The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer.
The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer.
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新型 KLF4/MSI2 信号通路调节胰腺癌的生长和转移
DOI：
10.1158/1078-0432.ccr-16-1064
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发表时间：
2017-02-01
期刊：
影响因子：
--
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Guo K;Cui J;Quan M;Xie D;Jia Z;Wei D;Wang L;Gao Y;Ma Q;Xie K
目的：Musashi 2（MSI 2）是白血病和几种实体瘤中的潜在癌蛋白。然而，其在胰腺导管腺癌（PDAC）病例中的表达、功能和调节尚未得到证实。因此，在本研究中，我们研究了PDAC病例中MSI 2表达的临床意义和生物学效应，并试图描述新发现的Krüppel样因子4（KLF 4）/MSI 2调节通路的临床意义。实验设计：免疫组化分析了人类PDAC标本中MSI 2的表达及其与多种临床病理特征的相关性。MSI 2在PDAC细胞生长、迁移、侵袭和转移方面的生物学功能使用体外和体内的功能获得和丧失测定进行了研究。在几种癌细胞系中检测了KLF 4对MSI 2表达的调节，并使用分子生物学方法研究了其潜在机制。结果如下：在PDAC细胞系和人PDAC标本中，MSI 2表达显著增加，并且MSI 2高表达与PDAC的不良预后相关。强制MSI 2表达促进PDAC增殖、迁移和体外侵袭以及体内生长和转移，而敲低MSI 2表达则相反。KLF 4对MSI 2表达的转录抑制发生在多种PDAC细胞系以及PDAC小鼠模型中。结论：MSI 2的转录抑制因子KLF 4的表达缺失导致PDAC中MSI 2的过表达，这可能是准确预后的生物标志物。KLF 4/MSI 2信号通路失调促进PDAC进展和转移。临床癌症研究; 23（3）; 687-96。©2016 AACR.
Purpose: Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the current study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway. Experimental Design: MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biological functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain- and loss-of-function assays both in vitro and in vivo. Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods. Results: MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC. Conclusions: Lost expression of KLF4, a transcriptional repressor of MSI2 results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis. Clin Cancer Res; 23(3); 687–96. ©2016 AACR.