Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades.
Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades.
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DOI：
10.1186/1476-4598-11-24
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发表时间：
2012-04-26
期刊：
影响因子：
37.3
通讯作者：
Chellappan SP
中科院分区：
文献类型：
--
作者：
Kunigal S;Ponnusamy MP;Momi N;Batra SK;Chellappan SP
膜结合粘蛋白被认为在细胞与细胞、细胞与基质的相互作用、细胞信号转导以及调节癌细胞的生物学特性中发挥着重要的生物学作用。MUC4是一种跨膜型粘蛋白，在胰腺肿瘤中高表达，而在正常胰腺组织中检测不到，提示MUC4在胰腺癌的发病机制中具有潜在的作用。目前对MUC4基因调控的分子机制尚不完全清楚。吸烟与胰腺癌密切相关，在本研究中，我们阐明了尼古丁以及维甲酸(RA)和干扰素-γ(干扰素-γ)等药物诱导胰腺癌细胞CD18、CAPAN2、AsPC1和BxPC3表达MUC4的分子机制。染色质免疫沉淀法和实时定量聚合酶链式反应显示转录因子E2F1和STAT1可在转录水平上正向调节MUC4的表达。干扰素-γ和RA可利用E2F1和STAT1转录因子协同尼古丁上调MUC4的表达。去除STAT1或E2F1可阻断MUC4的诱导；尼古丁介导的MUC4的诱导似乎需要α7烟碱型乙酰胆碱受体亚单位。此外，由于抑制这些信号分子阻止了MUC4的诱导，所以Src和ERK家族激酶也介导了MUC4的诱导。MUC4在尼古丁介导的胰腺癌细胞侵袭中也是必需的，提示尼古丁和其他药物对MUC4的诱导可能有助于胰腺癌的发生和发展。我们的研究表明，能够促进胰腺癌细胞生长和侵袭的药物通过多条途径诱导MUC4基因，这种诱导需要E2F1和STAT1的转录活性。此外，Src和ERK信号通路似乎参与了该基因的诱导。靶向这些信号通路可能会抑制MUC4的表达，从而阻止胰腺癌细胞的增殖和侵袭。
The membrane-bound mucins are thought to play an important biological role in cell–cell and cell–matrix interactions, in cell signaling and in modulating biological properties of cancer cell. MUC4, a transmembrane mucin is overexpressed in pancreatic tumors, while remaining undetectable in the normal pancreas, thus indicating a potential role in pancreatic cancer pathogenesis. The molecular mechanisms involved in the regulation of MUC4 gene are not yet fully understood. Smoking is strongly correlated with pancreatic cancer and in the present study; we elucidate the molecular mechanisms by which nicotine as well as agents like retinoic acid (RA) and interferon-γ (IFN-γ) induce the expression of MUC4 in pancreatic cancer cell lines CD18, CAPAN2, AsPC1 and BxPC3. Chromatin immunoprecipitation assays and real-time PCR showed that transcription factors E2F1 and STAT1 can positively regulate MUC4 expression at the transcriptional level. IFN-γ and RA could collaborate with nicotine in elevating the expression of MUC4, utilizing E2F1 and STAT1 transcription factors. Depletion of STAT1 or E2F1 abrogated the induction of MUC4; nicotine-mediated induction of MUC4 appeared to require α7-nicotinic acetylcholine receptor subunit. Further, Src and ERK family kinases also mediated the induction of MUC4, since inhibiting these signaling molecules prevented the induction of MUC4. MUC4 was also found to be necessary for the nicotine-mediated invasion of pancreatic cancer cells, suggesting that induction of MUC4 by nicotine and other agents might contribute to the genesis and progression of pancreatic cancer. Our studies show that agents that can promote the growth and invasion of pancreatic cancer cells induce the MUC4 gene through multiple pathways and this induction requires the transcriptional activity of E2F1 and STAT1. Further, the Src as well as ERK signaling pathways appear to be involved in the induction of this gene. It appears that targeting these signaling pathways might inhibit the expression of MUC4 and prevent the proliferation and invasion of pancreatic cancer cells.
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影响因子：
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作者：
Middleton, Gary;Ghaneh, Paula;Neoptolemos, John P
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