Cancer Res.:骨肉瘤p53通路的新生物标志

6月14日，Cancer Research杂志在线报道了骨肉瘤中一种新颖的p53信号通路评价生物标记。该标记还可预测患者的预后。

普通型临床高评分等级骨肉瘤是最常见的恶性骨肿瘤。尽管，p53抑制子HDMX（Mdmx/Mdm4）与其他类型肿瘤的发病、进展及预后相关是已知的事实，但HDMX在骨肉瘤中的作用却不明确。

在多种肿瘤中，高Hdmx剪接变体HDMX-S与Hdmx全长转录物之比（HDMX-S/HDMX-FL）与较低的HDMX蛋白表达，较快的肿瘤病变进展和较差的预后相关。

研究者证实，在骨肉瘤中HDMX-S/HDMX-FL比率同样与较少的HDMX蛋白表达，较快的转移和较差的预后成正相关。他们还发现，HDMX-S/HDMX-FL比率与某些抑制p53的体细胞遗传损伤（如p53突变，HDM2的过表达）相关。有趣的是，这一发现并不仅限于骨肉瘤。在乳腺癌和一些癌细胞系，以及某些软组织肉瘤患者，都发现了这种相关性。HDMX-S/HDMX-FL比率比p53的突变状态能更好地预测肉瘤患者生存率。

由此，研究者提出，与p53突变相比HDMX可变剪接可作为p53信号通路减弱的一个更有效的生物标志。

doi:10.1016/j.cell.2011.10.017
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Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer

Kristiaan Lenos1, Anna M. Grawenda2, Kristen Lodder3, Marieke L. Kuijjer4, Amina F.A.S. Teunisse3, Emmanouela Repapi2, Lukasz F. Grochola2, Frank Bartel5, Pancras C. W. Hogendoorn6, Peter Wuerl7, Helge Taubert8, Anne-Marie Cleton-Jansen4, Gareth L Bond2,*, and Aart G Jochemsen1

Conventional high-grade osteosarcoma is the most common primary bone malignancy. Although altered expression of the p53 inhibitor HDMX (Mdmx/Mdm4) is associated with cancer risk, progression, and outcome in other tumor types, little is known about its role in osteosarcoma. High expression of the Hdmx splice variant HDMX-S relative to the full length transcript (the HDMX-S/HDMX-FL ratio) correlates with reduced HDMX protein expression, faster progression and poorer survival in several cancers. Here, we demonstrate that the HDMX-S/HDMX-FL ratio positively correlates with less HDMX protein expression, faster metastatic progression and a trend to worse overall survival in osteosarcomas. We found that the HDMX-S/HDMX-FL ratio associated with common somatic genetic lesions connected with p53 inhibition, such as p53 mutation and HDM2 overexpression in osteosarcoma cell lines. Interestingly, this finding was not limited to osteosarcomas as we observed similar associations in breast cancer and a variety of other cancer cell lines, as well as in tumors from soft tissue sarcoma patients. The HDMX-S/HDMX-FL ratio better defined sarcoma patients with worse survival rates than p53 mutational status. We propose a novel role for alternative splicing of HDMX, whereby it serves as a mechanism by which HDMX protein levels are reduced in cancer cells that have already inhibited p53 activity. Alternative splicing of HDMX could therefore serve as a more effective biomarker for p53 pathway attenuation in cancers than p53 gene mutation.