Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1
Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1
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DOI：
10.1074/jbc.m113.532887
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发表时间：
2014-05-23
影响因子：
4.8
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
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作者：
Bao, Bin;Azmi, Asfar S.;Sarkar, Fazlul H.
肿瘤干细胞(CSCs)或肿瘤干细胞样细胞(CSLCs)的亚群已经从包括胰腺癌(PC)在内的大多数肿瘤中被鉴定出来，这些细胞的存在具有临床意义。新的证据表明，CSLC参与了细胞的生长/增殖、迁移/侵袭、转移和化疗-放疗抵抗，最终导致了不良的临床预后。然而，CSLCs在PC中的发病机制和生物学意义尚未得到很好的描述。在本研究中，我们发现分离的人PC MiaPaCa-2和L3.6pl细胞的三重标记阳性(CD44(+)/CD133(+)/EpCAM(+))细胞表现为CSLC。这些CSLC表现出侵袭性行为，如细胞生长、迁移、克隆形成和自我更新能力增加。MRNA表达谱分析显示，CSLCs(CD44(+)/CD133(+)/EpCAM(+))与三重标记阴性(CD44(-)/CD133(-)/EpCAM(-))细胞相比，包括FoxQ1在内的1600多个mRNAs的表达存在差异。在CSLCs中，FoxQ1被其siRNA敲除，导致攻击行为的抑制，这与抑制EpCAM和Snail的表达一致。小鼠移植瘤研究表明，与其亲代MiaPaCa-2细胞相比，CSLC具有100倍的成瘤和快速肿瘤生长潜力，这与包括FoxQ1在内的CSC相关标记/介质的过度表达一致。抑制FoxQ1抑制肿瘤的形成和生长，抑制MIaPaCa-2细胞CSLC来源的移植瘤中CSC标志的表达。这些数据清楚地表明差异表达基因在调节CSLC特征中的作用，进一步表明靶向其中一些基因对于开发新的治疗方法以获得更好的PC治疗结果可能是重要的。
Subpopulations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors, including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/invasion, metastasis, and chemo-radiotherapy resistance, ultimately contributing to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that isolated triple-marker-positive (CD44(+)/CD133(+)/EpCAM(+)) cells of human PC MiaPaCa-2 and L3.6pl cells behave as CSLCs. These CSLCs exhibit aggressive behavior, such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (CD44(+)/CD133(+)/EpCAM(+)) exhibit differential expression of more than 1,600 mRNAs, including FoxQ1, compared with the triple-marker-negative (CD44(-)/CD133(-)/EpCAM(-)) cells. The knockdown of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with the inhibition of EpCAM and Snail expression. Mouse xenograft tumor studies showed that CSLCs have a 100-fold higher potential for tumor formation and rapid tumor growth, consistent with overexpression of CSC-associated markers/mediators, including FoxQ1, compared with its parental MiaPaCa-2 cells. The inhibition of FoxQ1 attenuated tumor formation and growth, and expression of CSC markers in the xenograft tumor derived from CSLCs of MiaPaCa-2 cells. These data clearly suggest the role of differentially expressed genes in the regulation of CSLC characteristics, further suggesting that targeting some of these genes could be important for the development of novel therapies for achieving better treatment outcome of PC.