Cancer-associated fibroblasts promote cancer cell growth through a miR-7-RASSF2-PAR-4 axis in the tumor microenvironment
Cancer-associated fibroblasts promote cancer cell growth through a miR-7-RASSF2-PAR-4 axis in the tumor microenvironment
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癌症相关成纤维细胞通过肿瘤微环境中的 miR-7-RASSF2-PAR-4 轴促进癌细胞生长
DOI：
10.18632/oncotarget.13609
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发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Chen, Wantao
中科院分区：
文献类型：
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作者：
Shen, Zongze;Qin, Xing;Chen, Wantao
癌相关成纤维细胞（CAFs）是肿瘤间质的主要成分，在肿瘤的发生发展中起着重要作用，但对CAFs如何影响肿瘤的发生和发展知之甚少。MicroRNA（miRNAs）是一类非编码小RNA，可在转录后水平负调控靶基因mRNA的表达。在头颈癌（HNC）中，我们的miRNA阵列分析显示，与配对的正常成纤维细胞（NF）相比，miR-7，miR-196和miR-335在CAFs中显著上调。CAFs的特异性标志物FAP、α-SMA和FSP在CAFs中表达明显。在功能上，NF中miR-7的外源性表达诱导NF向CAFs的功能性转化。相反，抑制CAFs中的miR-7表达可诱导CAFs功能性转化为NF。我们的研究表明，在共培养实验中，NF中miR-7的过表达显著增加了癌细胞的迁移活性和生长速率。从机制上讲，我们使用生物信息学方法证实RASSF 2-PAR-4轴主要负责CAFs中miR-7的功能。miR-7在CAFs中的过表达导致RASSF 2的下调，从而显著降低CAFs中PAR-4的分泌，进而促进共培养癌细胞的增殖和迁移。因此，这些结果表明，由miR-7控制的RASSF 2-PAR-4轴的失活可能是HNC基因治疗的新策略。
Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, play an important role in cancer progression but little is known about how CAFs affect tumorigenesis and development. MicroRNAs (miRNAs) are small non-coding RNAs that can negatively regulate target mRNA expression at post-transcriptional levels. In head and neck cancer (HNC), our analysis of miRNA arrays showed that miR-7, miR-196 and miR-335 were significantly up-regulated in CAFs when compared with their paired normal fibroblasts (NFs). FAP, α-SMA and FSP, specific markers of CAFs, were significantly expressed in CAFs. Functionally, exogenous expression of miR-7 in NFs induced a functional conversion of NFs into CAFs. In contrast, inhibition of miR-7 expression in CAFs could induce a functional conversion of CAFs into NFs. Our study demonstrated that overexpression of miR-7 in NFs significantly increased the migration activity and growth rates of cancer cells in co-culture experiments. Mechanistically, we confirmed that the RASSF2-PAR-4 axis was mainly responsible for miR-7 functions in CAFs using bioinformatics methods. Overexpression of miR-7 in CAFs led to down-regulation of RASSF2, which dramatically decreased the secretion of PAR-4 from CAFs and then enhanced the proliferation and migration of the co-cultured cancer cells. Thus, these results reveal that the inactivation of the RASSF2-PAR-4 axis controlled by miR-7 may be a novel strategy for gene therapy in HNCs.