因的作用，目前已经在几种癌症（如乳腺癌，前列腺癌等）中发现Pax2的表达升高。因此，Pax2成为癌症治疗一个潜在的靶标。目前，Pax2在肿瘤中发挥什么样的作用、它是如何推动肿瘤发展的、其中的分子机制是什么？这些问题还不清楚。

结肠癌是人类常见的消化道肿瘤，全球每年有近50万人死于结肠癌，居癌症死因第3位。在我国，结肠癌居恶性肿瘤发病率第4位，且近年呈明显上升趋势。营养所博士研究生张海生等在方靖研究员的指导下，开展了Pax2在结肠癌中作用与机制研究，发现Pax2在结肠癌中的表达也异常增高。体内、外实验显示，Pax2具有促进结肠癌细胞增殖和肿瘤生长的作用。

研究表明，Pax2促进细胞周期蛋白cyclin D1的表达。进一步的机制研究发现，Pax2通过激活转录因子AP-1来提高cyclin D1的表达。Pax2阻止JunB与c-Jun的结合，促进了c-Jun和c-Fos的结合以及c-Jun的磷酸化，导致AP-1活力的升高和cyclin D1转录的增加。这些结果提示Pax2通过激活AP-1来诱导cyclin D1的表达，进而促进结肠癌细胞的生长。这些发现为深入认识Pax2在肿瘤生长过程中的作用机理和今后的疾病治疗提供了理论依据。

该研究受到国家自然科学基金委和中国科学院的经费支持。

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.