Mesothelin-Induced Pancreatic Cancer Cell Proliferation Involves Alteration of Cyclin E via Activation of Signal Transducer and Activator of Transcription Protein 3
Mesothelin-Induced Pancreatic Cancer Cell Proliferation Involves Alteration of Cyclin E via Activation of Signal Transducer and Activator of Transcription Protein 3
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DOI：
10.1158/1541-7786.mcr-08-0095
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发表时间：
2008-11-01
影响因子：
5.2
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Bharadwaj, Uddalak;Li, Min;Yao, Qizhi
间皮素（MSLN）是一种在人胰腺癌中过表达的细胞表面糖蛋白。尽管其作为肿瘤诊断和预后标志物的价值以及作为免疫干预的首选靶点已被评估，但关于MSLN在肿瘤细胞上的生长优势的信息很少。在这项研究中，我们研究了MSLN对两种胰腺癌细胞系MIA-MSLN （MIA PaCa-2细胞中过表达MSLN）和BxPC-siMSLN （BxPC-3细胞中沉默MSLN）胰腺癌细胞增殖、细胞周期进程、细胞周期调节蛋白表达和信号转导途径的影响。与对照细胞相比，MIA-MSLN细胞中cyclin E和cyclin依赖性激酶2表达的增加与细胞增殖和细胞周期进展的显著增加相关。BxPC-siMSLN细胞比对照细胞增殖慢，进入S期慢。在MIA-MSLN细胞中，转录蛋白3的信号传导和激活因子（Stat3）被组成性激活，而在对照细胞中没有被激活。janus激活的激酶选择性抑制剂tyrphostin AG490抑制MIA-MSLN细胞中Stat3的激活后，细胞增殖显著降低。Stat3的小干扰RNA显著降低MIA-MSLN细胞周期进程，同时降低细胞周期蛋白E的表达。我们的数据表明，胰腺癌细胞中MSLN的过表达导致转录因子Stat3的组成性激活，从而导致cyclin E和cyclin E/cyclin依赖性激酶2复合物的表达增强以及G(1)-S转化的增加。[j] .现代医学杂志，2008;6(11):1755-65。
Mesothelin (MSLN) is a cell surface glycoprotein that is overexpressed in human pancreatic cancer. Although its value as a tumor marker for diagnosis and prognosis and as a preferred target of immunointervention has been evaluated, there is little information on the growth advantage of MSLN on tumor cells. In this study, we examined the effect of MSLN on pancreatic cancer cell proliferation, cell cycle progression, expression of cell cycle regulatory proteins, and signal transduction pathways in two pancreatic cancer cell lines, MIA-MSLN (overexpressing MSLN in MIA PaCa-2 cells) and BxPC-siMSLN (silencing MSLN in BxPC-3 cells). Increased cyclin E and cyclin-dependent kinase 2 expression found in MIA-MSLN cells correlated with significantly increased cell proliferation and faster cell cycle progression compared with control cells. BxPC-siMSLN cells showed slower proliferation and slower entry into the S phase than control cells. Signal transducer and activator of transcription protein 3 (Stat3) was constitutively activated in MIA-MSLN cells, but not in control cells. Inhibition of Stat3 activation in MIA-MSLN cells by the Janus-activated kinase-selective inhibitor tyrphostin AG490 was followed by a marked decrease in proliferation of the cells. Small interfering RNA against Stat3 significantly reduced the MIA-MSLN cell cycle progression with a concomitant decrease in cyclin E expression. Our data indicate that overexpression of MSLN in pancreatic cancer cells leads to constitutive activation of the transcription factor Stat3, which results in enhanced expression of cyclin E and cyclin E/cyclin-dependent kinase 2 complex formation as well as increased G(1)-S transition. (Mol Cancer Res 2008;6(11):1755-65)