Protein inhibitor of activated STAT3 expression in lung cancer.
Protein inhibitor of activated STAT3 expression in lung cancer.
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DOI：
10.1016/j.molonc.2011.03.004
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发表时间：
2011-06
影响因子：
6.6
通讯作者：
Dowlati A
中科院分区：
文献类型：
--
作者：
Kluge A;Dabir S;Vlassenbroeck I;Eisenberg R;Dowlati A
PIAS3 （Protein Inhibitor of Activated Signal Transducer and Activators of Transcription 3）是一种内源性的STAT3转录活性抑制剂。我们之前已经证明了PIAS3对STAT3信号的浓度依赖性负调控作用及其减少肺癌增殖和与表皮生长因子抑制协同的能力。我们现在研究了PIAS3在非小细胞肺癌（NSCLC）细胞系和人类非小细胞肺癌切除标本中的表达。我们还研究了一些肺癌显著降低PIAS3表达的机制。PIAS3在肺癌细胞系中的表达是可变的，3种鳞状细胞癌（SCC）细胞系中有2种没有或很少表达PIAS3蛋白。同样，通过免疫组化检测，大多数人肺SCCs缺乏PIAS3的表达；尽管发现与腺癌相比，SCCs具有显著更高水平的PIAS3 mRNA。在SCC细胞系和人类标本中，PIAS3的高表达通常与STAT3磷酸化降低相关，这与该蛋白对STAT3信号传导的负调控作用相一致。为了研究PIAS3的这种可变表达，我们首先对PIAS3基因进行了测序，该基因显示了单核苷酸多态性，但没有突变。肺癌细胞暴露于5-氮杂胞苷和曲古菌素A导致PIAS3 mRNA和蛋白表达显著增加。然而，甲基化特异性PCR显示PIAS3的启动子区域缺乏CpG岛甲基化。细胞暴露于阻断蛋白体降解的药物会导致PIAS3显著增加。因此，我们的数据表明，肺SCC通常缺乏PIAS3蛋白表达，翻译后修饰可能解释了某些情况下的这一发现。PIAS3是靶向STAT3通路治疗肺癌的潜在治疗分子。
Protein Inhibitor of Activated Signal Transducer and Activators of Transcription 3 (PIAS3) is an endogenous inhibitor of STAT3 transcriptional activity. We have previously demonstrated the concentration-dependent negative regulatory effect of PIAS3 on STAT3 signaling and its capacity to decrease lung cancer proliferation and synergize with epidermal growth factor inhibition. We now investigate PIAS3 expression in both non-small cell lung cancer (NSCLC) cell lines and human resected NSCLC specimens. We also investigated the mechanism by which some lung cancers have significantly decreased PIAS3 expression. Expression of PIAS3 is variable in lung cancer cells lines with 2 of 3 squamous cell carcinoma (SCC) cell lines having no or little PIAS3 protein expression. Similarly, the majority of human SCCs of the lung lack PIAS3 expression by immunohistochemistry; this despite the finding that SCCs have significantly higher levels of PIAS3 mRNA compared to adenocarcinomas. High PIAS3 expression generally correlates with decreased phosphorylated STAT3 in both SCC cell lines and human specimens compatible with the negative regulatory effect of this protein on STAT3 signaling. To investigate this variable expression of PIAS3 we first performed sequencing of the PIAS3 gene that demonstrated single nucleotide polymorphisms but no mutations. Exposure of lung cancer cells to 5-azacytidine and trichostatin A results in a significant increase in PIAS3 mRNA and protein expression. However, methylation-specific PCR demonstrates a lack of CpG island methylation in the promoter region of PIAS3. Exposure of cells to an agent blocking proteosomal degradation results in a significant increase in PIAS3. Our data thus shows that SCC of the lung commonly lacks PIAS3 protein expression and that post-translational modifications may explain this finding in some cases. PIAS3 is a potential therapeutic molecule to target STAT3 pathway in lung cancer.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
DOI：
10.1158/1541-7786.mcr-09-0313
发表时间：
2009-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Dabir S;Kluge A;Dowlati A
通讯作者：
Dowlati A
影响因子：
4.8
作者：
Ogata, Yoshitaka;Osaki, Tadashi;Kawase, Ichiro
通讯作者：
Kawase, Ichiro
DOI：
10.1158/1078-0432.ccr-08-0618
发表时间：
2008-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brantley EC;Nabors LB;Gillespie GY;Choi YH;Palmer CA;Harrison K;Roarty K;Benveniste EN
通讯作者：
Benveniste EN
影响因子：
64.8
作者：
SHEN, SH;BASTIEN, L;CHRETIEN, P
通讯作者：
CHRETIEN, P