The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells.
The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells.
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DOI：
10.1136/gutjnl-2014-308470
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发表时间：
2015-12
期刊：
影响因子：
24.5
通讯作者：
Heeschen C
中科院分区：
文献类型：
--
作者：
Cioffi M;Trabulo SM;Sanchez-Ripoll Y;Miranda-Lorenzo I;Lonardo E;Dorado J;Reis Vieira C;Ramirez JC;Hidalgo M;Aicher A;Hahn S;Sainz B Jr;Heeschen C
癌症干细胞（CSCs）是包括胰腺导管腺癌在内的许多实体癌的根源，具有高度的化疗耐药性，是疾病复发的细胞来源。然而，在这些过程中所涉及的机制仍然需要充分阐明。了解胰腺癌化疗耐药和转移的相关机制对改善患者预后至关重要。微rna （miRNA）表达分析用于鉴定胰腺csc富集球源性细胞和吉西他滨耐药胰腺csc的功能定义表观遗传特征。我们发现miR-17-92簇在化疗耐药的CSC中与非CSC相比下调，并证明其与CSC生物学的重要相关性。特别是，miR-17-92的过表达通过靶向多个NODAL/ACTIVIN/TGF-β1信号级联成员以及直接抑制下游靶点p21、p57和TBX3，降低了CSC的自我更新能力、体内致瘤性和化疗耐药。过表达miR-17-92可通过下调p21和p57导致CSC增殖增加并最终衰竭。最后，我们的发现的转化影响可以在胰腺癌的临床前模型中得到证实。因此，我们的研究结果确定了miR-17-92簇是CSCs中一个功能决定mirna家族，并强调了开发该簇调节剂以克服胰腺CSCs耐药的假定潜力。
Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-β1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.