Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness.
Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness.
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DOI：
10.1371/journal.pone.0004478
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Pages, Gilles
中科院分区：
文献类型：
--
作者：
Essafi-Benkhadir, Khadija;Grosso, Sebastien;Puissant, Alexandre;Robert, Guillaume;Essafi, Makram;Deckert, Marcel;Chamorey, Emmanuel;Dassonville, Olivier;Milano, Gerard;Auberger, Patrick;Pages, Gilles
由于转录因子Sp3被描述为转录抑制因子或激活因子，因此其在肿瘤进展中的模糊作用仍有争议。在这里，我们试图破译在侵袭性肿瘤中观察到的Sp3积累所涉及的分子机制。我们产生了正常和肿瘤细胞系有条件地表达Sp3。在体外和在裸鼠中接种后分析细胞生长。通过泛半胱天冬酶活性测定、计数碎裂的细胞核和测定半胱天冬酶9裂解来评估细胞凋亡。通过定量PCR测定基因表达。在[S35]标记的甲硫氨酸存在下，Sp3 cDNA体外翻译后，通过不同的半胱天冬酶进行切割。不同的肿瘤细胞系和头颈部肿瘤样品通过蛋白质印迹测试Sp3的存在。Sp3表达和总生存率之间的相关性已被统计学确定。Sp3的条件性过表达诱导细胞凋亡并改变涉及细胞周期调节的基因以及促凋亡基因和抗凋亡基因的表达。Sp3过表达强烈地减少了裸鼠中肿瘤的发展，证实了其在体内的促凋亡潜力。然而，细胞可以通过caspase选择性切割Sp3而存活至凋亡。在已建立的肿瘤中，Sp3诱导导致短暂的消退，然后进展。进展与全长形式的Sp3的再积累一致。Sp3在不同来源的肿瘤细胞系中过表达。高水平的全长形式的Sp3的存在表明头颈部肿瘤患者的总体生存预后不良。全长Sp3积累突出了肿瘤细胞凋亡能力的旁路，并指示头颈部肿瘤的侵袭性。
The ambiguous role of transcription factor Sp3 for tumour progression is still debated since it was described as a transcriptional repressor or activator. Here we tried to decipher the molecular mechanisms implicated in Sp3 accumulation observed in aggressive tumours. We generated normal and tumour cell lines conditionally expressing Sp3. Cell growth was analyzed in vitro and after inoculation in nude mice. Apoptosis was assessed by pan- caspase activity assays, by counting fragmented nuclei and by determination of caspase 9 cleavage. Gene expression was determined by quantitative PCR. Cleavage by different caspases was performed after in vitro translation of the Sp3 cDNA in the presence of [S35] labelled methionine. Different tumour cell lines and head and neck tumour samples were tested for the presence of Sp3 by western blots. Correlation between Sp3 expression and overall survival has been statistically determined. Conditional over-expression of Sp3 induces apoptosis and modifies expression of genes implicated in the regulation of cell cycle and pro and anti apoptotic genes. Sp3 over-expression strongly reduces the development of tumours in nude mice confirming its pro-apoptotic potential in vivo. However, cells can survive to apoptosis through selective Sp3 cleavage by caspase. Sp3 induction in established tumours resulted in transient regression then progression. Progression coincides with re-accumulation of the full length form of Sp3. Sp3 is over-expressed in tumour cell lines of different origins. The presence of high levels of the full-length form of Sp3 indicates a poor prognosis for overall survival of patients with head and neck tumours. Full length Sp3 accumulation highlights bypass of tumour cell apoptotic capacities and is indicative of head and neck tumours aggressiveness.
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