6月14日,，Cancer Research雜志在線報道了骨肉瘤中一種新穎的p53信號通路評價生物標(biāo)記。該標(biāo)記還可預(yù)測患者的預(yù)后,。
普通型臨床高評分等級骨肉瘤是最常見的惡性骨腫瘤,。盡管，p53抑制子HDMX（Mdmx/Mdm4）與其他類型腫瘤的發(fā)病,、進展及預(yù)后相關(guān)是已知的事實,，但HDMX在骨肉瘤中的作用卻不明確。
在多種腫瘤中,，高Hdmx剪接變體HDMX-S與Hdmx全長轉(zhuǎn)錄物之比（HDMX-S/HDMX-FL）與較低的HDMX蛋白表達，較快的腫瘤病變進展和較差的預(yù)后相關(guān),。
研究者證實,，在骨肉瘤中HDMX-S/HDMX-FL比率同樣與較少的HDMX蛋白表達，較快的轉(zhuǎn)移和較差的預(yù)后成正相關(guān),。他們還發(fā)現(xiàn),，HDMX-S/HDMX-FL比率與某些抑制p53的體細胞遺傳損傷（如p53突變，HDM2的過表達）相關(guān),。有趣的是,，這一發(fā)現(xiàn)并不僅限于骨肉瘤。在乳腺癌和一些癌細胞系,，以及某些軟組織肉瘤患者,，都發(fā)現(xiàn)了這種相關(guān)性。HDMX-S/HDMX-FL比率比p53的突變狀態(tài)能更好地預(yù)測肉瘤患者生存率,。
由此,，研究者提出，與p53突變相比HDMX可變剪接可作為p53信號通路減弱的一個更有效的生物標(biāo)志,。（生物谷bioon.com）
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.
